Long-term antigen-specific data in PMN among Chinese populations remain limited. This study evaluated six target antigens and their clinical significance during extended follow-up. We retrospectively Show more
Long-term antigen-specific data in PMN among Chinese populations remain limited. This study evaluated six target antigens and their clinical significance during extended follow-up. We retrospectively analyzed 132 treatment-naïve PMN patients diagnosed by biopsy (2010-2018) and followed for a median of 62.9 months. Renal tissue expression of PLA2R, THSD7A, NELL-1, PCDH7, EXT1, and EXT2 was assessed by immunohistochemistry, and serum anti-PLA2R antibodies were measured by ELISA. Associations between antigen profiles and 5-year outcomes (remission, renal survival, malignancy) were evaluated. PLA2R was the predominant antigen (84.1%), followed by THSD7A (5.3%) and NELL-1 (0.76%); no PCDH7, EXT1, or EXT2 positivity was detected. PLA2R-negative patients were more often female (71.4% vs. 36.0%, This >5-year Chinese PMN cohort provides the first comprehensive analysis of six target antigens. PLA2R remains predominant, while PLA2R-negative patients distinct immunopathologic features yet favorable long-term outcomes. A population-specific anti-PLA2R cutoff showed good diagnostic performance for predicting tissue antigen deposition. Rare antigens were infrequent and their malignancy associations require cautious interpretation. These findings provide long-term antigen-specific data supporting antigen-guided, population-adapted precision management of PMN. Show less
We employed a causal inference framework to estimate the counterfactual dose-response effects of light-intensity physical activity (LPA) on mortality across low, medium and high moderate- to vigorous- Show more
We employed a causal inference framework to estimate the counterfactual dose-response effects of light-intensity physical activity (LPA) on mortality across low, medium and high moderate- to vigorous-intensity physical activity (MVPA) levels, and the lower and higher thresholds of current MVPA recommendations. Eligible participants from the UK Biobank (n=71 715) were included in the current study. LPA and MVPA were measured via accelerometers, and mortality data were derived from death registry. Flexible parametric survival models were used under the counterfactual framework to estimate the marginal predicted probability of death after 10 years of follow-up. During a median follow-up period of 8.0 years, 2195 deaths occurred. A non-linear dose-response effect of LPA on all-cause mortality was evident, and the effect diminished as MVPA level increased. If all participants achieved the lower threshold of the WHO recommended 22 min/day of MVPA, the 10-year probability of death would be expected to decrease from 9.5% at 60 min/day LPA to 4.2% at 360 min/day. If all participants achieved the higher threshold of 44 min/day of MVPA, the 10-year probability of death would be expected to decrease from 6.6% at 60 min/day of LPA to 3.7% at 345 min/day. Across the MVPA values examined, the optimal dose for LPA ranged from 195 to 225 min/day. LPA may complement MVPA to reduce risk of all-cause mortality, particularly among those with low MVPA or those unable to engage in higher-intensity activities. Our study highlights the potential for integrating LPA into public health strategies and future physical activity guidelines. Show less
This study was conducted to investigate the clinical and genetic characteristics of a family affected by hereditary spherocytosis (HS) combined with familial chylomicronemia syndrome (FCS), identify t Show more
This study was conducted to investigate the clinical and genetic characteristics of a family affected by hereditary spherocytosis (HS) combined with familial chylomicronemia syndrome (FCS), identify the pathogenic cause, and provide a basis for the clinical diagnosis, treatment, and genetic counseling of affected children. Clinical data were collected from family members. High-throughput sequencing was performed to identify pathogenic variants in genes associated with HS and FCS in the proband. Suspected pathogenic mutations were confirmed in family members via PCR-Sanger sequencing. Bioinformatics analysis and three-dimensional protein structure prediction were also conducted. The proband presented with severe anemia, splenomegaly, and jaundice. Genetic testing revealed a heterozygous mutation, c.6005G>A (p.Trp2002*), in the spectrin beta chain ( The heterozygous mutations Show less
Diabetes constitutes a risk factor for atherosclerotic calcification, which is highly associated with phenotypic switching in vascular smooth muscle cells (VSMCs). Protein cysteine S-nitrosylation pla Show more
Diabetes constitutes a risk factor for atherosclerotic calcification, which is highly associated with phenotypic switching in vascular smooth muscle cells (VSMCs). Protein cysteine S-nitrosylation plays a crucial role in multiple cardiovascular diseases. The objective of this study is to examine whether diabetic atherosclerotic calcification is regulated by S-nitrosylation of AMP-activated protein kinase (AMPK), a regulator of VSMC phenotype switching. The atherosclerotic plaque was induced by feeding Apoe In cultured VSMCs, high glucose (HG), but not high osmotic pressure, triggered nitrosative stress, reduced AMPKβ1 protein levels, increased AMPKβ1 S-nitrosylation and ubiquitination, and led to calcification. These effects were abolished by mutating AMPKβ1 at cysteine 173 or 223. Furthermore, mutations of AMPKβ1 at Cys173/223 to alanine restored AMPKβ1 protein levels and suppressed the AKT/Runx2 pathway in HG-treated VSMCs. In vivo, enforced expression of mutated AMPKβ1 (Cys173Ala plus Cys223Ala), but not overexpression of wild-type AMPKβ1, significantly prevented atherosclerotic calcification in diabetic Apoe Nitrosative stress contributes to atherosclerotic calcification in diabetes through AMPKβ S-nitrosylation. In perspective, it is advisable to consider inhibiting AMPKβ S-nitrosylation in diabetic patients with atherosclerosis. Show less
Alterations in the FGFR family act as oncogenic drivers for multiple pediatric and adult tumors, leading to the development and approval of several FGFR inhibitors. However, the on-target gatekeeper a Show more
Alterations in the FGFR family act as oncogenic drivers for multiple pediatric and adult tumors, leading to the development and approval of several FGFR inhibitors. However, the on-target gatekeeper and "molecular brake" mutations confer clinically acquired resistance to the FDA-approved FGFR inhibitors, which presents a significant unmet medical need. Herein, we report the first novel macrocycle-based FGFR inhibitors targeting both wild-type and clinically acquired variants of the FGFR family. The representative compound Show less
Aging is asynchronous across cells and organs, but whether plasma proteins can capture cell type-specific aging and predict disease and mortality remains unknown. We developed machine learning models Show more
Aging is asynchronous across cells and organs, but whether plasma proteins can capture cell type-specific aging and predict disease and mortality remains unknown. We developed machine learning models to estimate the biological age of more than 40 distinct cell types-spanning neuronal, immune, glial, endocrine, epithelial, and musculoskeletal origins-using over 7,000 plasma proteins measured in 60,000 individuals across three cohorts, comprising the largest human plasma proteomics aging study to date. Individuals showed heterogeneous aging profiles, with 20-25% exhibiting accelerated aging in a single cell type and 1-3% across ten or more cell types. APOE genotype showed antagonistic aging effects in different cell types: APOE4 carriers exhibited older astrocytes but younger macrophages, while APOE2 carriers showed the inverse. Cellular aging signatures were uniquely associated with disease status and predicted incident disease and mortality over 15 years of follow-up. Amyotrophic lateral sclerosis (ALS) showed the strongest association with skeletal myocyte aging (hazard ratio = 12.7 for extreme accelerated versus youthful aging). In Alzheimer's disease (AD), prevalent cases showed accelerated aging across multiple neural and peripheral cell types, with extreme astrocyte aging conferring AD risk comparable to APOE4 carrier status. Moreover, extreme astrocyte aging increased AD risk in APOE4/4 carriers threefold, while youthful astrocytes strikingly reduced risk. Beyond neurodegeneration, respiratory cell aging identified smokers at 58% higher lung cancer risk, and myeloid aging identified normoglycemic individuals at higher diabetes risk. Both specific cellular vulnerabilities and cumulative aging burden influenced survival, wherein youthful immune or neuronal profiles were protective. A polycellular aging risk score provided robust mortality risk stratification across platforms and cohorts. These findings establish a framework for quantifying biological aging at the cellular resolution using plasma proteomics, revealing heterogeneity in aging trajectories and their impact on disease susceptibility and resilience. Show less
Carotid atherosclerosis is a significant risk factor for cardiovascular and cerebrovascular diseases. Maintaining plaque stability can prevent plaque rupture and thrombus formation, slow disease progr Show more
Carotid atherosclerosis is a significant risk factor for cardiovascular and cerebrovascular diseases. Maintaining plaque stability can prevent plaque rupture and thrombus formation, slow disease progression, and is critically important for preventing cerebrovascular events (such as stroke, transient ischemic attack (TIA), and similar events). Mechanisms influencing plaque stability are still unclear. In this study, stable plaques (n = 5) and unstable plaques (n = 5) were collected from patients and analyzed using RNA-sequencing. 594 differently expressed genes were found by RNA-seq. Pathways enriched by KEGG analysis of differentially expressed genes included inflammation related pathway, cell adhesion related pathway and TGFβ signaling pathway. Especially, we found AMIGO1 was significantly upregulated in stable plaques. Functional assays including cell adhesion, and inflammation-related factor detection revealed that AMIGO1 significantly promotes endothelial cell adhesion while downregulating inflammatory cytokines (e.g., IL-6, IL-1β, TNF-α) production, thereby mitigating inflammatory responses. Co-immunoprecipitation (Co-IP) experiments further found that AMIGO1 interacts with transforming growth factor beta receptor II (TGFRII), stabilizing TGFRII protein levels and subsequently activating the TGFβ signaling pathway. AMIGO1 overexpression with AAV9 virus tail vein injection markedly stabilized plaques in ApoE Show less
Acetylation, a key post-translational modification, is dynamically regulated by histone acetyltransferases (HATs) and histone deacetylases (HDACs). Among HDACs, HDAC6-a class II deacetylase with predo Show more
Acetylation, a key post-translational modification, is dynamically regulated by histone acetyltransferases (HATs) and histone deacetylases (HDACs). Among HDACs, HDAC6-a class II deacetylase with predominant cytoplasmic localization-plays a unique role in cellular processes that extend beyond histone modification. It is ubiquitously expressed throughout the central and peripheral nervous systems and is integral to key physiological functions including protein quality control, autophagy, mitochondrial transport, and oxidative stress responses. Notably, under pathological conditions such as Alzheimer's disease, Parkinson's disease, Huntington's disease, epilepsy, and peripheral nerve injury, HDAC6 undergoes nuclear translocation and contributes to epigenetic dysregulation by modulating the transcription of genes such as brain-derived neurotrophic factor, thereby impairing synaptic integrity and function. This dual role-cytoplasmic in protein homeostasis and nuclear in transcriptional regulation-highlights the HDAC6 paradox in neurological disorders. This review summarizes recent understanding of HDAC6's structure, expression, and functions within the nervous system, and discuss how targeting HDAC6 with selective inhibitors offers a promising therapeutic strategy for mitigating neurological disease pathogenesis. The goal is to provide insights that bridge HDAC6's roles in protein quality control and epigenetic regulation, fostering further exploration of HDAC6 inhibition in neurologic therapeutics. Show less
Despite therapeutic advances, atherosclerosis remains a major global health challenge. Most current treatments target systemic risk factors rather than the diseased vascular wall. Our previous work id Show more
Despite therapeutic advances, atherosclerosis remains a major global health challenge. Most current treatments target systemic risk factors rather than the diseased vascular wall. Our previous work identified genistein, a soy isoflavone, as a cannabinoid receptor 1 (CB1) antagonist capable of suppressing CB1-mediated vascular inflammation and atherosclerosis. However, its poor water solubility and low oral bioavailability limit clinical application. We aimed to develop water-soluble, orally bioavailable CB1 antagonists for atherosclerosis and to investigate the role of endothelial CB1 in hemodynamic regulation. RNA-sequencing datasets from the NCBI GEO repository were analyzed to assess CB1 expression in atherosclerotic patients. Apolipoprotein E-deficient (Apoe We found CB1 was upregulated in atherosclerotic lesions from patients and mice, and in endothelial cells exposed to disturbed flow. Mechanistically, this was driven by ZNF610 and Spi1 binding and KLF4 dissociation at the CB1 promoter. Daidzein, a soy isoflavone structurally similar to genistein, was identified as a novel CB1 antagonist. To enhance solubility and bioavailability, we developed genistein 7-O-phosphate (G7P) and daidzein 7-O-phosphate (D7P). Pharmacological treatment with these isoflavone monophosphates or genetic CB1 ablation reversed disturbed flow-induced endothelial dysfunction and endothelial-to-mesenchymal transition (EndMT). Oral administration of G7P and D7P significantly reduced atherosclerotic plaque formation in mice. This is the first study to identify transcriptional regulators that drive endothelial CB1 upregulation in response to disturbed flow. We further demonstrated that isoflavone monophosphates ameliorate disturbed flow-induced endothelial dysfunction and EndMT via CB1 inhibition, offering promising oral therapeutics for atherosclerosis. Show less
Molecular genetic testing was performed on a fetus with ectrodactyly of the right foot to clarify the pathogenic cause and provide evidence for prenatal counseling. Trio whole-exome sequencing (trio-W Show more
Molecular genetic testing was performed on a fetus with ectrodactyly of the right foot to clarify the pathogenic cause and provide evidence for prenatal counseling. Trio whole-exome sequencing (trio-WES) was performed on the fetus and his parents to identify the underlying genetic cause. Candidate variants were validated by Sanger sequencing, and their molecular effects were analyzed through minigene assays. Trio-WES identified a novel heterozygous variant (c.1977+1G>C) in FGFR1, which is consistent with FGFR1-related Hartsfield syndrome (HS; OMIM#615465). Sanger sequencing confirmed that this variant was de novo. The minigene assay revealed that all variants (c.1977+1G>C, c.1977+1G>A, and c.1977+1G>T) at the splice site generated two aberrant splicing events: (1) complete retention of intron 14, leading to a frameshift and premature termination codon; and (2) skipping of exon 14, causing an in-frame deletion of 41 amino acids. These events collectively impaired the function of the FGFR1 protein's tyrosine kinase domain. To our knowledge, prenatal reports of FGFR1-related HS remain extremely limited, and this is the first molecularly confirmed prenatal diagnosis of HS in China. The findings not only expand the mutational spectrum of HS but also provide genetic counseling and reproductive guidance for this family. Show less
Anxiety and depression are highly comorbid mental health disorders with heterogeneous symptom patterns and poorly understood transdiagnostic mechanisms. This study aims to characterize latent subgroup Show more
Anxiety and depression are highly comorbid mental health disorders with heterogeneous symptom patterns and poorly understood transdiagnostic mechanisms. This study aims to characterize latent subgroups, risk factors, and symptom-level interactions underlying depression-anxiety comorbidity across adolescents and adults in multi-ethnic Southwest China. The study included a total of 41,394 adolescents (aged 9-19) and 17,345 adults (aged 18-80). Adolescents were recruited using multistage stratified cluster sampling, whereas adults were recruited by convenience sampling. All participants completed a self-designed sociodemographic questionnaire, the Patient Health Questionnaire-9 (PHQ-9), and the Generalized Anxiety Disorder-7 (GAD-7). Latent profile analysis identified subgroups, logistic regression analyzed risk/protective factors, and network analysis mapped symptom interactions and bridge nodes. This study found that three adolescent profiles emerged: high (11.66 %), moderate (31.95 %), and low/no depression-anxiety (56.39 %). Adults were classified into low/no comorbidity (90.63 %) and comorbid depression-anxiety (9.37 %). Risk factors for adolescents included female gender (OR = 2.77, 95 %CI: 2.55-3.00; OR = 1.59, 95 %CI: 1.52-1.67), higher grade levels (OR = 3.45, 95 %CI: 3.10-3.84; OR = 3.56, 95 %CI: 3.33-3.80), smoking (OR = 1.72, 95 %CI: 1.51-1.96; OR = 1.28, 95 %CI: 1.17-1.41),drinking (OR = 2.45, 95 %CI: 2.23-2.70; OR = 1.66, 95 %CI: 1.55-1.77), family instability (OR = 1.16, 95 %CI: 1.02-1.31; OR = 1.33, 95 %CI: 1.14-1.56) and "other" ethnic minority (OR = 1.15, 95 %CI: 1.04-1.26). For adults, female gender(OR = 1.68; 95 %CI: 1.44-1.97), living alone(OR = 1.37; 95 %CI: 1.14-1.65), poor self-rated health (OR = 0.13, 95 %CI: 0.11-0.15), and Dai ethnicity (OR = 0.70, 95 %CI: 0.49-0.96) predicted comorbidity. Network analysis revealed distinct bridge symptoms: adolescents in the high depression-anxiety group had five symptoms: depressed or sad mood (phq2), psychomotor agitation/retardation (phq8), nervousness or anxiety (gad1), restlessness (gad5), and irritable (gad6); however, adults with comorbidity had one symptom: afraid something will happen (gad7). This study identified three patterns of depression-anxiety comorbidity in adolescents and two in adults. Efforts should prioritize adolescents from "other" ethnic minorities, strengthening family and peer support, as well as smoking and drinking interventions for adolescents, and addressing social isolation, physical health, and catastrophizing cognition in adults may mitigate the comorbidity burden. Show less
Long-term alcohol consumption drives systemic damage through metabolites such as acetaldehyde, which trigger oxidative stress, inflammation, and gut dysbiosis. This study evaluated the protective effe Show more
Long-term alcohol consumption drives systemic damage through metabolites such as acetaldehyde, which trigger oxidative stress, inflammation, and gut dysbiosis. This study evaluated the protective effects of fermented red quinoa (FRQ) in an alcohol-exposed mouse model, with a focus on cognitive function. Male C57BL/6J mice were randomized into three groups for a 28-day study: a normal control, an alcohol-treated group gavaged with ethanol (1 mL/100 g·BW), and a group receiving the same ethanol dose co-administered with FRQ powder (human equivalent dose: 9 g/60 kg·BW). Our results demonstrated that fermentation with Lactobacillus kisonensis significantly increased the content of phenolic compounds (e.g., quercetin and veratric acid) in FRQ. FRQ intervention improved cognitive function, ameliorated synaptic structural impairment and blood-brain barrier disruption, and attenuated hepatic steatosis. The protective mechanisms involved three pathways: 1) The specific phenolic compounds in FRQ promoted alcohol metabolism by regulating ADH/ALDH activity, leading to reduced acetaldehyde levels. As a primary initiating pathway, this metabolic enhancement dominantly attenuated subsequent oxidative stress and inflammation, mitigating injury in the liver, brain, and colon. 2) It directly modulated AP-1 subunits (ΔFOSB/JUND), restored BDNF, and rebalanced the glutamate/GABA systems. 3) It regulated the gut-liver-brain axis by remodeling the gut microbiota (e.g., enriching butyrate-producing Butyricicoccus), reinforcing intestinal barrier integrity, and thereby suppressing systemic LPS translocation and inflammation. In conclusion, FRQ mitigates alcohol-induced cognitive and hepatic damage via multiple mechanisms, highlighting its promise as an integrative dietary intervention. Show less
Older adults typically have higher sedentary behaviour (SB) and lower physical activity (PA) than younger adults. Studies on replacing SB with PA in relation to all-cause mortality in racially diverse Show more
Older adults typically have higher sedentary behaviour (SB) and lower physical activity (PA) than younger adults. Studies on replacing SB with PA in relation to all-cause mortality in racially diverse older adults remain limited. This study included 122 966 older adults from the China Kadoorie Biobank (CKB) and 207 212 older adults from the UK Biobank (UKB). SB and PA were assessed using baseline questionnaires, with PA classified as light (LPA), moderate (MPA) or vigorous (VPA) based on metabolic equivalents. Cox proportional hazards models and isotemporal substitution models were used to examine the associations between replacing SB with different PA intensities and all-cause mortality. Longer SB (per 30 min/day increase) was associated with a higher risk of all-cause mortality in both cohorts (CKB: HR 1.013, 95% CI 1.010 to 1.017; UKB: HR 1.012, 95% CI 1.009 to 1.015). PA of any intensity was associated with a reduced risk of all-cause mortality. In the CKB, replacing 30 min/day of SB with an equivalent duration of PA showed comparable protective associations (LPA: HR 0.963, 95% CI 0.958 to 0.968; MPA: HR 0.967, 95% CI 0.961 to 0.972; VPA: HR 0.965, 95% CI 0.960 to 0.971). In the UKB, replacing 30 min/day of SB with VPA was associated with the largest reduction in mortality risk (HR: 0.950, 95% CI 0.931 to 0.970). Replacing SB with PA of any intensity was associated with reduced all-cause mortality risk in older adults, with variations across populations. These findings highlight the need for population-specific PA recommendations to promote healthy ageing. Show less
Apigenin is a bioactive flavonoid and widely found in herbs, fruits, and vegetables. Accumulated evidences have demonstrated the protective potential of apigenin on cardiovascular diseases, but its ro Show more
Apigenin is a bioactive flavonoid and widely found in herbs, fruits, and vegetables. Accumulated evidences have demonstrated the protective potential of apigenin on cardiovascular diseases, but its role in atherosclerosis remains unclear. Here, we aim to investigate the therapeutic effects of apigenin on atherosclerosis in vivo and explore the potential mechanism. ApoE Apigenin obviously reduced lesion areas in both en-face aortas and aortic root in HFD fed ApoE Apigenin alleviated atherosclerosis development by inhibiting macrophage foam cell formation via PPARγ-LXRα-ABCA1/ABCG1 pathway. Show less
Growing evidence highlights that long-term orbital flight may lead to structural changes in brains and cognitive impairments in astronauts. However, effective strategies to counteract these effects re Show more
Growing evidence highlights that long-term orbital flight may lead to structural changes in brains and cognitive impairments in astronauts. However, effective strategies to counteract these effects remain limited. Compound Gastrodia elata Formula (CGEF), composed of Gastrodia elata Bl., Polygonatum sibirium Red., and Poria cocos (Schw.) Wolf has been shown to improve learning and memory. The present study aimed to evaluate the effects and underlying mechanisms of CGEF in attenuating cognitive deficiency induced by simulated weightlessness in mice. A cognitive impairment model was induced in mice using Hindlimb unloading (HU) method. Cognitive function was assessed through Object recognition test (ORT), the Morris water maze (MWM), and the Step-down Test (SDT). Serum and hippocampus levels of inflammatory markers, including Interleukin-1 beta (IL-1β), Tumor Necrosis Factor alpha (TNF-α), and Interleukin-6 (IL-6) were evaluated using ELISA. Neurotransmitter concentrations in the hippocampus and cortex were measured using LC-MS/MS. While Brain-derived neurotrophic factor (BDNF) / Tropomyosin receptor kinase B (TrkB) protein expression signaling pathway in hippocampus was evaluated by western blot. Results showed that CGEF treatment significantly reversed the memory deficits induced by four weeks of HU exposure. Furthermore, CGEF treatment markedly suppressed the production of inflammatory factors. It also assisted in the recovery of neurotransmitter balance and regulated tryptophan metabolism to improve cognitive disorder. Western blotting analysis revealed that CGEF treatment upregulated the expression of Synaptophysin, Postsynaptic density 95 proteins, while also activating the brain-derived neurotrophic factor-Tropomyosin receptor kinase B pathway. These findings suggest that CGEF has substantial potential for development as an aerospace health product to improve memory decline associated with spaceflight. 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 mechani Show more
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
Rodents are widely used in immunology but do not always recapitulate human immune functions. The tree shrew (Tupaia belangeri) is phylogenetically closer to primates than rodents and may help bridge t Show more
Rodents are widely used in immunology but do not always recapitulate human immune functions. The tree shrew (Tupaia belangeri) is phylogenetically closer to primates than rodents and may help bridge this gap, yet its immune system has not been comprehensively characterised at single-cell resolution. Here, we present a single-cell transcriptomic atlas of the tree shrew immune system, profiling 39 cell types across 12 tissues. We uncover human-like tonsillar structures and two transcriptionally distinct splenic macrophage subsets: an NR1H3 Show less
This study employs latent profile analysis (LPA) to identify potential categories of nurse burnout and to analyze differences in characteristics and influencing factors across burnout categories. From Show more
This study employs latent profile analysis (LPA) to identify potential categories of nurse burnout and to analyze differences in characteristics and influencing factors across burnout categories. From June to August 2025, a mixed sampling approach combining convenience and snowball sampling was used to recruit nurses from hospitals of varying levels in Southwest China. Three tools were used for data collection: A self-designed routine information questionnaire, Maslach Burnout Inventory-General Survey (MBI-GS) and Practice Environment Scale of the Nursing Work Index (PES-NWI), LPA identifies potential categories of nurses' professional burnout and uses multivariate logistic regression analysis to explore the factors associated with these categories. This study comprised a total of 809 participants. LPA identified four distinct latent classes of nursing burnout: Class 1, low-burnout-high-efficacy (11.5%); Class 2, mild-burnout-unfulfilled (33.9%); Class 3, moderate-burnout-exhausted (44.6%); and Class 4, severe-burnout-dysfunctional (10.0%). Multivariate logistic regression analysis showed that age, years of work experience, hospital level, nurses' participation in hospital management, nursing quality standards, staffing and resource adequacy, and medical care cooperation are significant predictors of burnout among nurses ( Nurse burnout in southwest China is mainly moderate to severe and exhibits distinctive characteristics. It is recommended to implement personalized interventions tailored to the specific characteristics of nurses' professional burnout to alleviate the situation. Particular attention should be given to nurses with fewer than five years of experience by providing enhanced job support and psychological assistance to help them navigate critical periods of professional burnout. These measures aim to safeguard nurses' physical and mental health, improving the overall quality of nursing, and promoting the healthy development of global medical care. Show less
Residual cardiovascular risk persists in statin-treated patients with coronary artery disease (CAD), even when low-density lipoprotein cholesterol (LDL-C) targets are met. Excess apolipoprotein B (apo Show more
Residual cardiovascular risk persists in statin-treated patients with coronary artery disease (CAD), even when low-density lipoprotein cholesterol (LDL-C) targets are met. Excess apolipoprotein B (apoB), defined as measured apoB minus LDL-C-predicted apoB, may capture atherogenic particle burden beyond LDL-C, but its prognostic value for long-term mortality in secondary prevention remains uncertain. We conducted a pooled analysis of two nationwide Chinese cohorts (CIN-II and RED-CARPET) comprising 68,616 statin-treated CAD patients. Excess apoB was calculated using an internal reference population (triglycerides ≤ 1.0 mmol/L). Associations with all-cause and cardiovascular mortality were assessed using multivariable Cox models, with adjustment for clinical covariates including nutritional status. External validation was performed in 13,702 participants from the UK Biobank. Over a median follow-up of 5.2 years, 10,835 deaths occurred (5,090 cardiovascular). Each 1-standard deviation (15.4 mg/dL) increase in excess apoB was associated with a 12% higher risk of all-cause mortality (adjusted hazard ratio [aHR] 1.12, 95% CI 1.06-1.18) and a 24% higher risk of cardiovascular mortality (aHR 1.24, 95% CI 1.15-1.34). Patients in the highest excess apoB quartile (≥ 11.5 mg/dL) had significantly worse survival. Notably, these associations persisted consistently across all achieved LDL-C strata (< 2.0 to > 4.0 mmol/L). These findings were robustly confirmed in the external validation cohort. Excess apoB is an independent predictor of long-term mortality in statin-treated CAD patients, even among those with well-controlled LDL-C. Its incorporation into risk assessment could improve prognostic stratification and guide personalized management in secondary prevention. CIN-II: ClinicalTrials.gov, NCT05050877 (Retrospectively registered, 21 September 2021); RED-CARPET: Chinese Clinical Trial Registry, ChiCTR2000039901 (Prospectively registered, 14 November 2020). The UK Biobank study is covered by generic ethical approval from the NHS National Research Ethics Service (Ref: 99231). Show less
Prednisone is used clinically during pregnancy. This study investigates whether prenatal prednisone exposure (PPE) affects susceptibility to high-fat diet (HFD)-induced metabolic dysfunction-associate Show more
Prednisone is used clinically during pregnancy. This study investigates whether prenatal prednisone exposure (PPE) affects susceptibility to high-fat diet (HFD)-induced metabolic dysfunction-associated fatty liver disease (MAFLD) in adult offspring and explores underlying mechanisms. Pregnant Kunming mice were administered prednisone (0.25 or 1 mg/kg; PPE-L or PPE-H) or vehicle control (5% carboxymethyl cellulose; Ctrl) by daily gavage from gestational days 0-18. Offspring were assessed metabolically, histologically, and via RNA-Seq. Primary hepatocytes were treated with fatty acids with or without the epigenetic inhibitors to evaluate Nr1h3 expression and lipid deposition. Offspring body weight was similar in PPE-L vs Ctrl, but was reduced in PPE-H group followed by delayed growth. After 6-week HFD feeding, PPE-L offspring showed mild metabolic issues, while PPE-H males exhibited significant glucose/lipid disorders and hepatic steatosis compared to controls. RNA-Seq showed upregulation of hepatic lipid pathways in the PPE-H male offspring when challenged by HFD. The liver X receptor alpha (LXRα)-sterol regulatory element-binding protein 1 (SREBP1) signaling pathway and the expression of genes involved in de novo fatty acid synthesis were increased in PPE-H offspring under HFD. A485 significantly downregulated the expression of Nr1h3 in primary hepatocytes from male PPE-H offspring and alleviated lipid deposition in these hepatocytes treated with fatty acids. The H3K27ac level in the Nr1h3 promoter in the PPE-H offspring's liver was significantly upregulated. PPE-L impairs offspring glucose/lipid homeostasis, whereas PPE-H increase MAFLD risk of the offspring by epigenetic programming of the hepatic LXRα-SREBP1 pathway, especially in the males. Show less
Ye Yang, Anne P Beigneux, Troy L Lowe+21 more · 2026 · Proceedings of the National Academy of Sciences of the United States of America · National Academy of Sciences · added 2026-04-24
Apolipoprotein AV (APOA5) regulates intravascular triglyceride metabolism by binding to the angiopoietin-like protein 3/8 complex (ANGPTL3/8) and suppressing its ability to unfold the native conformat Show more
Apolipoprotein AV (APOA5) regulates intravascular triglyceride metabolism by binding to the angiopoietin-like protein 3/8 complex (ANGPTL3/8) and suppressing its ability to unfold the native conformation of lipoprotein lipase (LPL). LPL unfolding results in loss of catalytic activity and the detachment of LPL from the surface of cells. An Show less
Alcohol use disorder (AUD) is a chronic condition marked by compulsive drinking and withdrawal-related negative affect. Histamine (HA) signaling, particularly via the histamine H3 receptor (H3R), may Show more
Alcohol use disorder (AUD) is a chronic condition marked by compulsive drinking and withdrawal-related negative affect. Histamine (HA) signaling, particularly via the histamine H3 receptor (H3R), may modulate alcohol-related behaviors. We investigated the effects of pitolisant, an FDA-approved H3R antagonist, on ethanol (EtOH)-related behaviors in mice. Adult male C57BL/6J mice underwent acute or chronic (2 or > 8 weeks) intermittent alcohol exposure. Pitolisant pretreatment was administered, and then pharmacological behavior, histologic, and molecular assays were conducted. Pitolisant administration reduced acute EtOH-induced locomotor activation, conditioned place preference, and sedative effects, and also curtailed EtOH intake. It alleviated anxiety and depression-like behavior during 24-h withdrawal (Post-EtOH). Mechanistically, the Post-EtOH condition was featured by complicated brain cFos expression mapping, including elevated cFos, [HA] and [glutamine]/[glutamate] ratio in the lateral habenula (LHb). However, systemic pitolisant treatment significantly increased [norepinephrine]/[normetanephrine] ratio, and restored the diminished phosphorylated CREB and BDNF levels in the LHb. Intra-LHb H2R antagonist cimetidine infusion partly blocked the pitolisant therapeutic effect on alcohol-related behavior. These findings highlight the HAergic system as a critical regulator of alcohol-related behaviors. The LHb HA signaling and norepinephrine neurotransmission might underlie pitolisant's potential novel therapeutic strategy for AUD. Show less
Alzheimer's disease (AD), the most prevalent form of dementia, is characterized as a slowly progressing neurodegenerative disease marked by senile plaques and neurofibrillary tangles due to the buildu Show more
Alzheimer's disease (AD), the most prevalent form of dementia, is characterized as a slowly progressing neurodegenerative disease marked by senile plaques and neurofibrillary tangles due to the buildup of amyloid-beta peptide (Aβ) and phosphorylated tau in the brain. It is reported that arctigenin (ATG) reduces the level of the enzyme 1 that cleaves β-site amyloid precursor protein and increases Aβ clearance by enhancing autophagy. Compound ARC-18 is a derivative of ATG. The main objective of this study is to investigate whether ARC-18 could improve cognitive function and disease progression by promoting autophagy in Alzheimer-like animal models. Three-month-old 5 × FAD mice were orally treated with the drug for three consecutive months. Water maze and novel object recognition were used to assess cognitive abilities of 5 × FAD mice. In the hippocampus of the mice' brain, APP processing-related proteins (sAPP Show less
The Hedgehog (Hh) signaling pathway is a key regulator of adipogenesis and lipid metabolism. However, the specific role of its receptor, Patched2 (Ptch2), in these processes remains unclear. Here, usi Show more
The Hedgehog (Hh) signaling pathway is a key regulator of adipogenesis and lipid metabolism. However, the specific role of its receptor, Patched2 (Ptch2), in these processes remains unclear. Here, using a CRISPR/Cas9-mediated Show less
The integrated stress response (ISR) has been implicated in cognitive decline associated with ageing and neurodegenerative diseases. Pharmacological inhibition of the ISR using the small-molecule ISRI Show more
The integrated stress response (ISR) has been implicated in cognitive decline associated with ageing and neurodegenerative diseases. Pharmacological inhibition of the ISR using the small-molecule ISRIB has demonstrated promising neuroprotective effects in several preclinical models. However, its potential therapeutic value in vascular cognitive impairment (VCI) remains largely unexplored. Here, we established a modified permanent bilateral carotid occlusion (2-VO) rat model of VCI and investigated the therapeutic potential of the ISRIB via microinjection in hippocampal dentate gyrus (DG). VCI rats exhibited elevated expression of vascular endothelial growth factor (VEGF), cluster of differentiation 34 (CD34), ionized calcium-binding adapter molecule 1 (Iba1), interleukin-1 beta (IL-1β), and interleukin-6 (IL-6), indicating successful establishment of the model. Behavioral assessments revealed that VCI rats exhibited impaired spatial, working, and recognition memory. Bioinformatic analysis highlighted ISR pathway activation in VCI. Furthermore, elevated phosphorylated eukaryotic initiation factor 2 alpha (p-eIF2α) and activating transcription factor 4 (ATF4) protein levels in the DG confirmed ISR activation in the DG of VCI rats. VCI also reduced neuronal integrity, as evidenced by decreased Nissl body density. ISRIB treatment significantly improved cognitive performance, suppressed ATF4 expression, enhanced puromycin-labeled protein synthesis, and restored phosphorylated cAMP response element-binding protein (p-CREB) and brain-derived neurotrophic factor (BDNF) signaling. Notably, ISRIB increased c-fos activation and upregulated synaptophysin and postsynaptic density protein 95 (PSD95) expression in the DG of VCI rats, indicating enhanced neuronal activity and synaptic function. Our results indicate that ISR activation contributes to hippocampal-dependent memory impairment in VCI. ISRIB effectively restores synaptic function and cognition, underscoring its therapeutic value and translational potential in treating VCI. Show less
Dietary fat absorption is among the most energy-demanding processes of nutrient uptake. Fatty acid activation, triglyceride synthesis, and the trafficking of chylomicrons through the secretory pathway Show more
Dietary fat absorption is among the most energy-demanding processes of nutrient uptake. Fatty acid activation, triglyceride synthesis, and the trafficking of chylomicrons through the secretory pathway - all require ATP. How enterocytes accommodate the surge in ATP consumption following fat uptake is unclear. We show that the purine biosynthesis/salvage pathway supplies necessary ATP and that Ankyrin Repeat Domain 9 (ANKRD9) couples ATP synthesis and lipoprotein trafficking. Ankrd9 regulates enzymes within the purine biosynthesis pathway to increase ATP synthesis and facilitate Golgi dynamics. Intracellular localization of ANKRD9 is lipid and ATP-dependent. Inactivation of Ankrd9 in mice reduces intestinal ATP despite intact mitochondrial and glycolytic function, alters Golgi morphology, delays ApoB/chylomicron trafficking, and causes lipid accumulation in enterocytes, along with a lean body phenotype. Taken together, the results reveal a previously unrecognized mechanism that regulates lipid absorption in enterocytes and identify ANKRD9 as a central component of this mechanism. Show less
Hypertrophic scar (HS) is a fibroproliferative disorder characterized by fibroblast hyperactivation and aberrant extracellular matrix deposition. This study identifies macrophage-derived lactate as a Show more
Hypertrophic scar (HS) is a fibroproliferative disorder characterized by fibroblast hyperactivation and aberrant extracellular matrix deposition. This study identifies macrophage-derived lactate as a key mediator of fibroblast phenotypic remodeling via monocarboxylate transporter 1 (MCT1)-mediated histone H3 lysine 23 lactylation (H3K23la) in HS. Elevated lactate levels and MCT1 expression were observed in HS tissues, with macrophages in stiff mechanical microenvironments identified as the primary lactate source. Lactate influx through MCT1 upregulated H3K23la, thereby promoting transcriptional activation of profibrotic genes HEY2 and COL11A1. Mechanistically, HEY2 activated YAP1/SMAD2 signaling, while COL11A1 stabilized MCT1 to enhance lactate transport, forming a positive loop that amplified fibrosis. Fibroblast-specific Mct1 deletion or pharmacological inhibition of Mct1 in male mice reduced collagen deposition, accelerated wound healing, and attenuated scar formation. Our findings redefine the macrophage-fibroblast crosstalk in HS and establish the MCT1-H3K23la-HEY2/COL11A1 axis, particularly its self-reinforcing loop, as a novel therapeutic target. Show less
ObjectiveTo evaluate the effects of a combined psychological and functional exercise intervention on emotion, quality of life, and brain-derived neurotrophic factor (BDNF) levels in patients with Park Show more
ObjectiveTo evaluate the effects of a combined psychological and functional exercise intervention on emotion, quality of life, and brain-derived neurotrophic factor (BDNF) levels in patients with Parkinson's disease (PD).MethodsIn this randomized controlled trial, 172 patients with PD were randomly assigned into 2 groups with 86 patients in each group. The control group received routine care, while the intervention group received a 12-week intervention combining psychological support with functional exercise in addition to routine care. Hamilton Anxiety Scale (HAMA), Hamilton Depression Scale (HAMD), Parkinson's Disease Questionnaire-39 (PDQ-39), Barthel Index, Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS), and serum BDNF levels were assessed before and after the intervention. Adherence rates were also determined for each group. Spearman correlation analysis was used to examine associations between changes in BDNF (ΔBDNF) and changes in HAMA (ΔHAMA) and HAMD (ΔHAMD) scores.ResultsAt the end of the 12-week clinical trial, the intervention group demonstrated significantly lower HAMA, HAMD, PDQ-39, and MDS-UPDRS scores ( Show less
To investigate the causal relationship between inflammatory proteins and Alzheimer's disease (AD) and the mediating role of plasma metabolites therein. Using Mendelian mandomization (MR) methods and p Show more
To investigate the causal relationship between inflammatory proteins and Alzheimer's disease (AD) and the mediating role of plasma metabolites therein. Using Mendelian mandomization (MR) methods and publicly available genome-wide association study (GWAS) data, we selected 91 single nucleotide polymorphisms (SNPs) that were strongly linked to inflammatory proteins without reverse causality with AD as the outcome. A bidirectional two-sample MR analysis was performed. Inflammatory proteins with causal links to AD were identified via inverse variance weighted (IVW) analysis. A mediation MR analysis was then performed using 1400 plasma metabolites to assess their mediating role in this causal pathway. The preliminary bidirectional MR analysis identified 3 inflammatory proteins that had a potential positive causal association with AD without reverse causality: Axin-1, C-X-C motif chemokine ligand 11 (CXCL11), and interleukin-12β (IL-12β). Elevated levels of Axin-1 were positively causally associated with AD risk (OR=1.082, 95% This study reveals how specific inflammatory proteins influence AD risk via plasma metabolites and provides genetic evidence for inflammatory-metabolic interactions in AD to facilitate the identification of potential biomarkers and targets for early detection and intervention of AD. Show less
Glioblastoma (GBM) is a prevalent and aggressive intracranial malignant tumor characterized by high mortality and recurrence rates. Serine proteinase inhibitor A3 (SERPINA3) has been reported to be ov Show more
Glioblastoma (GBM) is a prevalent and aggressive intracranial malignant tumor characterized by high mortality and recurrence rates. Serine proteinase inhibitor A3 (SERPINA3) has been reported to be overexpressed in various cancers; however, its clinical significance and biological role in GBM remain unclear. This study aims to investigate the impact of SERPINA3 on gliomagenesis. SERPINA3 expression in GBM was assessed. U87 cells were transfected, and the effects of SERPINA3 on GBM cells were investigated. The effect of SERPINA3 on GBM in vivo was investigated. The relationship between apolipoprotein E (APOE) and SERPINA3 was analyzed. The effect of APOE on ferroptosis-related markers glutathione, malondialdehyde, and Fe2 + was detected. U87 cells overexpressing SERPINA3 were treated, and the effect of SERPINA3 on the PI3K/AKT/FOXO1 pathway was investigated. SERPINA3 was highly expressed in GBM, and overexpressing SERPINA3 promoted the proliferation, migration, and invasion of GBM cells, enhanced the uptake of glucose and release of lactic acid from GBM cells, and inhibited apoptosis. Overexpressing SERPINA3 upregulated APOE. High expression of APOE inhibited ferroptosis in GBM cells, thereby promoting tumor progression. APOE was significantly upregulated in SERPINA3-overexpressing U87 cells and tumor tissues from xenografted mice. When overexpressing SERPINA3, PI3K/AKT/FOXO1 pathway-related proteins were increased in GBM cells. Inhibiting PI3K/AKT/FOXO1 expression reduced proliferation, migration, and invasion of GBM cells. SERPINA3 promotes GBM progression by promoting APOE expression and modulating the PI3K/AKT/FOXO1 pathway. Show less
no PDFDOI: 10.4103/neurol-india.Neurol-India-D-24-00649