👤 Kexin Kang

Infiltration of T cell acute lymphoblastic leukemia (T-ALL) into the meninges worsens prognosis, underscoring the need to understand mechanisms driving meningeal involvement. Here, we show that T-ALL cells expressing CXCR3 exploit normal T cell function to infiltrate the inflamed meninges. CXCR3 deletion hampered disease progression and extramedullary dissemination by reducing leukemic cell proliferation and migration. Conversely, forced expression of CXCR3 facilitated T-ALL trafficking to the meninges. We identified the ubiquitin-specific protease 7 as a key regulator of CXCR3 protein stability in T-ALL. Furthermore, we discovered elevated levels of CXCL10, a CXCR3 ligand, in the cerebrospinal fluid from patients with T-ALL and leukemia-bearing mice. Our studies demonstrate that meningeal stromal cells, specifically pericytes and fibroblasts, induce CXCL10 expression in response to leukemia and that loss of CXCL10 attenuated T-ALL influx into the meninges. Moreover, we report that leukemia-derived proinflammatory cytokines, TNF-α, IL-27, and IFN-γ, induced CXCL10 in the meningeal stroma. Pharmacological inhibition or deletion of CXCR3 or CXCL10 reduced T-ALL cell migration and adhesion to meningeal stromal cells. Finally, we reveal that CXCR3 and CXCL10 upregulated VLA-4/VCAM-1 signaling, promoting cell-cell adhesion and thus T-ALL retention in the meninges. Our findings highlight the pivotal role of CXCR3-CXCL10 signaling in T-ALL progression and meningeal colonization. Show less

Job satisfaction is a critical factor influencing workplace efficiency and employee well-being. In the context of Industry 5.0 transformation, understanding the latent profiles of job satisfaction and their relationship with mental health outcomes, such as depression, anxiety, and digital-intelligence job insecurity, is critical for promoting employee well-being and organizational sustainability. This study aims to explore the latent profiles of job satisfaction among industrial workers and explore their associations with mental health outcomes. This study used cross-sectional data from 3,420 male frontline workers from a large automobile manufacturing enterprise in Jilin Province, China in April 2024. Latent profile analysis (LPA) was employed to identify distinct latent profiles of job satisfaction among industrial workers, while hierarchical linear regression analysis was used to analyze the relationship between job satisfaction and psychological health outcomes (depression, anxiety and digital-intelligence job insecurity). The score of job satisfaction among industrial workers in Jilin Province was 3.62 ± 0.90. Four profiles were identified: very low (5.97%), low-to-moderate (31.14%), moderately high (42.63%), and high job satisfaction (20.26%). Depression and anxiety showed a clear level-gradient pattern across profiles, whereas digital-intelligence job insecurity displayed a non-monotonic pattern with higher levels in the low-to-moderate and moderately high profiles. Work stress showed consistent associations with all outcomes, and job satisfaction profiles remained associated with depression and anxiety after covariate and stress adjustment; associations with digital-intelligence job insecurity were smaller but detectable. This study examined heterogeneity in job satisfaction among frontline industrial workers and its associations with mental health outcomes. Latent profile analysis identified four job satisfaction profiles. Job satisfaction profile membership remained strongly associated with depression and anxiety. Digital-intelligence job insecurity showed a non-monotonic pattern across profiles. These findings suggest that an individual-centered profile approach provides actionable differentiation of mental health symptom burden across distinct job satisfaction patterns, supporting more targeted workplace strategies. Show less

Inflammatory bowel disease (IBD) is an immune-mediated disorder driven by overactivation of autotaxin (ATX), which elevates lysophosphatidic acid (LPA) signaling and suppresses autophagy, exacerbating intestinal inflammation. Given the pivotal role of autophagy in maintaining intestinal homeostasis, inhibiting ATX offers a dual therapeutic mechanism by both restoring autophagic activity and attenuating LPA-mediated inflammatory responses. Current treatments are hindered by nonspecific immunosuppression and frequent systemic side effects, underscoring the need for targeted, multifunctional therapeutic strategies. Here, we present a dual-functional nanotherapeutic platform, ATX-scavenging liposomes loaded with rapamycin (AS-Lipo@R), engineered for the oral treatment of acute colitis. Our proposed formulation incorporates BMP-22, a lipid ATX inhibitor that simultaneously functions as a structural building block of the liposomal membrane. Rapamycin, an autophagy activator, is encapsulated within the bilayer of liposomes. We confirmed that AS-Lipo@R exhibits strong binding affinity to extracellular ATX and mediates its lysosomal degradation upon cellular internalization, thereby demonstrating its ATX-scavenging property. In vitro, AS-Lipo@R inhibited inflammatory macrophage activation, promoted M2 macrophage polarization, and substantially restored autophagic activity in LPS/IFN-γ-stimulated macrophages. In vivo, oral administration of AS-Lipo@R led to preferential accumulation in ATX-overexpressing inflamed colonic tissue, resulting in reduced pro-inflammatory cytokine production, recovered autophagy, and enhanced intestinal barrier integrity in colitis mice. These findings highlight AS-Lipo@R as a synergistic and targeted nanomedicine that simultaneously modulates ATX and autophagy pathways, offering novel insights into immunomodulatory strategies for IBD treatment. Show less

This study aimed to identify different symptom profiles of complicated grief/bereavement-related posttraumatic stress disorder (PTSD) and examine the associations with social life factors, posttraumatic growth, and quality of life in a sample of parents whose children died in Sewol ferry accident. A total of 272 bereaved parents affected by the Sewol ferry accident participated and completed self-report scales about traumatic loss-related symptoms. The latent profile analysis (LPA) of complicated grief and posttraumatic symptoms was classified. To examine the predictors (interpersonal stress/familial conflict/social support) and outcomes (posttraumatic growth/quality of life) of the traumatic loss symptom profiles, an automatic three-step approach was chosen. The LPA identified three symptom profiles of complicated grief and posttraumatic stress: low symptomatology group (30.4%), moderate symptomatology group (49.6%), and high symptomatology group (20.0%). Higher perceived interpersonal stress significantly increased the odds of moderate and high symptomatology, while higher family stress was a significant predictor for high symptomatology compared to both low and moderate symptomatology groups. In addition, higher perceived social support significantly decreased the odds of being in both moderate and high symptomatology groups compared to the low group. The low symptomatology group showed the highest quality of life, followed by the moderate and high groups. Posttraumatic growth was also significantly different between the classes, with the moderate symptomatology group reporting higher growth than the low symptomatology group. Our findings suggest that managing the mental health of people who have experienced a traumatic loss will be a critical component of their quality of life in the future. In addition, interventions to help reduce family conflict and interpersonal stress may be necessary to reduce difficulties associated with psychopathology. 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-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

Autotaxin (ATX), the enzyme responsible for generating lysophosphatidic acid (LPA), is a validated target for fibrosis and cancer immunotherapy. Current ATX inhibitors face challenges related to insufficient efficacy or safety concerns, reflecting trade-offs between zinc engagement and selectivity. Here, we report a rigid triazolyl-azabicyclo[3.1.0]hexanyl-oxadiazolyl-pyrimidine scaffold developed through structure-based design, designed to potentially enhance ATX selectivity by promoting defined binding geometry. Systematic studies identified 14e as the most potent inhibitor (IC Show less

Lipoprotein(a) [Lp(a)] is a causal, genetically determined risk factor for atherosclerotic cardiovascular disease (ASCVD) and calcific aortic valve stenosis (CAVS). Although elevated Lp(a) affects approximately 20% of the global population, specific pharmacological options have long been unavailable, leaving a major gap in residual risk management. This review synthesizes current understanding of Lp(a) molecular architecture, genetics, and metabolism, and integrates mechanistic evidence linking Lp(a) to pro-atherogenic, pro-inflammatory, and pro-thrombotic pathways. We summarize epidemiological and genetic data associating Lp(a) with a broad spectrum of cardiovascular outcomes and discuss current clinical guidelines on screening and risk stratification. Furthermore, we provide an up-to-date overview of the emerging therapeutic landscape, including RNA-targeted therapies and novel oral small molecules. With pivotal phase 3 outcome trials nearing completion, the field is transitioning from viewing Lp(a) as an untreatable biomarker to an actionable therapeutic target, with important implications for precision cardiovascular prevention. Show less

AI literacy is increasingly important in college students' academic achievement, daily life, and future employability. However, current research predominantly overlooks the heterogeneity in students' AI literacy, especially how individual psychological characteristics and features of AI technology contribute to this variation. This oversight limits the formulation of tailored strategies to meet the students' various demands in an era shaped by rapid AI advancement. This study aims to adopt an individual-centered approach to identify distinct AI literacy profiles among college students. In addition, it investigates, based on affordance theory, how positive emotions, instrumental motivation, perceived ease of use, and psychological anthropomorphism predict assignment to different profiles. A total of 808 Chinese college students participated in this survey. Latent profile analysis (LPA) was employed to classify students into distinct AI literacy profiles. Multinomial logistic regression was conducted to examine how psychological and technological factors predict profile classification. This study identified four distinct AI literacy profiles among college students: preliminary contact type, ethical orientation type, balanced development type, and behavioral conservatism type. These profiles showed significant differences in positive emotions, instrumental motivation, perceived ease of use, and psychological anthropomorphism, highlighting diverse psychological and technological characteristics inherent to each group. This study underscores the heterogeneity of AI literacy within the college student population and detects four distinct AI literacy profiles with unique psychological and technological traits. The findings indicate that students' AI literacy is profoundly affected by emotional tendencies, motivational drives, and technological variables, highlighting the need for tailored educational strategies that address the distinct psychological and technological drivers of each literacy profile. Show less

G-protein-coupled receptors (GPCRs) are high-value therapeutic targets, yet antibody discovery remains limited by difficulties in preparing antigens that preserve native conformations. Here, we engineered a native-like, full-length human LPA2 antigen by combining N-terminal P9* fused with amphipathic poly-γ-glutamate (APG) stabilization, affording an antigen suitable for the selection of antibodies with therapeutic efficacy. By screening a large synthetic human scFv library, we isolated an antagonistic antibody against LPA2 that bound LPA2 selectively over LPA1 (EC Show less

Langya chickens, a Chinese indigenous breed, exhibit rich genetic resources but relatively low egg production performance. To investigate the genetic basis of egg production traits, we performed low-depth genome resequencing of 1,183 Langya hens and evaluated six phenotypic traits, including age at first egg (AFE), egg number at different laying stages-EN1 (from first egg to 26 weeks), EN2 (27-36 weeks), EN3 (37-43 weeks), total egg number at 43 weeks (E43), and maximal clutch length (MCL). Genetic parameter analysis revealed that MCL exhibited high heritability (0.42) and strong genetic correlations with both egg production and AFE, suggesting its potential as a more effective selection indicator for egg production traits. Genome-wide association studies identified a total of 245 SNPs associated with these traits. Notably, a 6.58 Mb region on chromosome 5 (GGA5, 40.03-46.61 Mb) was enriched for multiple traits and in strong linkage disequilibrium. Candidate genes in this core region, including TSHR, GTF2A1, DIO2, STON2, NRXN3, KCNK10, EML5, and FOXN3, were implicated in transcriptional regulation, thyroid hormone signaling, neuroendocrine modulation, and ovarian function. Additional trait-specific candidate genes, such as ATG2B for EN2, FMNL1 for EN1/EN2, TDP1 for E43, and TPMT for MCL, were also identified. Functional enrichment analyses highlighted pathways related to cellular processes, lipid metabolism, and signal transduction. These findings provide genomic insights into the molecular mechanisms underlying egg production traits and offer valuable candidate genes for marker-assisted breeding in Langya chickens. Show less

Colorectal cancer (CRC) is widely recognized for its high prevalence and significant mortality rates, and purine metabolism has been serving as a potential therapeutic target. However, purine metabolism has not yet been validated as a prognostic marker through immunohistochemical analysis. In this study, we utilized a combination of bulk transcriptome analysis, immunohistochemistry (IHC), and single-cell RNA sequencing (scRNA-seq) to assess the clinical relevance of purine metabolism in CRC. Low expression levels of five purine metabolism-related genes-ADSL, APRT, ADCY3, NME3, and NME6-were associated with worse prognosis in CRC patient subgroups, including wild-type TP53, mutant TP53, and microsatellite-stable phenotypes. IHC-based validation showed that NME3 expression was an independent prognostic factor, whereas ADSL and NME6 expressions were associated with clinical variables in prediction of prognosis. Notably, NME3 expression predicted a high risk in patients with early-stage CRC, while ADSL and NME6 expressions were predictive in late-stage CRC. scRNA-seq analysis showed that four genes, excluding NME6, had low expression levels in epithelial cells at the late-stage CRC. Despite the reversible nature of purine metabolism reactions, we demonstrated a consistent directional expression of these five prognostic purine metabolism-related proteins in CRC tissues. We suggest that alterations in purine metabolism could serve as a clinically useful prognostic marker in CRC. Show less

This study investigated whether employment status moderates associations between baseline serum biomarkers and antidepressant remission at 12 weeks and 12 months. A prospective cohort of 1086 outpatients diagnosed with depressive disorders received stepwise antidepressant therapy using a naturalistic, flexible treatment protocol. Fourteen serum biomarkers covering immune (hsCRP, TNF-α, IL-1β, IL-6, IL-4, IL-10), metabolic (leptin, ghrelin, total cholesterol), neuroplastic (BDNF), neurotransmitter (serotonin), endocrine (cortisol), and nutritional (folate, homocysteine) domains were analyzed at baseline. Employment-dependent biomarker associations with remission (Hamilton Depression Rating Scale ≤7) at 12 weeks and 12 months were evaluated using logistic regression with biomarker-by-employment interactions and stratified analyses, adjusting for relevant covariates. Higher serotonin levels significantly predicted 12-week remission exclusively among employed patients, with a significant employment interaction. At 12 months, lower leptin levels predicted remission specifically in employed patients, whereas lower TNF-α and higher BDNF levels predicted remission only in unemployed patients, each demonstrating significant employment interactions. Baseline serum biomarkers showed employment-dependent associations with antidepressant remission outcomes, highlighting serotonin's short-term relevance and leptin, TNF-α, and BDNF as longer-term indicators. Although exploratory, these findings suggest that integrating employment status with biomarker profiles may enhance clinical decision-making by identifying patients who are more or less likely to benefit from treatment across different phases of recovery. Replication in independent cohorts is needed to establish the clinical applicability of such employment-tailored, biomarker-informed strategies. Show less

Early-onset fetal growth restriction (FGR) is associated with prolonged fetoplacental hypoxia and altered brain development, including deficits in hippocampal structure and function. Neuroprotective actions of lactoferrin have been described, mediated via anti-inflammatory and antioxidant properties. Here, we investigated whether the antenatal administration of lactoferrin (1) improves hippocampal structure, (2) promotes neuronal growth, and (3) mitigates neuroinflammation in the hippocampus of fetal sheep with FGR. Early-onset FGR was induced by performing single umbilical artery ligation surgery on ovine fetuses at ~89 days gestational age (dGA; term ~148 dGA), compared with appropriate for gestational age (AGA) controls. Lactoferrin supplementation to the ewe commenced at 95 dGA (oral, 36 g/day) and continued until 127 dGA (fetal group) or birth (newborn group). Experimental fetal groups included control appropriate for gestational age (AGA; n = 8), FGR (n = 5), control + lactoferrin (AGA + Lacto; n = 6), and FGR + lactoferrin (FGR + Lacto; n = 6). In the fetal group, results showed that neither FGR nor lactoferrin altered hippocampal structure at 127 dGA. Lactoferrin exposure significantly increased neuronal abundance but also altered neuronal morphology. Lactoferrin increased the neurotrophic factor, brain-derived neurotrophic factor (BDNF) in the hippocampus. Lactoferrin exerted region-specific anti-inflammatory effects, with reduced total microglial cell count and resting microglia count in the Show less

The mechanism(s) by which exercise training induces multiple beneficial effects for Alzheimer's disease (AD) patients are not well-understood. This study aimed to examine the link between the brain-derived neurotrophic factor (BNDF)-tropomyosin receptor kinase B (TrkB) signaling complex and the beneficial effects of exercise training on cognitive impairment and neuropathology due to AD. At 4 months of age, twenty triple transgenic mice of AD (3x-Tg AD) were randomly assigned to either an AD control (n = 10) or AD exercise (n = 10) group. In parallel, twenty wild-type mice were randomly assigned to either a wild-type control (n = 10) or wild-type exercise (n = 10) group. After 20 weeks of treadmill running, the Morris water maze test was performed, and the mice were then sacrificed for biochemical analyses of plasma and brain tissues. The results indicated that 20 weeks of treadmill running upregulated markers of the BDNF-TrkB signaling complex and mitigated AD neuropathology, along with full recovery from AD-like cognitive impairments. Exercise training also decreased inflammatory cytokines, increased anti-inflammatory cytokines, shifted microglia and astrocytes toward anti-inflammatory phenotypes, improved mitochondrial function, reduced markers of myelin damage, and reduced apoptotic neuronal cell death. In summary, our study findings suggest that exercise training-induced recovery of AD-like cognitive impairments and mitigation of AD neuropathologic biomarkers are associated with modulation of the BDNF-TrkB complex and downstream signaling pathways in 3xTg-AD mice. Show less

Transcranial direct current stimulation (tDCS) is a promising non-invasive intervention for mild cognitive impairment (MCI). This prospective study investigated the relationship between optimized electrical field (EF) strength of tDCS and white matter (WM) microstructural changes in 55 individuals with MCI. Magnetic resonance imaging (MRI)-based computational modeling was used to optimize EF strength targeting the left dorsolateral prefrontal cortex (DLPFC). Diffusion tensor imaging (DTI) assessed WM integrity through fractional anisotropy (FA), mean diffusivity (MD), and radial diffusivity (RD). Higher EF strength was significantly associated with increased FA and reduced MD and RD in specific left-lateralized tracts, including the anterior thalamic radiation, corticospinal tract, inferior fronto-occipital fasciculus, and inferior longitudinal fasciculus. These EF-dependent WM changes were moderated by Alzheimer's disease (AD)-related factors. Greater WM plasticity was observed in Aβ-positive individuals, APOE ε4 non-carriers, and BDNF Met non-carriers. Moreover, APOE ε4 status significantly moderated the relationship between EF strength and executive function; in non-carriers, stronger EF strength was associated with improved Stroop performance, potentially reflecting enhanced WM integrity in the right superior longitudinal fasciculus. However, no significant associations were observed between EF-sensitive tracts and short-term cognitive changes in the full sample, suggesting that structural modifications may precede functional improvements or require longer follow-up. These findings emphasize the importance of individual AD-related factors in shaping neuromodulatory responses. They also support the need for longitudinal, sham-controlled studies to clarify the clinical implications of EF strength in personalized tDCS for MCI. Show less

This study aimed to determine whether a history of childhood abuse (CA) and baseline serum brain-derived neurotrophic factor (sBDNF) levels predict remission at 12 weeks and 12 months in patients with depressive disorders, and to examine potential interactions between these factors. A total of 1,086 patients with depressive disorders, participating in a naturalistic, stepwise antidepressant treatment study, were assessed at baseline. CA was evaluated using the Nemesis Childhood Trauma Interview, and sBDNF levels were measured. Remission was defined as a Hamilton Depression Rating Scale score of ≤ 7. Logistic regression analyses examined the independent and interactive effects of CA and sBDNF on remission outcomes, adjusting for relevant covariates. Low baseline sBDNF independently predicted poorer remission at 12 months (p = 0.045) but not at 12 weeks (p = 0.720). In adjusted analyses, CA alone did not significantly predict remission at either time point (all p > 0.05). However, patients who had both a CA history and low baseline sBDNF showed significantly lower remission rates at 12 weeks (p = 0.018) and 12 months (p = 0.009), indicating a significant interaction between these factors. These findings underscore the importance of integrating psychosocial and biological factors in personalized depression treatment. Routine screening for childhood trauma, combined with assessment of sBDNF levels, may help identify high-risk patients needing targeted interventions. Further prospective research is necessary to validate these findings. Show less

The Gold Coast criteria permit diagnosis of amyotrophic lateral sclerosis (ALS) even without upper motor neuron (UMN) signs. However, whether ALS patients with UMN signs (ALSwUMN) and those without (ALSwoUMN) share similar characteristics and prognoses remains unclear. This study compared clinical features, disease progression, electrophysiological findings, biomarker profiles, imaging parameters, and survival between these groups. ALS patients diagnosed according to the Gold Coast criteria were classified into ALSwUMN (n = 51) and ALSwoUMN (n = 20) groups. We evaluated clinical data, motor evoked potentials (MEP), and serum biomarkers, including cardiac Troponin T, neurofilament light chain, glial fibrillary acidic protein, and brain-derived neurotrophic factor. Imaging parameters, including cortical thickness and white matter volume, were also evaluated. Survival was analyzed using the Kaplan-Meier method. The groups showed broadly similar clinical features, disease progression, and biomarker profiles. Abnormal MEPs were more frequent in ALSwUMN (94.0%) than in ALSwoUMN (63.2%, p = 0.017). Both groups demonstrated cortical thinning in the precentral and entorhinal regions compared to healthy controls. ALSwUMN exhibited thinning in the lateral orbitofrontal, insular, and temporal pole regions, while ALSwoUMN showed thinning in the pars opercularis. White matter volume was reduced in both groups in the thalamus, cerebellum, and amygdala, with additional brainstem atrophy in ALSwUMN. No significant survival difference was observed. Despite minor distinctions in electrophysiological and imaging findings, ALSwoUMN had overall comparable clinical profiles and outcomes to ALSwUMN. These findings support recognizing ALSwoUMN within the ALS spectrum under the Gold Coast criteria. Show less

Atherosclerosis progresses through endothelial dysfunction, vascular inflammation, endothelial-to-mesenchymal transition (EndMT), and plaque instability. While ANGPTL4 (angiopoietin-like 4) is known for its metabolic functions, its role in endothelial homeostasis remains unclear. We investigated the protective effects of ANGPTL4 on endothelial inflammation, vascular integrity, and EndMT using ANGPTL4 suppressed TNF-α (tumor necrosis factor alpha)-induced and IL-1β (interleukin-1 beta)-induced endothelial inflammation and preserved vascular barrier integrity in vitro and in vivo. It also inhibited TGF-β (transforming growth factor-β)-driven EndMT by restoring endothelial markers and suppressing mesenchymal marker expression. Mechanistically, ANGPTL4 attenuated TGF-β-Smad2 (suppressor of mothers against decapentaplegic 2) signaling and restored KLF2 (Krüppel-like factor 2) expression, which was essential for its anti-inflammatory and anti-EndMT effects. KLF2 knockdown abolished ANGPTL4-mediated endothelial protection, confirming its pivotal role in maintaining endothelial identity. In human atherosclerotic plaques, EndMT marker expression strongly correlated with plaque complexity, suggesting that EndMT exacerbates atherosclerosis progression. Plasma ANGPTL4 levels were significantly reduced in patients with coronary artery disease with coronary microvascular dysfunction and were positively correlated with coronary flow reserve, supporting its potential as a biomarker and preventive modulator of endothelial dysfunction. These findings identify ANGPTL4 as a critical modulator of endothelial inflammation and EndMT via suppression of TGF-β-Smad2 signaling and restoration of KLF2. By preserving vascular integrity and promoting endothelial homeostasis, ANGPTL4 may serve as a preventive modulator in EndMT-driven vascular pathology and coronary microvascular dysfunction. Show less

The etiology of spontaneous abortion (SA) is complex, and the underlying mechanisms remain largely elusive. Environmental toxins have been implicated in the increased occurrence of SA. However, the association between aminomethylphosphonic acid (AMPA) exposure and SA has not yet been established. We found that AMPA, along with the lactate were significantly elevated in villous tissues from SA patients compared to normal controls, with a robust positive correlation between AMPA and lactate concentrations. More importantly, AMPA exposure induced SA in C57BL/6 mice probably through the dysfunctions of human trophoblast cell. Further studies indicated that the L-lactate production which can be induced by AMPA via PPARγ/ANGPTL4 pathway caused similar defects of human trophoblast cells. A global elevation of protein lactylation has been detected in the villous tissues from SA patients as well as AMPA or lactate treated human trophoblast cells. Pan-Kla antibody coimmunoprecipitation coupled with mass spectrometry of AMPA or lactate treated human trophoblast cells revealed JunB, which was reduced in the placenta villus from SA patients and AMPA/lactate treated human trophoblast cells, could be lactylated at lysine (K) 36. JunB K36R mutation abolished JunB lactylation and ameliorated AMPA induced JunB loss via ubiquitination in human trophoblast cells. In comparison to wild type JunB, JunB K36R mutation had better protective roles in AMPA induced trophoblast dysfunctions. In conclusion, our results demonstrate that AMPA exposure promotes lactate production via the PPARγ/ANGPTL4 pathway, which subsequently inhibits the proliferation, migration and invasion of trophoblasts through JunB K38 lactylation, ultimately leading to SA. Show less

JOURNAL/nrgr/04.03/01300535-202512000-00030/figure1/v/2025-01-31T122243Z/r/image-tiff Studies have shown that vascular dysfunction is closely related to the pathogenesis of Alzheimer's disease. The middle temporal gyrus region of the brain is susceptible to pronounced impairment in Alzheimer's disease. Identification of the molecules involved in vascular aberrance of the middle temporal gyrus would support elucidation of the mechanisms underlying Alzheimer's disease and discovery of novel targets for intervention. We carried out single-cell transcriptomic analysis of the middle temporal gyrus in the brains of patients with Alzheimer's disease and healthy controls, revealing obvious changes in vascular function. CellChat analysis of intercellular communication in the middle temporal gyrus showed that the number of cell interactions in this region was decreased in Alzheimer's disease patients, with altered intercellular communication of endothelial cells and pericytes being the most prominent. Differentially expressed genes were also identified. Using the CellChat results, AUCell evaluation of the pathway activity of specific cells showed that the obvious changes in vascular function in the middle temporal gyrus in Alzheimer's disease were directly related to changes in the vascular endothelial growth factor (VEGF)A-VEGF receptor (VEGFR) 2 pathway. AUCell analysis identified subtypes of endothelial cells and pericytes directly related to VEGFA-VEGFR2 pathway activity. Two subtypes of middle temporal gyrus cells showed significant alteration in AD: endothelial cells with high expression of Erb-B2 receptor tyrosine kinase 4 (ERBB4 high ) and pericytes with high expression of angiopoietin-like 4 (ANGPTL4 high ). Finally, combining bulk RNA sequencing data and two machine learning algorithms (least absolute shrinkage and selection operator and random forest), four characteristic Alzheimer's disease feature genes were identified: somatostatin ( SST ), protein tyrosine phosphatase non-receptor type 3 ( PTPN3 ), glutinase ( GL3 ), and tropomyosin 3 ( PTM3 ). These genes were downregulated in the middle temporal gyrus of patients with Alzheimer's disease and may be used to target the VEGF pathway. Alzheimer's disease mouse models demonstrated consistent altered expression of these genes in the middle temporal gyrus. In conclusion, this study detected changes in intercellular communication between endothelial cells and pericytes in the middle temporal gyrus and identified four novel feature genes related to middle temporal gyrus and vascular functioning in patients with Alzheimer's disease. These findings contribute to a deeper understanding of the molecular mechanisms underlying Alzheimer's disease and present novel treatment targets. Show less

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

Exposure to persistent organic pollutants such as 2,3,7,8-tetrachlorodibenzodioxin (TCDD) increases metabolic disorder risk. In this study, we show that a single intraperitoneal injection of TCDD (10 μg/kg) in C57BL/6J mice induced body weight gain, lipid accumulation in the liver and adipose tissue, macrophage infiltration, and elevated hepatic and serum triglyceride levels after 12 weeks. Despite serum aryl hydrocarbon receptor (AhR) ligand levels normalizing by 12 weeks, the persistent effects suggest TCDD sequestration in fat tissue. TCDD inhibited the expression of mitochondrial proteins (COX1, TOM20, TFAM, H2AX) and reduced mitochondrial oxygen consumption. Liver-specific AhR knockout ameliorated TCDD-induced mitochondrial dysfunction, lipid accumulation, and macrophage infiltration. Mechanistically, TCDD-induced hepatic plasminogen activator inhibitor-1 (PAI-1) promoted adipocyte hypertrophy. In the liver, PAI-1 disrupted the interaction between tissue-type plasminogen activator (tPA) and apolipoprotein B (ApoB), thereby enhancing very-low-density lipoprotein (VLDL) assembly. These findings reveal that hepatocyte-derived circulating PAI-1, upregulated via hepatic AhR activation, contributes to adipocyte hypertrophy and hepatosteatosis through the intracellular modulation of the tPA-PAI-1 axis. Thus, hepatic AhR activation drives mitochondrial dysfunction and obesity, even after a single TCDD exposure. Show less

Highly effective therapies to reduce triglyceride levels are lacking. Olezarsen is an In this phase 3, international, double-blind, randomized, placebo-controlled trial, we enrolled patients with moderate hypertriglyceridemia (triglyceride level, 150 to 499 mg per deciliter) and elevated cardiovascular risk or with severe hypertriglyceridemia (triglyceride level, ≥500 mg per deciliter) and randomly assigned them in a 1:3 ratio to a 50-mg or 80-mg cohort. The patients were then randomly assigned in a 3:1 ratio to receive monthly subcutaneous olezarsen or matching placebo within each cohort. The primary outcome was the least-squares mean percent change in triglyceride level from baseline to 6 months among the patients with moderate hypertriglyceridemia, reported as the difference between each olezarsen dose group and the placebo group (the placebo-adjusted change). A total of 1349 patients (254 in the olezarsen 50-mg group, 766 in the olezarsen 80-mg group, and 329 in the placebo group) were included in the primary efficacy analysis. The median age was 64 years, 40% of the patients were women, and the median triglyceride level at baseline was 238.5 mg per deciliter (interquartile range, 190.5 to 307.5). At 6 months, the placebo-adjusted least-squares mean change in triglyceride level was -58.4 percentage points (95% confidence interval [CI], -65.1 to -51.7; P<0.001) in the olezarsen 50-mg group and -60.6 percentage points (95% CI, -67.1 to -54.0; P<0.001) in the olezarsen 80-mg group. The incidence of serious adverse events appeared to be similar across the trial groups. Among patients with moderate hypertriglyceridemia and elevated cardiovascular risk, treatment with olezarsen resulted in significantly greater reduction in triglyceride levels at 6 months than placebo. (Funded by Ionis Pharmaceuticals; ESSENCE-TIMI 73b ClinicalTrials.gov number, NCT05610280.). Show less

Despite increasing heavy metal pollution, traditional epidemiology often fails to link exposure to health outcomes. This study used multi-omics to investigate associations between heavy metal exposure and health. Blood and urine samples from 294 participants in heavy metal-exposed and control areas were analyzed, revealing key biomarkers. Meta P analysis revealed consistent trends in apolipoprotein C3 (APOC3) expression, and mediation analysis showed significant effects of APOC3 and zinc-alpha-2-glycoprotein (ZA2G) on metabolites: the mediating effect of APOC3 from blood cadmium to serotonin was 0.023 (P < 0.001) and that to 3-phosphoglyceric acid (3PG) was 0.0125 (P = 0.002). Mendelian randomization confirmed the positive impact of APOC3 and Complement Factor I (CFAI) and the negative effect of ZA2G on metabolites, with apolipoprotein H (APOH) methylation significantly altering APOC3 (β = -0.22, P = 0.017), CFAI (β = 0.176, P = 0.035), and ZA2G (β = 0.139, P = 0.048) protein levels. Liver function variables, including albumin, total protein, calcium, and lactate dehydrogenase, correlated with 3PG and serotonin levels in the exposed areas. Sex-specific analysis showed that men exhibited stronger compensatory mechanisms via CFAI and myo-inositol, while women's greater vulnerability to heavy metal exposure highlighted the need for targeted interventions. These findings suggest APOH methylation affects APOC3, CFAI, and ZA2G levels, elevating 3PG, inosine monophosphate, and serotonin levels and harming liver function via lipolysis, supporting the use of these markers in health monitoring, therapies, and policies to limit heavy metal risks. Show less

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by memory loss, cognitive decline, and neuroinflammation, primarily mediated by microglia. In this study, we investigate the role of adenylate kinase 5 (AK5) in microglial function and its association with AD-related pathology. Analysis of brain tissues from AD patients and AD model mice revealed a significant reduction in AK5 expression. In vitro knockdown of AK5 in microglial cells attenuated lipopolysaccharide-induced pro-inflammatory responses, including decreased nitric oxide and tumor necrosis factor-alpha production, while enhancing phagocytic activity. Moreover, AK5 silencing induced metabolic reprogramming, evidenced by reduced lipid droplet accumulation and adipose triglyceride lipase mRNA levels, alongside increased farnesoid X receptor mRNA expression. Genome-wide association studies further identified two AK5 single nucleotide polymorphisms (SNPs), rs59556669 and rs75224576, significantly associated with hippocampal and amygdala atrophy as well as increased AD risk. Notably, these SNPs were not in linkage disequilibrium with the apolipoprotein E (APOE) locus, suggesting that AK5 may represent an independent genetic risk factor for AD. Collectively, our findings identify AK5 as a key regulator of microglial immune and metabolic function. The presence of AK5 variants may contribute to AD susceptibility, and AK5 expression or genetic status could serve as a potential biomarker for early risk assessment. Further exploration of AK5-targeted interventions may provide new therapeutic avenues for AD prevention or treatment. Show less

A key methodological challenge for genome-wide association studies is how to leverage haplotype diversity and allelic heterogeneity to improve trait association power, especially in noncoding regions where it is difficult to predict variant impacts and define functional units for variant aggregation. Genealogy-based association methods have the potential to bridge this gap by testing combinations of common and rare haplotypes based purely on their ancestral relationships. In parallel work, we have developed an efficient local ancestry inference engine and a novel statistical method (LOCATER) for combining signals present on different branches of a locus specific haplotype tree. Here, we developed a genome-wide LOCATER analysis pipeline and applied it to a genome sequencing study of 6,795 Finnish individuals with 101 cardiometabolic traits and 18.9 million autosomal variants. We identify 351 significant trait associations at 47 distinct genomic loci and find that LOCATER boosts single marker test (SMT) association signal at 5 loci by combining independent signals from distinct alleles. LOCATER successfully recovers known quantitative trait loci not found by SMT, including Show less

Evidence is accumulating that links gut microbiota, a crucial component of the immune environment, to Sjogren's syndrome (SS). The mechanisms underlying the influence of gut microbiota on the onset and development of SS are still not completely understood. To this end, we applied a Mendelian randomization (MR) framework to investigate whether inflammatory cytokines mediate the association of gut microbiota with SS. Our MR analysis leveraged publicly available GWAS data, including information on 211 gut microbiota taxa sourced from the MiBioGen consortium (18,340 participants), summary statistics for 91 inflammatory cytokines obtained from a study of 14,824 individuals, and genetic data for SS derived from the UK Biobank (407,746 participants). To investigate causal associations between gut microbiota and SS, we primarily employed the inverse variance weighted method, supported by additional techniques such as MR-Egger, simple mode, weighted median, and weighted mode for validation. The potential mediating effect of inflammatory cytokines in the gut microbiota-SS relationship was investigated using both mediation MR and multivariable MR (MVMR) analyses. MR analysis identified five microbiota taxa causally associated with SS. Particularly, class Gammaproteobacteria (OR = 3.468, 95% CI = 1.139-10.557, The findings suggest that certain gut microbiota is sociated with an increased risk of SS, mediated by specific inflammatory cytokines. Show less

Cardiac hypertrophy as one of the major predisposing factors for chronic heart failure lacks effective interventions. It has been shown that protein ubiquitination plays an important role in cardiac hypertrophy. SMURF2 (SMAD-specific E3 ubiquitin ligase 2) is an important member of NEDD4 (neuronal precursor cell expressed developmentally downregulated 4) family of HECT E3 ubiquitin ligases. In this study we investigated the regulatory role of SMURF2 in cardiac hypertrophy. Experiment models were established in mice by transverse aortic constriction (TAC) in vivo, as well as in neonatal rat cardiomyocytes (NRCMs) by treatment with angiotensin II (Ang II, 1 μM) in vitro. We showed that the expression levels of SMURF2 were significantly elevated in cardiac tissues from patients with cardiac hypertrophy and the two experiment models. In NRCMs, SMURF2 knockdown or treatment with a specific SMURF2 inhibitor heclin (8 μM) significantly inhibited Ang II-induced cardiomyocyte hypertrophy, evidenced by reduced mRNA levels of Anp, Bnp and β-Mhc as well as cell surface. Prophylactic or therapeutic administration of heclin (10 mg·kg Show less

CFTR modulator therapies have positive clinical outcomes, yet chronic inflammation and bacterial infections persist in people with CF (pwCF). How elexacaftor-tezacaftor-ivacaftor (ETI) fails to improve innate immune signaling responsible for bacterial clearance and inflammation resolution remains unknown. We used an unbiased proteomics approach to measure the effect of ETI on inflammatory proteins. Plasma from 20 pediatric pwCF and 20 non-CF (NCF) was collected during routine examination and 3 months after ETI initiation. Protein screening was performed with an inflammation panel (Target 96, Olink There were significantly fewer pulmonary exacerbations after ETI initiation, along with sustained improvement in lung function and reduced bacterial colonization. Unpaired analysis of CF pre-ETI and NCF resulted in 34 significantly different proteins. Of these, CCL20, MMP-10, EN-RAGE, and AXIN1 had a log This study showed that ETI in a pediatric cohort had a modest effect on several inflammatory proteins with potential as biomarkers. Pathways significantly impacted by ETI can be further studied for future therapies to combat persistent inflammation and dysregulated immunity. Show less

Dual specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) is associated with the pathoprogression of neurodevelopmental and neurodegenerative disorders. However, the effects of direct genetic manipulation of DYRK1A in the brain on cognitive function, neuroinflammation and Alzheimer's disease (AD) pathology and underlying molecular mechanisms have not been fully investigated. To determine whether overexpressing or knocking down DYRK1A expression directly in the brain affects cognitive function, neuroinflammation and AD pathology, adeno-associated viruses (AAVs) were injected into the hippocampus of wild-type (WT), 5xFAD, and PS19 mice. Then, cognitive function was assessed via Y-maze and novel object recognition (NOR) tests, and neuroinflammatory responses and AD pathologies were analyzed by real-time PCR, Western blotting, immunofluorescence staining, AD-associated protein activity assays and ELISA. In WT mice, hippocampal DYRK1A overexpression significantly reduced short-term spatial/recognition memory and SynGAP expression while increasing p-P38 levels. Conversely, in amyloid-beta (Aβ)-overexpressing 5xFAD mice, hippocampal DYRK1A knockdown improved short-term spatial/recognition memory and significantly increased CaMKIIα and CREB phosphorylation. Moreover, hippocampal DYRK1A knockdown in 5xFAD mice significantly suppressed mRNA levels of proinflammatory cytokines and markers of AD-associated reactive astrocytes (RAs), disease-associated microglia (DAMs), and RA-DAM interactions. However, hippocampal DYRK1A overexpression in 5xFAD mice increased mRNA levels of the proinflammatory cytokine IL-1β, RA markers and the microglial marker Iba-1. Interestingly, hippocampal DYRK1A knockdown in 5xFAD mice significantly increased levels of the anti-oxidative/inflammatory molecule HO-1 without altering p-STAT3/p-NF-κB levels. By contrast, hippocampal DYRK1A overexpression in 5xFAD mice enhanced STAT3/NF-κB phosphorylation but did not affect ROS levels. Importantly, hippocampal DYRK1A knockdown in 5xFAD mice significantly reduced Aβ plaque number, soluble Aβ40 levels, and soluble/insoluble Aβ42 levels by suppressing β-secretase BACE1 activity but not tau hyperphosphorylation. Finally, hippocampal DYRK1A knockdown in PS19 mice [a model of AD that overexpresses human mutant tau (P301S)] selectively decreased insoluble tau hyperphosphorylation at Ser396 and Ser404 and alleviated proinflammatory responses/glial-associated neuroinflammatory dynamics. Taken together, our data indicate that DYRK1A modulates cognitive function, neuroinflammation, and AD pathology (Aβ and tauopathy) in mouse models of AD and/or WT mice and support DYRK1A as a potential therapeutic target for AD. Show less