The deer antler is a fully regenerable and the fastest-growing osseous organ. Circular RNA (circRNA), a novel member of the non-coding RNA family, has significant research potential and crucial roles Show more
The deer antler is a fully regenerable and the fastest-growing osseous organ. Circular RNA (circRNA), a novel member of the non-coding RNA family, has significant research potential and crucial roles in biological processes. This study aims to explore the impact and mechanisms of circRNA505 on antler chondrocytes. Functional experiments demonstrated that m5C-modified circRNA505 inhibits antler chondrocyte proliferation, enhances osteogenic differentiation, and facilitates cellular glycolysis. Mechanistically, dual luciferase and AGO2-RIP assays revealed a direct binding relationship between circRNA505, miR-127, and p53. Rescue assays further showed that circRNA505 affects cell proliferation and differentiation through the miR-127/p53 axis. Meanwhile, RNA Antisense Purification (RAP) screening and analysis of related proteins binding to circRNA505 demonstrated that circRNA505 binds to LDHA and increases the level of LDHA phosphorylation through FGFR1 to promote cellular glycolysis by FISH-IF, RIP, and Western blot experiments. Additionally, Me-RIP assays confirmed the m5C methylation modification of circRNA505. NSUN2 mediates the m5C modification of circRNA505, affecting its stability, while the m5C reader ALYREF promotes the nuclear export of circRNA505 in an ALYREF-dependent manner. This study provides new insights into the regulatory mechanisms underlying rapid antler development. Show less
Dual-specificity protein phosphatase 6 (DUSP6), also known as mitogenactivated protein kinase phosphatase 3 (MKP-3), was considered as a functional candidate gene for white fat accumulation in mice. H Show more
Dual-specificity protein phosphatase 6 (DUSP6), also known as mitogenactivated protein kinase phosphatase 3 (MKP-3), was considered as a functional candidate gene for white fat accumulation in mice. However, the physiological function of the DUSP6 gene on white adipocyte adipogenesis in farm animals remains unknown. In this study, we aimed to clarify the effect of DUSP6 on porcine subcutaneous preadipocyte proliferation and differentiation. We first make clear that the patterns of DUSP6 expression is associated with fat contents in porcine fat deposition related tissues. Porcine subcutaneous preadipocytes were isolated and induced to differentiation. Small interfering RNAs were applied to deplete DUSP6. MTT assay, CCK-8 analysis, Oil Red O staining, triglyceride determination and reverse transcription quantitative polymerase chain reaction were applied to study the regulatory role of DUSP6 during adipocyte adipogenesis in pigs. We found that the expression levels of DUSP6 were significantly higher in backfat and longissimus dorsi tissues from fat-type pigs than in those from lean-type pigs. Consistently, the significantly induced expression of DUSP6 was also observed in differentiated adipocytes. In addition, knockdown of DUSP6 greatly inhibited preadipocytes proliferation, through the decreased cell viability and downregulated mRNA expressions of cell proliferation-associated genes, including PCNA, CDK1, CDK2. Furthermore, knockdown of DUSP6 significantly inhibited preadipocytes differentiation, as evidenced by markedly reduced lipid droplet formation, attenuated triglyceride accumulation and downregulated expression levels of adipogenic transcription masters (PPARĪ³, C/EBPĪ², FASN and FABP4) in DUSP6 knockdown cells. Our results demonstrate that DUSP6 is required for white adipocyte adipogenesis in pigs. Show less
Dominant follicular development and atresia are governed by the proliferation of granulosa cells (GCs), a process influenced by the delicate balance between apoptosis and autophagy. Oxidative stress, Show more
Dominant follicular development and atresia are governed by the proliferation of granulosa cells (GCs), a process influenced by the delicate balance between apoptosis and autophagy. Oxidative stress, a pivotal catalyst of GCs apoptosis, modulates gene expression through epigenetic mechanisms, including chromatin remodeling. Nevertheless, the regulatory mechanisms underpinning GCs functionality in relation to prolificacy remain inadequately elucidated. In this study, we discovered that the chromatin accessibility of nuclear receptor subfamily 1 group D member 1 (NR1D1) was markedly enhanced in dominant follicular GCs from low-prolificacy sheep, as evidenced by Assay for Transposase-Accessible Chromatin with high-throughput sequencing (ATAC-seq), which correlated with elevated NR1D1 transcript levels. Remarkably, NR1D1 emerged as a novel regulator of follicular development, exhibiting heightened expression in dominant follicles. The overexpression of NR1D1 induced cell cycle arrest, autophagy activation, and mitochondrial dysfunction via the AMPK pathway, while its knockdown fostered GCs survival and functionality. Furthermore, NR1D1 inhibits the transcription of HSD17B12, thereby contributing to oxidative stress (ROS)-induced apoptosis, as demonstrated by CUT&Tag-qPCR and dual luciferase assays. The downregulation of HSD17B12 partially alleviated the effects of NR1D1 knockdown on GCs functionality. These findings indicate that NR1D1 orchestrates GCs proliferation and apoptosis through the suppression of HSD17B12 and the activation of the AMPK pathway, establishing NR1D1 as a novel transcription factor implicated in follicular development and ovarian function, with significant implications for prolificacy. Show less
Currently, understanding of the nonlinear relationship between age and hepatocellular carcinoma (HCC) prognosis is insufficient. Thus, this study aimed to analyze the relationship between age at HCC d Show more
Currently, understanding of the nonlinear relationship between age and hepatocellular carcinoma (HCC) prognosis is insufficient. Thus, this study aimed to analyze the relationship between age at HCC diagnosis and overall survival (OS) and identify possible influencing mechanisms. Clinical data from the TCGA public database were analyzed. Restricted cubic spline and segmented logistic regression were employed to explore the nonlinear relationship between age at diagnosis and mortality risk following hepatectomy. Furthermore, bioinformatics methods were employed to understand the possible mechanisms of this nonlinear relationship at the genetic level. The results indicated a nonlinear relationship between age at diagnosis and OS, with the age of 60 years identified as a critical point. Segmented regression showed that age ā„60 years is an unfavorable prognostic factor. The "DNA mismatch repair" pathway was considerably enriched in patients aged <60 years. However, the gene mutation rate of "APOB," "MUC16," "ALB," and "PCLO" and the median tumor mutation burden were relatively more evident in patients aged ā„60 years. MGEA12 was more highly expressed in tumor tissues than in normal ones, particularly in patients aged ā„60 years. The survival rate of the high-expression group was lower than that of the low-expression group. At the mRNA level, the MGEA12 expression in Huh-7 and SUN449 was higher than that in the HSC-LX2 cell line. A nonlinear relationship was found between age at HCC diagnosis and OS, with the age of 60 years being the critical point. MGEA12 may affect the prognosis of elderly people. Show less
As one of the most common malignant tumors in men, prostate cancer (PCa) still lacks convenient, non-invasive and highly specific diagnostic markers. The advantages of Extracellular vesicle (EV) DNA i Show more
As one of the most common malignant tumors in men, prostate cancer (PCa) still lacks convenient, non-invasive and highly specific diagnostic markers. The advantages of Extracellular vesicle (EV) DNA in tumor diagnosis have gradually attracted the attention of researchers. However, methylation detection, which is more advantageous than mutation detection in tumor diagnosis, has not been widely practiced in EV DNA, and its value in PCa diagnosis also remains underexplored. This study aims to establish and optimize an EV DNA methylation detection system and evaluate its diagnostic and classification potential for PCa. We characterized EV DNA biological properties, optimized pretreatment strategies, validated its correlation with genomic DNA methylation, and explored urine EV DNA methylation targets in 86 benign prostatic hyperplasia (BPH) and 109 PCa patients across three cohorts (screening: 30 BPH/33 PCa; training: 27 BPH/30 PCa; validation: 29 BPH/46 PCa). Heterogeneous biological characteristics were observed among DNA from different subtypes of EV, but methylation profiles remained consistent across subtypes and post-DNase I treatment. EV DNA accurately reflected the methylation state of source cell genomic DNA. By combining our screening results with data from the TCGA database and previously reported, we developed a panel consisting of 667 PCa-specific methylation targets for detection. Among these, six methylation sites (MACF1ćLINC01359-1ćLINC01359-2ćADCY4ćGAPLINCćC19orf25) demonstrated high diagnostic value for PCa, enabling construction of PCa and aggressive PCa differential diagnosis model with AUCs up to 0.74 and 0.91 respectively. The diagnostic value of these six markers was further confirmed using methylight PCR in the validation cohort which also displayed promising performance as a tool for diagnosing PCa. This study highlights the potential of urine EV DNA methylation as a novel diagnostic marker for PCa and lays a foundation for future EV DNA research. Show less
Macropinocytosis is a nonselective form of endocytosis that allows cancer cells to largely take up the extracellular fluid and its contents, including nutrients, growth factors, etc. We first elaborat Show more
Macropinocytosis is a nonselective form of endocytosis that allows cancer cells to largely take up the extracellular fluid and its contents, including nutrients, growth factors, etc. We first elaborate meticulously on the process of macropinocytosis. Only by thoroughly understanding this entire process can we devise targeted strategies against it. We then focus on the central role of the MTOR (mechanistic target of rapamycin kinase) complex 1 (MTORC1) in regulating macropinocytosis, highlighting its significance as a key signaling hub where various pathways converge to control nutrient uptake and metabolic processes. The article covers a comprehensive analysis of the literature on the molecular mechanisms governing macropinocytosis, including the initiation, maturation, and recycling of macropinosomes, with an emphasis on how these processes are hijacked by cancer cells to sustain their growth. Key discussions include the potential therapeutic strategies targeting macropinocytosis, such as enhancing drug delivery via this pathway, inhibiting macropinocytosis to starve cancer cells, blocking the degradation and recycling of macropinosomes, and inducing methuosis - a form of cell death triggered by excessive macropinocytosis. Targeting macropinocytosis represents a novel and innovative approach that could significantly advance the treatment of cancers that rely on this pathway for survival. Through continuous research and innovation, we look forward to developing more effective and safer anti-cancer therapies that will bring new hope to patients. Show less
Altered levels of human plasma metabolites have been implicated in the etiology of bipolar disorder (BD). However, the causality between metabolites and the disease was not well described. We performe Show more
Altered levels of human plasma metabolites have been implicated in the etiology of bipolar disorder (BD). However, the causality between metabolites and the disease was not well described. We performed a bidirectional metabolome-wide Mendelian randomization (MR) analysis to evaluate the potential causal relationships between 871 plasma metabolites and BD. We used DrugBank and ChEMBL to evaluate whether related metabolites are potential therapeutic targets. Finally, Bayesian colocalization analysis was performed to identify shared genomic loci BD and identified metabolites. Our MR results showed that six metabolites were significantly associated with a reduced risk of BD, including arachidonate (20:4n6) (OR: 0.90, 95% CI: 0.84-0.95) and sphingomyelin (d18:2/24:1, d18:1/24:2) (OR: 0.92, 95% CI: 0.87-0.96), while five metabolites were significantly associated with an increased risk of BD, including 1-palmitoyl-2-linoleoyl-GPE (16:0/18:2) (OR: 1.09, 95% CI: 1.05-1.13). However, our reverse MR analysis showed that BD was not associated with the levels of any metabolite. Additionally, the leave-one-out analysis revealed SNPs within chromosome 11 loci harboring MYRF, FADS1, and FADS2 as ones with the potential to influence partial causal effects. Druggability evaluation showed that 10 of the BD-related metabolites, such as sphingomyelin and cytidine, have been targeted by pharmacologic intervention. Colocalization analysis highlighted one colocalized region (chromosome 11q12) shared by 11 metabolites and BD and pointed to some genes as possible players, including FADS1, FADS2, FADS3, and SYT7. Our study supported a causal role of plasma metabolites in the susceptibility to BD, and the identified metabolites may provide a new avenue for the prevention and treatment of BD. Show less
No studies have explored the genetic differences between the Chinese and other ethnic hypertrophic cardiomyopathy (HCM) populations. This cross-sectional study included Chinese patients ( Chinese HCM Show more
No studies have explored the genetic differences between the Chinese and other ethnic hypertrophic cardiomyopathy (HCM) populations. This cross-sectional study included Chinese patients ( Chinese HCM patients have a higher proportion of rare variants (52.8% vs 13.6%, Our findings suggested that patients of Chinese ancestry with HCM have a higher proportion of rare variants but are less likely to be classified as P/LP variants in HCM genes than those of European origin. The variants of c.3624del in Show less
Individual differences in immune responses to African swine fever virus (ASFV), whether induced by vaccination or natural infection, may be linked to genetic variation in the genes involved in antigen Show more
Individual differences in immune responses to African swine fever virus (ASFV), whether induced by vaccination or natural infection, may be linked to genetic variation in the genes involved in antigen presentation. A total of nine pigs from the 112-population were selected for RNA-seq analysis. To pinpoint key transcription factors (TFs) regulating gene expression in the lymph nodes, weighted Kendall's Tau rank correlation analysis was performed to link the TF binding potential with the extent of differential expression of target genes. CD8 These mutations may disrupt TFs binding to the ELK4 promoter, potentially reducing ELK4 expression and impairing antigen processing and presentation. Show less
Evidence has linked self-reported sedentary behaviors with dementia and cognitive impairment; however, the underlying mechanisms remain poorly understood. We investigated the associations of accelerom Show more
Evidence has linked self-reported sedentary behaviors with dementia and cognitive impairment; however, the underlying mechanisms remain poorly understood. We investigated the associations of accelerometer-measured sedentary behavior patterns with gray matter atrophy patterns in rural-dwelling older adults, while taking into account the manner in which sedentary time is accrued (in short or long bouts). This community-based study involved 911 dementia-free older adults (ageāā„ā60 years, 59% women) who participated in both ActiGraph and brain MRI substudies within MIND-China (2018-2020). Sedentary behavior parameters (total sedentary time, mean sedentary bout duration, and sedentary breaks) were recorded with accelerometers. Regional gray matter volumes (GMV) were measured using voxel-based morphometry (VBM) methods. Data were analyzed using the general linear regression models, restricted cubic spline curves, and VBM analysis. There was an inverted U-shaped association between daily sedentary time and GMV in temporal, cingulate, and medial temporal cortex, while longer mean sedentary bout duration was linearly related to decreased GMV in total, frontal, temporal, insula, cingulate, and medial temporal cortex. Greater daily time spent in light or moderate-to-vigorous physical activity (LPA and MVPA) was correlated with larger insula GMV. The VBM analysis suggested that prolonged daily total sedentary time and mean sedentary bout duration were significantly associated with smaller GMV in extensive brain regions, especially in thalamus and insula. In conclusion, gray matter atrophy associated with sedentary behavior in older adults is characterized by reduced GMV in global, frontal, temporal, medial temporal, and cingulate cortex, especially in the insula and thalamus regions. Show less
William Stewart, Bin Hu, Fengqiao Li+6 more Ā· 2025 Ā· Journal of controlled release : official journal of the Controlled Release Society Ā· Elsevier Ā· added 2026-04-24
Obesity, a widespread global health issue affecting millions, is characterized by excess fat deposition and metabolic dysfunction, significantly elevating the risk of comorbidities like type 2 diabete Show more
Obesity, a widespread global health issue affecting millions, is characterized by excess fat deposition and metabolic dysfunction, significantly elevating the risk of comorbidities like type 2 diabetes, cardiovascular disease, and certain cancers, all of which contribute to rising rates of preventable morbidity and mortality. Current approaches to obesity, including lifestyle modifications, and pharmacotherapy, often face limitations such as poor long-term adherence, side effects, and insufficient targeting of the complex, multifactorial pathways underlying the disease. Herein we report a dual, RNA-mediated combinatorial approach using targeting lipid nanoparticles (LNP) for the treatment of obesity. LNPs were co-encapsulated with mRNA encoding Interleukin-27 (mIL-27) to coactivate PGC-1Ī±, PPARĪ±, and UCP-1, thereby promoting adipocyte differentiation and enhancing adaptive thermogenesis within adipocytes, and siRNA targeting Dipeptidyl peptidase-4 (siDPP-4) to silence the primary inhibitory enzyme of GLP-1, and GIP within the incretin system, effectively restoring glucose homeostasis. Following post translational silencing of DPP-4 and upregulation of IL-27 in a diet-induced obesity (DIO) mice model, increased expression of thermogenic biomarkers PGC-1Ī±, PPARĪ±, and UCP-1 was observed at the molecular, protein, and tissue level, and insulin sensitivity was restored. Importantly, this gene modulation led to a 21.1Ā % reduction of bodyweight after treatment in the DIO model. These findings demonstrate for the first time a dual RNA-mediated combinatorial approach, leveraging liver targeting LNP delivery with synergistic effects from incretin system regulation and induction of adipocyte differentiation and thermogenesis after codelivery of siDPP-4 and mIL-27. This innovative strategy provides a promising alternate framework for addressing obesity and its associated metabolic dysfunction. Show less
Pulmonary Hypertension (PH) is a significant contributor to cardiac mortality in Dilated Cardiomyopathy (DCM) patients. Inflammatory processes and oxidative stress play pivotal roles in the advancemen Show more
Pulmonary Hypertension (PH) is a significant contributor to cardiac mortality in Dilated Cardiomyopathy (DCM) patients. Inflammatory processes and oxidative stress play pivotal roles in the advancement of Pulmonary Hypertension (PH). The Monocyte-to-High-- Density-Lipoprotein Cholesterol Ratio (MHR), a newly identified biomarker indicative of inflammatory and oxidative stress, has not been extensively researched in the context of pulmonary hypertension, especially within the scope of dilated cardiomyopathy. Given the reason mentioned above, our research explores the correlation between the MHR and the severity of PH in patients suffering from DCM. In this study, we conducted a retrospective review of medical data from 107 individuals diagnosed with non-ischemic DCM, evaluating their clinical profiles, biochemical indicators, MHR, and echocardiographic parameters. We analyzed the relationships between Pulmonary Arterial Systolic Pressure (PASP) and the Ejection Fraction of the Left Ventricle (LVEF). Utilizing logistic regression analysis, we determined the predictors of PH. Findings indicated that the DCM-PH group exhibited a significantly larger male population and elevated New York Heart Association (NYHA) classification scores (both with p-values <0.001 and 0.01, respectively) compared to the DCM-only group. A positive association was observed between the PASP and parameters, such as the Dimensions of the Left Atrium (LAD) and Left Ventricle in Systole (LVDs), Monocyte (M) levels, Direct Bilirubin (DB), and MHR. Conversely, an inverse relationship was noted with serum lipid profiles, including Total Cholesterol (TC), HDL Cholesterol (HDL-c), and apolipoprotein A1. LVEF demonstrated positive linkage with the same lipid profiles and the Left Ventricular Posterior Wall Thickness (LVPWT) yet showed negative correlations with the NYHA classification, Red Blood Cell Distribution Width Standard Deviation (RDW-SD), Total Bilirubin (TB), Direct Bilirubin (DB), and dimensions of the left ventricle in diastole and systole, as well as MHR. Through logistic regression analysis, several factors were recognized as significant predictors for the severity of PH within the DCM cohort, with weight (OR1.20, CI 1.022-1.409, p=0.026), RDW-SD (OR1.988, CI 1.015-3.895, p=0.045), LVPW (OR3.577, CI 1.307-9.792, p=0.013), LVDd (OR1.333, CI 1.058-1.680, p=0.015), MHR (OR3.575, CI 1.502-8.506, p=0.032), and TB (OR1.416, CI 1.014-1.979, p=0.041) showing positive associations, while apoB (OR0.001 CI0.001-0.824, p=0.045) exhibiting negative associations, all with p-values <0.05. Higher MHR and LVD correlate with increased PASP and reduced LVEF in DCMPH patients. MHR and LVPW are independent predictors of PH severity, indicating their potential as novel severity markers in DCM-related PH. Show less
Halide perovskite nanomaterials have emerged as a transformative platform for generating and manipulating polarized luminescence, offering unprecedented opportunities for next-generation optoelectroni Show more
Halide perovskite nanomaterials have emerged as a transformative platform for generating and manipulating polarized luminescence, offering unprecedented opportunities for next-generation optoelectronic technologies. This review comprehensively examines recent advances in engineering both linearly polarized luminescence (LPL) and circularly polarized luminescence (CPL) from perovskite nanostructures, focusing on structural design principles, chirality transfer mechanisms, and performance optimization strategies. Methods are systematically analyzed to achieve polarized emission, including anisotropic nanocrystal growth, chiral ligand functionalization, and liquid crystal-mediated alignment, while highlighting critical optical factors such as dissymmetry factors and photoluminescence quantum yield. Key challenges in enhancing the precision control over perovskite nanostructures, room-temperature CPL efficiency, and scalable assembly are discussed, with a forward-looking perspective on the integration of artificial intelligence (AI) to accelerate progress in the development of perovskite nanomaterials with customized polarized luminescence. By bridging fundamental insights with technological applications, this review outlines a roadmap for developing perovskite-based polarized light sources that combine high performance, stability, and manufacturability, which are key enablers for the future of quantum photonics, ultra-secure communication, and intelligent optical systems. Show less
Heart failure is a complex trait, influenced by environmental and genetic factors, affecting over 30 million individuals worldwide. Here we report common-variant and rare-variant association studies o Show more
Heart failure is a complex trait, influenced by environmental and genetic factors, affecting over 30 million individuals worldwide. Here we report common-variant and rare-variant association studies of all-cause heart failure and examine how different classes of genetic variation impact its heritability. We identify 176 common-variant risk loci at genome-wide significance in 2,358,556 individuals and cluster these signals into five broad modules based on pleiotropic associations with anthropomorphic traits/obesity, blood pressure/renal function, atherosclerosis/lipids, immune activity and arrhythmias. In parallel, we uncover exome-wide significant associations for heart failure and rare predicted loss-of-function variants in TTN, MYBPC3, FLNC and BAG3 using exome sequencing of 376,334 individuals. We find that total burden heritability of rare coding variants is highly concentrated in a small set of Mendelian cardiomyopathy genes, while common-variant heritability is diffusely spread throughout the genome. Finally, we show that common-variant background modifies heart failure risk among carriers of rare pathogenic truncating variants in TTN. Together, these findings discern genetic links between dysregulated metabolism and heart failure and highlight a polygenic component to heart failure not captured by current clinical genetic testing. Show less
While previous genome-wide association studies (GWAS) identified multiple risk loci for suicide ideation (SI) and suicide attempt (SA), there is still a limited understanding of the genetic predisposi Show more
While previous genome-wide association studies (GWAS) identified multiple risk loci for suicide ideation (SI) and suicide attempt (SA), there is still a limited understanding of the genetic predisposition underlying suicidal behaviors in diverse populations. This study aimed to conduct a large-scale investigation of the suicidality spectrum (SP) to generate new insights into its biology and epidemiology. Leveraging ancestrally diverse participants (SI N This study provides convergent genetic evidence for both shared and phenotype-specific components of suicidal behaviors and delineates their associated factors spanning from proximal clinical and behavioral traits to more distal social determinants. These findings refine our understanding of the etiology of suicidal behaviors and may inform targeted strategies for suicide prevention in both clinical and public health settings. Show less
Stroke is a leading cause of mortality and disability globally, with post-stroke depression and post-stroke anxiety being common and significant complications that hinder recovery and adversely affect Show more
Stroke is a leading cause of mortality and disability globally, with post-stroke depression and post-stroke anxiety being common and significant complications that hinder recovery and adversely affect quality of life. Although these conditions frequently co-occur, their heterogeneity remains poorly understood. This study integrates the Health Ecology Model (HEM) and employs Latent Profile Analysis (LPA) to identify distinct psychological profiles of depression and anxiety among patients with acute ischemic stroke (AIS), as well as to investigate their multilevel determinants. Patients with AIS from a tertiary hospital in Guangdong Province, China, from January to November 2024 were included. Within one week of stroke onset, the data of sociodemographic, clinical characteristics, swallowing function, stroke severity, activities of daily living, resilience and social support were collected according to the HEM guidelines. The Patient Health Questionnaire-9 and the Generalized Anxiety Disorder-7 were used to assess the depression and anxiety symptoms of the patients three months after stroke onset. LPA was employed to identify distinct psychological profiles, and variables with a A total of 551 patients with AIS were included in the study, 49 were lost to follow-up or withdrew, resulting in a final analytic sample of 502 participants (91.11%). Three distinct psychological profiles were identified: no depression-anxiety (67.93%), high-risk depression-anxiety (21.12%) and major depression-anxiety (10.95%). In the multivariate analysis, the results indicated that occupation (OR = 0.61, 95% CI [0.40-0.93]), National Institutes of Health Stroke Scale (NIHSS, OR = 1.60, 95% CI [1.06-2.42]), Barthel Index (BI, OR = 1.67, 95% CI [1.27-2.19]) and hypertension (OR = 2.37, 95% CI [1.29-4.35]) were independent predictors of the high-risk depression-anxiety profile, while NIHSS (OR = 2.33, 95% CI [1.42-3.85]), BI (OR = 2.65, 95% CI [1.62-4.35]) and resilience (OR = 0.92, 95% CI [0.87-0.98]) were significantly associated with the major depression-anxiety profile. This study reveals significant heterogeneity in psychological distress among AIS survivors. Key predictors of post-stroke emotional comorbidity include occupation, hypertension, stroke severity, activities of daily living and low resilience. Early identification of high-risk individuals can significantly enhance screening and intervention strategies, particularly by focusing on symptoms such as anhedonia and nervousness. Future research should focus on longitudinal designs and objective biomarkers to better understand the mechanisms behind post-stroke emotional comorbidity. Show less
Breast cancer (BRCA) is a prevalent malignant tumor among women, and the use of anesthetic drugs during surgical resection may influence tumor biology and patient prognosis. This study aimed to identi Show more
Breast cancer (BRCA) is a prevalent malignant tumor among women, and the use of anesthetic drugs during surgical resection may influence tumor biology and patient prognosis. This study aimed to identify prognostic biomarkers associated with dexmedetomidine and dezocine (DD) in BRCA patients. Through Mendelian Randomization analysis, we screened four DD targets that had a causal relationship with BRCA. Subsequently, utilizing TCGA-BRCA data, univariate and Lasso Cox analyses revealed two significant prognostic biomarkers (NR1H3 and ADRB1) associated with BRCA patient prognosis, leading to the successful construction and validation of a prognostic risk model. Kaplan-Meier survival curves indicated that patients with higher NR1H3 and ADRB1 expression had longer overall survival (OS). Immunoinfiltration analysis showed that high-risk group patients exhibited increased infiltration levels of CD56 bright natural killer cells, CD56 dim natural killer cells, eosinophils, and plasmacytoid dendritic cells. Conversely, activated B cells and immature B cells demonstrated greater infiltration in the low-risk group. Correlation analysis revealed significant associations between prognostic biomarkers and various immune cells, including CD56 bright natural killer cells, CD56 dim natural killer cells, and activated CD8 T cells. NR1H3 was highly positively correlated with immune checkpoints such as TIGIT, PDCD1, CD274, CTLA4, LAG3, and HAVCR2 (|cor|ā„0.3, The online version contains supplementary material available at 10.1007/s12672-025-03694-7. Show less
For small ruminants, meat quality-an economically significant characteristic-results from the combined effects of genetic, dietary, and physiological elements. However, the contribution of gastrointes Show more
For small ruminants, meat quality-an economically significant characteristic-results from the combined effects of genetic, dietary, and physiological elements. However, the contribution of gastrointestinal (GI) tract gene expression to meat quality remains unclear. Here, we performed bulk RNA-seq on 130 samples from Liangshan Black Sheep and Meigu Black Goats, including 10 GI tract segments and semitendinosus muscle, integrating these data with measurements of amino acid composition, fatty acid profiles, and volatile flavor compounds. We found distinct, segment-specific transcriptional programs across the GI tract, with major functional shifts at the rumen-reticulum, omasum-abomasum, and abomasum-duodenum transitions. In the ileum and jejunum, genes involved in lipid metabolism showed links to fatty acid profiles, whereas genes governing amino acid metabolism in the small intestine were connected to the amino acid composition of muscle. Cecum- and colon-enriched genes were linked to flavor precursor biosynthesis. Species-specific differences revealed that sheep muscle contained higher levels of key amino acids (Asp, Glu, Hyp, Cys, Tyr), whereas goats showed higher Ī±-linolenic acid and other polyunsaturated fatty acids. This work establishes a gut-muscle transcriptomic axis in small ruminants, identifying candidate genes (e.g., Show less
Primordial follicle formation and activation are key for the reproductive ability of females. In mice, primordial follicles are formed and begin to activate during the perinatal period, when the level Show more
Primordial follicle formation and activation are key for the reproductive ability of females. In mice, primordial follicles are formed and begin to activate during the perinatal period, when the levels of estrogen are fluctuating. Whether estrogen plays a role in primordial follicle formation and activation, and its mechanism are still not fully elucidated. In this study, estrogen remained at high levels before birth and declined after birth. When fetal mouse ovaries (E16.5) were cultured in vitro, higher levels (10 nM) of estrogen maintained the germ cell cysts, prevented primordial follicles from forming prematurely, and promoted the full differentiation of oocytes. Furthermore, it was found that estrogen-regulated JNK-signal pathway through both nuclear and membrane receptors, thereby inhibited the degradation of E-cadherin and maintained the germ cell cysts. After birth, ovarian estrogen concentration decreases and is accompanied by the activation of primordial follicles. Hence, the ovaries of newborn mice (P3) were treated with lower concentrations (0.1 nM) of estrogen to investigate the effect of estrogen on primordial follicle activation. The results demonstrated that estrogen regulated the protein expression of cAMP synthase adenylyl cyclase 3 (ADCY3) through the membrane receptor G-protein-coupled estrogen receptor (GPER), increased the level of cAMP in the ovary, and activated the cAMP-PKA signaling pathway to promote the activation of primordial follicles. This study revealed the regulatory role of perinatal estrogen levels on primordial follicle formation and activation before and after birth, which would help to better understand the potential physiological effect of estrogen in vivo. Show less
Alzheimer's Disease (AD), a progressive neurodegenerative disorder, is marked by cognitive deterioration and heightened neuroinflammation. The influence of Insulin-like Growth Factor 1 Receptor (IGF1R Show more
Alzheimer's Disease (AD), a progressive neurodegenerative disorder, is marked by cognitive deterioration and heightened neuroinflammation. The influence of Insulin-like Growth Factor 1 Receptor (IGF1R) and its post-translational modifications, especially sumoylation, is crucial in understanding the progression of AD and exploring novel therapeutic avenues. This study investigates the impact of exercise on the sumoylation of IGF1R and its role in ameliorating AD symptoms in APP/PS1 mice, with a specific focus on neuroinflammation and innovative therapeutic strategies. APP/PS1 mice were subjected to a regimen of moderate-intensity exercise. The investigation encompassed assessments of cognitive functions, alterations in hippocampal protein expressions, neuroinflammatory markers, and the effects of exercise on IGF1R and SUMO1 nuclear translocation. Additionally, the study evaluated the efficacy of KPT-330, a nuclear export inhibitor, as an alternative to exercise. Exercise notably enhanced cognitive functions in AD mice, possibly through modulations in hippocampal proteins, including Bcl-2 and BACE1. A decrease in neuroinflammatory markers such as IL-1Ī², IL-6, and TNF-Ī± was observed, indicative of reduced neuroinflammation. Exercise modulated the nuclear translocation of SUMO1 and IGF1R in the hippocampus, thereby facilitating neuronal regeneration. Mutant IGF1R (MT IGF1R), lacking SUMO1 modification sites, showed reduced SUMOylation, leading to diminished expression of pro-inflammatory cytokines and apoptosis. KPT-330 impeded the formation of the IGF1R/RanBP2/SUMO1 complex, thereby limiting IGF1R nuclear translocation, inflammation, and neuronal apoptosis, while enhancing cognitive functions and neuron proliferation. Moderate-intensity exercise effectively mitigates AD symptoms in mice, primarily by diminishing neuroinflammation, through the reduction of IGF1R Sumoylation. KPT-330, as a potential alternative to physical exercise, enhances the neuroprotective role of IGF1R by inhibiting SUMOylation through targeting XPO1, presenting a promising therapeutic strategy for AD. Show less
Histone deacetylase 3 (HDAC3) is an epigenetic modifying enzyme closely linked to the development of atherosclerosis. Endothelial inflammation is a critical factor in atherosclerosis. However, the rol Show more
Histone deacetylase 3 (HDAC3) is an epigenetic modifying enzyme closely linked to the development of atherosclerosis. Endothelial inflammation is a critical factor in atherosclerosis. However, the role of HDAC3 in mediating epigenetic modifications and regulating endothelial inflammation in atherosclerosis remains unclear. This study aims to investigate the impact of HDAC3 on endothelial inflammation and its contribution to atherosclerosis. Firstly, single-cell transcriptomic analysis identified elevated expression of HDAC3 and nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) in inflammatory endothelial cells of atherosclerotic plaques in symptomatic patients. Endothelial-specific knockout HDAC3 in an apolipoprotein E knockout (ApoE 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 mi Show more
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
Interleukin-27 (IL-27), an Interleukin-12 (IL-12) family heterodimeric cytokine, plays a central yet complex role in immunoregulation within the intestinal mucosa, where its context-dependent actions Show more
Interleukin-27 (IL-27), an Interleukin-12 (IL-12) family heterodimeric cytokine, plays a central yet complex role in immunoregulation within the intestinal mucosa, where its context-dependent actions can promote both protective and pathogenic outcomes. Although its cellular sources, receptor structure (IL-27RĪ±/gp130 complex), and involvement in regulating key immune cells (e.g., T-cell subsets, macrophages, neutrophils) and epithelial functions are established, the precise mechanisms underlying its paradoxical effects-balancing homeostasis with inflammation-remain incompletely resolved. This review synthesizes current understanding of IL-27 biology to clarify its multifaceted role. Crucial insights into these dual functions have emerged from preclinical models, including murine colitis (e.g., DSS-, TNBS-induced), enteric infection (e.g., Toxoplasma gondii, Citrobacter rodentium), and colorectal cancer models. These studies demonstrate that IL-27 critically orchestrates gut immunity, maintaining homeostasis through antimicrobial defense and barrier enhancement while suppressing immunopathology. Conversely, its dysregulation drives chronic inflammation and carcinogenesis. Clinically, IL-27 expression correlates with disease activity in inflammatory bowel disease (IBD), colorectal cancer (CRC), and infections, highlighting its biomarker potential. Consequently, targeting the IL-27 pathway presents promising therapeutic avenues: augmenting signaling may mitigate IBD hyperinflammation, while inhibition could bolster antitumor immunity or resolve infection-driven pathology. Future research must prioritize defining context-specific IL-27 functions, optimizing delivery strategies, and integrating IL-27 targeting with existing biologics to translate its immunomodulatory potential into novel therapies for intestinal diseases. Show less
Inhibition of branched-chain ketoacid dehydrogenase kinase (BDK or BCKDK), a negative regulator of branched-chain amino acid (BCAA) metabolism, is hypothesized to treat cardio-metabolic diseases. From Show more
Inhibition of branched-chain ketoacid dehydrogenase kinase (BDK or BCKDK), a negative regulator of branched-chain amino acid (BCAA) metabolism, is hypothesized to treat cardio-metabolic diseases. From a starting point with potential idiosyncratic toxicity risk, modification to a benzothiophene core and discovery of a cryptic pocket allowed for improved potency with 3-aryl substitution to arrive at PF-07328948, which was largely devoid of protein covalent binding liability. This BDK inhibitor was shown also to be a BDK degrader in cells and in vivo rodent studies. Plasma biomarkers, including BCAAs and branched-chain ketoacids (BCKAs), were lowered in vivo with enhanced pharmacodynamic effect upon chronic dosing due to BDK degradation. This molecule improves metabolic and heart failure end points in rodent models. PF-07328948 is the first known selective BDK inhibitor candidate to be examined in clinical studies, with Phase 1 single ascending dose data showing good tolerability and a pharmacokinetic profile commensurate with once-daily dosing. Show less
Citrin deficiency (CD) is caused by the inactivation of SLC25A13, a mitochondrial membrane protein required to move electrons from cytosolic NADH to the mitochondrial matrix in hepatocytes. People wit Show more
Citrin deficiency (CD) is caused by the inactivation of SLC25A13, a mitochondrial membrane protein required to move electrons from cytosolic NADH to the mitochondrial matrix in hepatocytes. People with CD do not like sweets. Here we show that SLC25A13 loss causes the accumulation of glycerol-3-phosphate (G3P), which activates the carbohydrate response element-binding protein (ChREBP) to transcribe FGF21, which acts in the brain to restrain intake of sweets and alcohol and to transcribe key genes driving lipogenesis. Mouse and human data suggest that G3P-ChREBP is a mechanistic component of the Randle Cycle that contributes to metabolic-dysfunction-associated steatotic liver disease and forms part of a system that communicates metabolic states from the liver to the brain in a manner that alters food and alcohol choices. The data provide a framework for understanding FGF21 induction in varied conditions, suggest ways to develop FGF21-inducing drugs and suggest potential drug candidates for lean metabolic-dysfunction-associated steatotic liver disease and support of urea cycle function in CD. Show less
Accumulating evidence has demonstrated that nucleic acid-based therapies are promising for atherosclerosis. However, nearly all nucleic acid delivery systems developed for atherosclerosis necessitate Show more
Accumulating evidence has demonstrated that nucleic acid-based therapies are promising for atherosclerosis. However, nearly all nucleic acid delivery systems developed for atherosclerosis necessitate injection, which results in rapid elimination and poor patient compliance. Consequently, oral delivery strategies capable of targeting atherosclerotic plaques are imperative for nucleic acid therapeutics. Herein we report the development of yeast-derived capsules (YCs) packaging an antisense oligonucleotide (AM33) targeting microRNA-33 (miR-33) for the oral treatment of atherosclerosis. YCs provide stability for AM33, preventing its premature release in the gastrointestinal tract. AM33-containing YCs, defined as YAM33, showed high transfection in macrophages, thus promoting cholesterol efflux and inhibiting foam cell formation by regulating the target genes/proteins of miR-33. Orally delivered YAM33 effectively accumulated within atherosclerotic plaques in Show less
Energy deprivation and metabolic rewiring of cardiomyocytes are widely recognized hallmarks of heart failure. Here, we report that HEY2 (a Hairy/Enhancer-of-split-related transcriptional repressor) is Show more
Energy deprivation and metabolic rewiring of cardiomyocytes are widely recognized hallmarks of heart failure. Here, we report that HEY2 (a Hairy/Enhancer-of-split-related transcriptional repressor) is upregulated in hearts of patients with dilated cardiomyopathy. Induced Hey2 expression in zebrafish hearts or mammalian cardiomyocytes impairs mitochondrial respiration, accompanied by elevated ROS, resulting in cardiomyocyte apoptosis and heart failure. Conversely, Hey2 depletion in adult mouse hearts and zebrafish enhances the expression of mitochondrial oxidation genes and cardiac function. Multifaceted genome-wide analyses reveal that HEY2 enriches at the promoters of genes known to regulate metabolism (including Ppargc1, Esrra and Cpt1) and colocalizes with HDAC1 to effectuate histone deacetylation and transcriptional repression. Consequently, restoration of PPARGC1A/ESRRA in Hey2- overexpressing zebrafish hearts or human cardiomyocyte-like cells rescues deficits in mitochondrial bioenergetics. Knockdown of Hey2 in adult mouse hearts protects against doxorubicin-induced cardiac dysfunction. These studies reveal an evolutionarily conserved HEY2/HDAC1-Ppargc1/Cpt transcriptional module that controls energy metabolism to preserve cardiac function. Show less
Physical fitness in preschoolers, encompassing muscular strength, speed-agility, balance, and cardiorespiratory fitness, serves as a key health indicator. While preschools are ideal settings for promo Show more
Physical fitness in preschoolers, encompassing muscular strength, speed-agility, balance, and cardiorespiratory fitness, serves as a key health indicator. While preschools are ideal settings for promoting physical fitness, the association between preschool-based movement behaviors and physical fitness remains unclear. This cross-sectional study included 1144 Chinese preschoolers aged 3-6 years. Preschool-based movement behaviors including moderate-to-vigorous physical activity (MVPA), light physical activity (LPA), and sedentary behavior (SB), were measured using ActiGraph GT9X accelerometers. Physical fitness was assessed via the PREFIT battery, which includes handgrip strength, standing long jump, 4āĆā10ām shuttle run, one-leg stance, and 20ām shuttle run. Compositional linear regression and isotemporal substitution modeling were employed to examine associations and time-reallocation effects, respectively. Greater amounts of MVPA during preschool hours were positively associated with better performance in muscular strength, speed-agility, and cardiorespiratory fitness. Reallocating time from SB or LPA to MVPA enhanced physical fitness, whereas substituting MVPA with SB or LPA reduced fitness levels, demonstrating an asymmetric effect. Moderate-to-vigorous physical activity during preschool hours significantly enhances physical fitness. Prioritizing the implementation of physical activity programs to increase MVPA in preschool settings is crucial for improving physical fitness and addressing insufficient MVPA in this age group. First large-scale study (Nā=ā1144) demonstrating preschool-based moderate-to-vigorous physical activity (MVPA) is essential for developing preschoolers' muscular strength, speed-agility, and cardiorespiratory fitness, complementing existing 24-h movement behavior research. Reveals critical asymmetry: Reducing MVPA time significantly harms fitness, with losses exceeding the benefits from equivalent MVPA increases. Provides objective evidence to guide policymakers in optimizing preschool schedules to prioritize MVPA for enhancing children's physical fitness. Show less