Lifestyle improvement may help reverse prediabetes. Indicators such as Life's Essential 8 (LE8) and biological aging measures (phenotypic age, cardiovascular biological age) partially reflect metaboli Show more
Lifestyle improvement may help reverse prediabetes. Indicators such as Life's Essential 8 (LE8) and biological aging measures (phenotypic age, cardiovascular biological age) partially reflect metabolic status in prediabetes, but their predictive value for cardiovascular mortality and stroke in this population remains unclear. We analyzed data from 74,678 White participants with prediabetes in the UK Biobank, defined by either HbA1c (5.7-6.4%) or fasting glucose (6.1-6.9Β mmol/L). Follow-up continued until October 10, 2023. Cox regression was used to examine associations between LE8, phenotypic age (PhenoAge), cardiovascular biological age (CBA), and outcomes of cardiovascular (CVD) mortality and stroke. Restricted cubic spline (RCS) models identified biological age risk thresholds. Mediation analysis assessed whether proteins such as CST3, EFEMP1, FES, IGFBP2, IGFBP6, LPA, PCSK9, and TIMP1 mediated these effects. Over a median follow-up of 13.4Β years, 2263 participants died from CVD causes. Each 1-year increase in CBA or PhenoAge was associated with aβ~β10% higher risk of CVD mortality (CBA aHRβ=β1.10; PhenoAge aHRβ=β1.09; both Pβ<β0.001), while each 1-point increase in LE8 score was linked to a 3% lower risk (HRβ=β0.97, Pβ<β0.001). The risk biological ages for these two indicators were also identified: PhenoAgeββ₯β58.52Β years and CBAββ₯β62.42Β years. Similar trends were observed for stroke. Mediation analysis revealed that CST3, TIMP1, IGFBP2, and IGFBP6 contributed to the biological pathways between aging/lifestyle and CVD outcomes. The combined LE8 and PhenoAge model showed the strongest predictive performance for CVD mortality (AUCβ=β0.716) and stroke (AUCβ=β0.638) over 15Β years. LE8 combined with phenotypic age provides prognostic value for CVD outcomes in prediabetes. These findings highlight the potential of lifestyle modification and delayed biological aging in reversing prediabetes and underscore comorbidity-related proteins as promising therapeutic targets. Show less
Derazantinib (DZB), a pan-fibroblast growth factor receptor (FGFR) inhibitor, exhibits potent activity against FGFR1-3 kinases and has been clinically approved for antitumor therapy. However, its anti Show more
Derazantinib (DZB), a pan-fibroblast growth factor receptor (FGFR) inhibitor, exhibits potent activity against FGFR1-3 kinases and has been clinically approved for antitumor therapy. However, its antibacterial properties remain unknown. Here, we demonstrated that DZB displays broad-spectrum activity against Show less
While most patients with stage I non-small cell lung cancer (NSCLC) remain recurrence-free after resection, some still develop recurrent disease. The surgical curative time window concept, defined as Show more
While most patients with stage I non-small cell lung cancer (NSCLC) remain recurrence-free after resection, some still develop recurrent disease. The surgical curative time window concept, defined as no recurrence through 5-year follow-up, helps identify potentially cured patients, yet predictive clinicopathologic features in stage I invasive NSCLC need clarification. This study sought to identify such features to enable risk-adapted surveillance. We analyzed a prospectively collected dataset of patients with stage I invasive NSCLC who underwent R0 resection between 2008 and 2015. Cox regression analysis was used to evaluate the association between clinicopathologic features and disease recurrence, aiming to identify independent prognostic factors. A total of 1,817 patients met the inclusion criteria. The 5-year cumulative incidence of recurrence was 14.6%. Female sex, tumor size β€2 cm, lepidic-predominant adenocarcinoma (LPA) histologic type, presence of a ground-glass opacity (GGO) component, and solid component size β€10 mm were identified as independent prognostic factors. A risk stratification system was subsequently developed, classifying patients into two groups: a low-risk group (with β₯4 factors; n=341) and an elevated-risk group (with <4 factors; n=1,476). Kaplan-Meier analysis revealed statistically significant differences in recurrence-free survival (RFS), overall survival (OS), and lung cancer-specific survival (LCSS) between the two groups (P<0.001). The low-risk group is considered to represent the population within the surgical curative time window. Patients with stage I invasive NSCLC who meet at least four of the following five criteria-female sex, tumor size β€2 cm, solid component β€10 mm, presence of a GGO component, and LPA histologic type-may be considered within the "surgical curative time window" and may therefore qualify for reduced surveillance intensity. Show less
Pancreatic cancer (PC), characterized by the absence of effective biomarkers and therapies, remains highly fatal. Data regarding the correlations between PC risk and individual plasma proteome known f Show more
Pancreatic cancer (PC), characterized by the absence of effective biomarkers and therapies, remains highly fatal. Data regarding the correlations between PC risk and individual plasma proteome known for minimally invasive biomarkers are scarce. Here, we analyzed 1,345 human plasma proteins using proteome-wide association studies, identifying 78 proteins significantly associated with PC risk. Of these, four proteins (ROR1, FN1, APOA5, and ABO) showed the most substantial causal link to PC, confirmed through Mendelian randomization and colocalization analyses. Data from two clinical cohorts further demonstrated that FN1 and ABO were notably overexpressed in both blood and tumor samples from PC patients, compared to healthy controls or para-tumor tissues. Additionally, elevated FN1 and ABO levels correlated with shorter median survival in patients. Multiple drugs targeting FN1 or ROR1 are available or in clinical trials. These findings suggest that plasma protein FN1 associated with PC holds potential as both prognostic biomarkers and therapeutic targets. Show less
This study investigates the relationship between serum homocysteine, blood lipids, and perinatal outcomes in patients with diet-controlled gestational diabetes mellitus (GDM) and those with normal glu Show more
This study investigates the relationship between serum homocysteine, blood lipids, and perinatal outcomes in patients with diet-controlled gestational diabetes mellitus (GDM) and those with normal glucose tolerance (NGT). A prospective cohort of 150 diet-controlled GDM patients and 150 pregnant women with NGT, all delivering at our hospital, were selected based on predefined criteria. Data on demographics, physical parameters, and perinatal outcomes were compiled. Blood samples for fasting plasma glucose (FPG), homocysteine (Hcy), total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (apoB), and apolipoprotein A1 (apoA1) were collected before delivery. GDM patients exhibited higher levels of FPG, Hcy, and the apoB/apoA1 ratio, but lower HDL-C and apoA1 levels compared to the NGT group. Adverse outcomes such as macrosomia, premature rupture of membranes, and postpartum hemorrhage were more prevalent in the GDM group. In GDM patients, neonatal birth weight positively correlated with FPG and TG levels. Stratified Hcy analysis in GDM showed no significant differences in perinatal outcomes. However, the third quartile of the apoB/apoA1 ratio had a lower incidence of macrosomia compared to the first quartile, and the second quartile showed a higher incidence of birth asphyxia. GDM patients demonstrated increased levels of Hcy, FPG, and the apoB/apoA1 ratio, correlating with more adverse perinatal outcomes than healthy pregnant individuals. The relationships between Hcy, lipids, and these outcomes remain inconclusive, highlighting the need for further research. Show less
PoorΒ featherΒ growth not onlyΒ affectsΒ the appearance of the organism but also decreases the feedΒ efficiency. Methionine (Met) is an essential amino acid required for feather follicle development; yet t Show more
PoorΒ featherΒ growth not onlyΒ affectsΒ the appearance of the organism but also decreases the feedΒ efficiency. Methionine (Met) is an essential amino acid required for feather follicle development; yet the exact mechanism involved remains insufficiently understood. A total of 180 1-day-old broilers were selected and randomly divided into 3 treatments: control group (0.45% Met), Met-deficiency group (0.25% Met), and Met-rescue group (0.45% Met in the pre-trial period and 0.25% Met in the post-trial period). The experimental period lasted for 56 d, with a pre-trial period of 1-28 d and a post-trial period of 29-56 d. In addition, Met-deficiency and Met-rescue models were constructed in feather follicle epidermal stem cell by controlling the supply of Met in the culture medium. Dietary Met-deficiency significantly (Pβ<β0.05) reduced the ADG, ADFI and F/G, and inhibited feather follicle development. Met supplementation significantly (Pβ<β0.05) improved growth performance and the feather growth in broilers. Met-rescue may promote feather growth in broilers by activating the Wnt/Ξ²-catenin signaling pathway (GSK-3Ξ², CK1, Axin1, Ξ²-catenin, Active Ξ²-catenin, TCF4, and Cyclin D1). Compared with Met-deficiency group, Met-rescue significantly (Pβ<β0.05) increased the activity of feather follicle epidermal stem cell and mitochondrial membrane potential, activated Wnt/Ξ²-catenin signaling pathway, and decreased the content of reactive oxygen species (Pβ<β0.05). CO-IP confirmed that mitochondrial protein PGAM5 interacted with Axin1, the scaffold protein of the disruption complex of the Wnt/Ξ²-catenin signaling pathway, and directly mediated Met regulation of Wnt/Ξ²-catenin signaling pathway and feather follicle development. PGAM5 binding to Axin1 mediates the regulation of Wnt/Ξ²-catenin signaling pathway, and promotes feather follicle development and feather growth of broiler chickens through Met supplementation. These results provide theoretical support for the improvement of economic value and production efficiency of broiler chickens. Show less
Atherosclerosis is characterized by persistent inflammatory condition, leading to various cardiovascular complications. Foam cell formation, resulting from macrophage uptake of oxidized low-density li Show more
Atherosclerosis is characterized by persistent inflammatory condition, leading to various cardiovascular complications. Foam cell formation, resulting from macrophage uptake of oxidized low-density lipoprotein (ox-LDL), contributes significantly to atherosclerosis progression. This study was designed to investigate the involvement of bispecific phosphatase-6 (DUSP6) and its potential regulatory mechanisms in foam cell formation and atherosclerosis. We employed THP-1 cells to induce foam cell formation. The lipid droplet accumulation, cholesterol content, tumor necrosis factor (TNF)-Ξ±, interleukin (IL)-1Ξ², and IL-6 levels were evaluated using Oil Red O staining, cholesterol assay, ELISA, and qRT-PCR techniques. We investigated DUSP6 ubiquitination via immunoprecipitation and western blot (WB) analysis. A bioinformatics approach identified FBXL14 as a potential E3 ligase involved in DUSP6 ubiquitination, further confirmed by siRNA and overexpression experiments. The impact of FBXL14 on the NRF2 signaling pathway was assessed using WB analysis. DUSP6 interference suppressed foam cell formation and inflammatory factor secretion. Upon ox-LDL treatment, DUSP6 underwent deubiquitylation, with FBXL14 emerging as the candidate E3 ligase. FBXL14 overexpression induced DUSP6 ubiquitination, leading to the NRF2 signaling pathway activation. It counteracted with DUSP6 overexpression on foam cell formation and inflammation. In ApoE-/- mice, sh-DUSP6 adenovirus injection mitigated atherosclerotic lesion progression and improved the lipid profile, with increased the proteins expression of NQO1, HO-1, and NRF2 in aortic tissue. DUSP6 and FBXL14 play vital roles in modulating foam cell formation and inflammatory responses in atherosclerosis. Targeting these molecules could offer therapeutic potential in attenuating atherosclerosis-related complications. Not applicable. Show less
Polycystic ovary syndrome (PCOS) is a prevalent metabolic and reproductive endocrine disorder with strong heritability. However, the independent role of oocytes in mediating this heritability remains Show more
Polycystic ovary syndrome (PCOS) is a prevalent metabolic and reproductive endocrine disorder with strong heritability. However, the independent role of oocytes in mediating this heritability remains unclear. Utilizing inΒ vitro fertilization-embryo transfer and surrogacy, we demonstrated that oocytes from androgen-exposed mice (F1) transmitted PCOS-like traits to F2 and F3 generations. Notably, caloric restriction (CR) in F1 or F2 effectively prevented this transmission by restoring disrupted DNA methylation in oocyte genes related to insulin secretion and AMPK signaling pathways. Further detection in adult tissues of offspring revealed dysregulated DNA methylation and expression of those genes (e.g., Adcy3, Gnas, and Srebf1) were reversed by maternal CR. Moreover, similar benefits of CR were observed in aberrant embryonic methylome of women with PCOS. These findings elucidate the essential role of CR in preventing PCOS transmission via methylation reprogramming, emphasizing the importance of preconception metabolic management for women with PCOS. Show less
Angiopoietin-like protein 4 (ANGPTL4) is a hepatokine implicated in fat metabolism regulation. Its genetic inactivation has been associated with improved glucose homeostasis, while elevated plasma ANG Show more
Angiopoietin-like protein 4 (ANGPTL4) is a hepatokine implicated in fat metabolism regulation. Its genetic inactivation has been associated with improved glucose homeostasis, while elevated plasma ANGPTL4 levels are observed in diabetic and obese individuals. However, the potential link between ANGPTL4 and diabetes- or obesity-related complications remains uncertain. This study aimed to explore whether plasma ANGPTL4 level could serve as a predictor of cancer mortality, cardiovascular mortality, and all-cause mortality in a community-based cohort. A community-based cohort study was conducted, where fasting plasma ANGPTL4 concentrations were measured at baseline, and vital status was ascertained through linkage with the National Health Insurance Research Database in Taiwan. During a 10.46-year follow-up period, 29 (2.49%) of the 1163 participants died. Subjects within the highest tertile of plasma ANGPTL4 levels exhibited the lowest survival rate. In unadjusted models, plasma ANGPTL4 significantly predicted all-cause mortality, cancer mortality, and cardiovascular or cancer-related mortality. Upon adjustment for confounders including age, sex, smoking, body mass index (BMI), hypertension, diabetes mellitus (DM), and renal function, each standard deviation increase in plasma ANGPTL4 was associated with HRs of 1.35 (95% CI: 1.01-1.80, Plasma ANGPTL4 emerges as a promising biomarker capable of predicting 10-year mortality and enhancing risk prediction beyond established risk factors. Show less
(1) Background: the epigenetic mechanisms underlying the progression from acute kidney injury (AKI) to chronic kidney disease (CKD) remain poorly understood; (2) Methods: to investigate this process, Show more
(1) Background: the epigenetic mechanisms underlying the progression from acute kidney injury (AKI) to chronic kidney disease (CKD) remain poorly understood; (2) Methods: to investigate this process, we conducted genome-wide DNA methylation sequencing to map the epigenetic changes during the AKI-CKD transition in a mouse model. By integrating DNA methylome and transcriptome analyses, we identified genes and signaling pathways regulated by DNA methylation throughout this progression; (3) Results: our analysis identified four candidate genes- Show less
The early detection of high-risk individuals is crucial to delay and reduce the incidence of type 2 diabetes. In this study, we aimed to explore the performance of a novel subgroup-specific biomarker Show more
The early detection of high-risk individuals is crucial to delay and reduce the incidence of type 2 diabetes. In this study, we aimed to explore the performance of a novel subgroup-specific biomarker strategy in the prediction of incident diabetes. In the Taiwan Lifestyle Cohort Study, adult subjects without diabetes were included and followed for the incidence of diabetes in 2006-2019. The biomarkers measured included blood secretogranin III (SCG3), vascular adhesion protein-1 (VAP-1), fibrinogen-like protein 1 (FGL1), angiopoietin-like protein 6 (ANGPTL6), and angiopoietin-like protein 4 (ANGPTL4). Among the 1,287 subjects, 12.2% developed diabetes during a 6 year follow-up. Blood VAP-1 was significantly associated with incident diabetes in the overall population (HRβ=β0.724, Pβ<β0.05), participants under 65βyears old (HRβ=β0.685, Pβ<β0.05), those with a BMI of β₯24βkg/m Gender- and BMI-specific biomarker strategy can improve the prediction of incident diabetes. A subgroup-specific biomarker strategy is a novel approach in the prediction of incident diabetes. Show less
Multiple myeloma (MM) remains an incurable disease primarily due to the emergence of drug resistance, and the underlying mechanisms remain unclear. Extrachromosomal circular DNAs (eccDNAs) are prevale Show more
Multiple myeloma (MM) remains an incurable disease primarily due to the emergence of drug resistance, and the underlying mechanisms remain unclear. Extrachromosomal circular DNAs (eccDNAs) are prevalent in cancer genomes of both coding and non-coding regions. However, the role of non-coding eccDNA regions that serve as enhancers has been largely overlooked. Here, genome-wide profiling of serum eccDNAs from donors and MM patients who responded well or poorly to bortezomib-lenalidomide-dexamethasone (VRd) therapy is characterized. A high copy number of eccDNA ANKRD28 (eccANKRD28) predicts poor therapy response and prognosis but enhanced transcriptional activity. Established VRd-resistant MM cell lines exhibit a higher abundance of eccANKRD28, and CRISPR/Cas9-mediated elevation of eccANKRD28 desensitizes bortezomib and lenalidomide treatment both in vitro and in vivo. Integrated multi-omics analysis (H3K27ac ChIP-seq, scRNA-seq, scATAC-seq, CUT&Tag, etΒ al.) identifies eccANKRD28 as an active enhancer involved in drug resistance driven by the key transcription factor, POU class 2 homeobox 2 (POU2F2). POU2F2 interacts with sequence-specific eccANKRD28 as well as RUNX1 and RUNX2 motifs to form the protein complex, which activates the promoter of oncogenes, including IRF4, JUNB, IKZF3, RUNX3, and BCL2. This study elucidates the potential transcriptional network of enhancer eccANKRD28 in MM drug resistance from a previously unrecognized epigenetic perspective. Show less
Yilin Chen, Xiaofeng Ding, Sonalika Ray+10 more Β· 2025 Β· bioRxiv : the preprint server for biology Β· Cold Spring Harbor Laboratory Β· added 2026-04-24
Despite effective viral suppression with antiretroviral therapy (ART), people living with HIV (PLWH) experience persistent inflammation, immune dysfunction, and premature onset of cardiovascular and a Show more
Despite effective viral suppression with antiretroviral therapy (ART), people living with HIV (PLWH) experience persistent inflammation, immune dysfunction, and premature onset of cardiovascular and aging-related comorbidities. To define the underlying mechanisms, we performed longitudinal transcriptomic profiling in peripheral blood mononuclear cells (PBMCs) from a cohort of simian immunodeficiency virus (SIV)-infected rhesus macaques spanning four key stages: pre-infection, acute infection, short-term ART, and long-term ART. Bulk RNA sequencing revealed dynamic immune remodeling across infection and treatment. Acute SIV infection induced robust antiviral and inflammatory programs, with upregulation of interferon-stimulated genes (ISGs), IL-27, JAK/STAT, and NF-ΞΊB signaling, coupled with suppression of T- and B-cell activation pathways. Short-term ART effectively reversed these transcriptional perturbations, restoring adaptive immune gene expression and reducing innate antiviral responses to near-baseline levels. In contrast, chronic SIV infection on long-term ART maintained viral suppression but was characterized by reactivation of innate immune pathways, including TLR2/TLR4/MYD88, NF-ΞΊB, and inflammasome (NLRP3/or NLRP12, caspase-1) signaling, along with sustained macrophage activation, platelet/coagulation signaling, and senescence-associated secretory phenotype. Protein analyses confirmed persistent CASPASE-1 and NF-ΞΊB activation in spleen tissue. Pathologic evaluation of a carotid artery from an SIV-infected, long-term ART-treated macaque revealed macrophage-rich plaques with p21 Show less
High-grade serous ovarian cancer (HGSOC) is the most lethal type of gynecological cancer, and platinum-resistance is a serious challenge in its treatment. Long non-coding RNAs (lncRNAs) play critical Show more
High-grade serous ovarian cancer (HGSOC) is the most lethal type of gynecological cancer, and platinum-resistance is a serious challenge in its treatment. Long non-coding RNAs (lncRNAs) play critical regulatory roles in the occurrence and development of cancers. Here, using RNA sequencing of tumor small extracellular vesicles (sEVs) from HGSOC patients, the lncRNA CATED is identified as significantly upregulated in both tumors and tumor-derived sEVs in platinum-resistant HGSOC, and low CATED levels correlate with good prognosis. Functionally, CATED enhances cisplatin resistance by promoting cell proliferation and inhibiting apoptosis in vitro and in vivo. These effects could be transferred via CATED-overexpressing sEVs from donor cells and HGSOC tumor sEVs. Mechanistically, CATED binds to and upregulates DHX36 via PIAS1-mediated SUMOylation at the K105 site, and elevated DHX36 levels increase downstream RAP1A protein levels by enhancing RAP1A mRNA translation, consequently activating the MAPK pathway to promote platinum-resistance in HGSOC. Antisense oligonucleotide mediated knockdown of CATED reverse platinum-resistance in sEV-transmitted mouse models via the DHX36-RAP1A-MAPK pathway. This study newly identifies a sEV-transmitted lncRNA CATED in driving HGSOC platinum-resistance and elucidates the mechanism it regulates the interacting protein through SUMOylation. These findings also provide a novel strategy for improving chemotherapy in HGSOC by targeting CATED. Show less
People with mild cognitive impairment (MCI) carry a considerable risk of developing dementia. Studies have shown that female sex hormones have long-lasting neuroprotective and anti-aging properties, a Show more
People with mild cognitive impairment (MCI) carry a considerable risk of developing dementia. Studies have shown that female sex hormones have long-lasting neuroprotective and anti-aging properties, and the increased risk of MCI and AD is associated with the lack of estrogen during menopause. Previous studies have shown that Tiao Geng Decoction (TGD) may have antioxidant and anti apoptotic properties, which may prevent neurodegenerative diseases. However, whether TGD is effective in improving mild cognitive impairment due to postmenopausal estrogen deficiency and its potential pharmacological mechanisms remain unclear. The aim of this study was to investigate the possible pharmacological mechanisms of TGD in preventing postmenopausal MCI. We utilized RNA-seq technology to screen for differentially expressed genes (DEGs) and enrichment pathways in the hippocampal tissue of different groups of mice. Additionally, we adopted single-cell sequencing technology to study the cell types of Alzheimer's disease (AD) group and Normal Control (NC) group, the differential marker genes of each cell subgroup, and the GO enrichment analysis of each cell type. Both RNA sequencing and single-cell sequencing results showed a significant correlation between TGD and NF-ΞΊb pathway in improving mild cognitive impairment in postmenopausal women. The experimental verification results showed that the spatial learning and memory abilities of APP/PS1 model mice were weakened after ovariectomy, and the reproductive cycle on vaginal smears was in the interphase of diestrus. The levels of serum E2, and P-tau181 in mice were significantly down regulated, while the levels of brain tissue homogenate A Ξ² 42, IL-1 Ξ², and IL-18 were significantly up-regulated, indicating successful modeling. Combining Western blotting, RT-qPCR, and transmission electron microscopy analyses, it was found that the low estrogen environment induced by oophorectomy can activate the NF-ΞΊb signaling pathway, activate the expression of NLRP3 inflammasome and A Ξ² secretase BACE1, and induce neuroinflammatory damage in hippocampal astrocytes. These results conform to the modeling characteristics of MCI. After TGD intervention, the spatial learning and memory abilities of MCI mice were significantly improved. The pharmacological validation results indicated that high concentration doses of TGD had a more significant effect on MCI. Subsequently, we used high concentration TGD (0.32 g/ml) as the traditional Chinese medicine group for further validation, protein blotting and RT-qPCR results indicated that TGD can effectively stimulate the secretion of ER Ξ± and ER Ξ², inhibit the NF-ΞΊb pathway, downregulate BACE1, and inhibit the expression of NLRP3 inflammasome related proteins. In addition, the immunofluorescence results of hippocampal astrocytes showed that TGD can effectively facilitate the expression of AQP1 and significantly lower the sedimentation of A Ξ² compared with the model group. Our research suggests that there is a high correlation between a low estrogen environment and the occurrence and development of MCI. TGD may regulate the ERs/NF - ΞΊ b/AQP1 signaling pathway, promote estrogen secretion, activate AQP1, reduce A Ξ² deposition, reverse MCI neuroinflammatory injury, improve mild cognitive impairment, and prevent the occurrence of AD. This study revealed for the first time that TGD may be a potential new alternative drug for preventing and improving menopausal MCI. Show less
Dan Zeng, Yunsheng Zhang, Hu Xia+4 more Β· 2025 Β· Comparative biochemistry and physiology. Part D, Genomics & proteomics Β· Elsevier Β· added 2026-04-24
To investigate the key regulatory genes and pathways related to growth traits in the Dongtingking crucian carp (Carassius auratus indigentiaus), the transcriptomes of brain, intestine, and muscle tiss Show more
To investigate the key regulatory genes and pathways related to growth traits in the Dongtingking crucian carp (Carassius auratus indigentiaus), the transcriptomes of brain, intestine, and muscle tissues were sequenced at early juvenile stage using RNA-Seq from two groups with extreme growth rates (fast-growing and slow-growing). A total of 65, 184, and 130 differentially expressed genes (DEGs) were detected in the brain, intestine, and muscle, respectively. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis highlighted that the PPAR signaling pathway, Insulin/PI3K/Akt/mTOR/FoxO/AMPK pathway, and Protein digestion and absorption pathways are crucial for growth in this species. Based on the transcriptome data, 32 key DEGs were identified, mainly participating in processes such as cell proliferation and differentiation, growth, development, and metabolism. Prominent examples are cyclic AMP-responsive element-binding protein 5 (creb5b), forkhead box protein O1-A (foxo1a), transcription factor AP-1-like (jun), lipoprotein lipase-like (lpl), angiopoietin-like 4 (angptl4), and egl nine homolog 3-like (egln3). This study enhances the understanding of the genetic factors and regulatory mechanisms responsible for variations in growth rates and provides a valuable basis for further studies on the regulatory mechanisms of growth in C. auratus indigentiaus. Show less
Oocyte maturation-coupled mRNA post-transcriptional regulation is essential for the establishment of developmental potential. Previously, oocyte mRNA translation efficiencies focused on the trans-regu Show more
Oocyte maturation-coupled mRNA post-transcriptional regulation is essential for the establishment of developmental potential. Previously, oocyte mRNA translation efficiencies focused on the trans-regulation of key RNA-binding protein (RBPs), rarely related to RNA structure. RNA G-quadruplexes (rG4s) are four-stranded RNA secondary structures involved in many different aspects of RNA metabolism. In this study, we have developed a low-input technique for rG4 detection (G4-LACE-seq) in mouse oocytes and found that rG4s were widely distributed in maternal transcripts, with enrichment in untranslated regions, and they underwent transcriptome-wide removal during meiotic maturation. The rG4-selective small-molecule ligand BYBX stabilized rG4s in the oocyte transcriptome and impaired spindle assembly and meiotic cell cycle progression. The proteomic spectrum results revealed that rG4 accumulation weakened the binding of a large number of RBPs to mRNAs, especially those associated with translational initiation. Ribosomal immunoprecipitation and translational reporter assays further proved that rG4s in the untranslated regions negatively affected the translational efficiency of key maternal mRNAs. Overexpression DEAH/RHA family helicase-36 partially reverses BYBX-induced oocyte developmental defects, suggesting its importance in rG4 regulation. Collectively, this study describes the distribution, dynamic changes, and regulation of rG4s in the mouse maternal transcriptome. Before meiosis resumption, a large number of rG4s in oocytes are necessary to maintain the translatome at a low level, and DHX36-mediated rG4 removal promotes a translational switch and is required for successful maternal-to-zygotic transition. Show less
This study aims to identify and characterize daily activity accumulation patterns (bouts of physical activity and sedentary behavior) among adolescents and then to explore the associations between the Show more
This study aims to identify and characterize daily activity accumulation patterns (bouts of physical activity and sedentary behavior) among adolescents and then to explore the associations between these groups and depressive symptoms. A total of 521 adolescents aged 13-18β―years from Wuhan and Changsha, China, were included. Bouts of physical activity (PA) and sedentary behavior (SED) were measured using accelerometers. The Center for Epidemiologic Studies Depression Scale was used to assess participants' depressive symptoms. Latent profile analysis was employed to identify distinct groups based on their activity patterns. Three distinct groups were identified: "Prolonged sitters" ( The synergistic effect of strategies to reduce total SED duration by limiting SED bouts to 30β―min or less and increasing light physical activity (LPA) may also be effective in alleviating depressive symptoms in adolescents. Show less
Genomic structural variants (SVs) are a major source of genetic diversity in humans. Here, through long-read sequencing of 945 Han Chinese genomes, we identify 111,288 SVs, including 24.56% unreported Show more
Genomic structural variants (SVs) are a major source of genetic diversity in humans. Here, through long-read sequencing of 945 Han Chinese genomes, we identify 111,288 SVs, including 24.56% unreported variants, many with predicted functional importance. By integrating human population-level phenotypic and multi-omics data as well as two humanized mouse models, we demonstrate the causal roles of two SVs: one SV that emerges at the common ancestor of modern humans, Neanderthals, and Denisovans in GSDMD for bone mineral density and one modern-human-specific SV in WWP2 impacting height, weight, fat, craniofacial phenotypes and immunity. Our results suggest that the GSDMD SV could serve as a rapid and cost-effective biomarker for assessing the risk of cisplatin-induced acute kidney injury. The functional conservation from human to mouse and widespread signals of positive natural selection suggest that both SVs likely influence local adaptation, phenotypic diversity, and disease susceptibility across diverse human populations. Show less
This pioneering genome-wide association study examined surrogate markers for insulin resistance (IR) in 147,880 Taiwanese individuals using data from the Taiwan Biobank. The study focused on two IR su Show more
This pioneering genome-wide association study examined surrogate markers for insulin resistance (IR) in 147,880 Taiwanese individuals using data from the Taiwan Biobank. The study focused on two IR surrogate markers: the triglyceride to high-density lipoprotein cholesterol (TG:HDL-C) ratio and the TyG index (the product of fasting plasma glucose and triglycerides). We identified genome-wide significance loci within four gene clusters: GCKR, MLXIPL, APOA5, and APOC1, uncovering 197 genes associated with IR. Transcriptome-wide association analysis revealed significant associations between these clusters and TyG, primarily in adipose tissue. Gene ontology analysis highlighted pathways related to Alzheimer's disease, glucose homeostasis, insulin resistance, and lipoprotein dynamics. The study identified sex-specific genes associated with TyG. Polygenic risk score analysis linked both IR markers to gout and hyperlipidemia. Our findings elucidate the complex relationships between IR surrogate markers, genetic predisposition, and disease phenotypes in the Taiwanese population, contributing valuable insights to the field of metabolic research. Show less
The objective was to assess the clinical efficacy of long non-coding RNA (lncRNA) alpha-2-macroglobulin-antisense 1 (A2M-AS1) in acute myocardial infarction (AMI). One hundred patients with AMI and ei Show more
The objective was to assess the clinical efficacy of long non-coding RNA (lncRNA) alpha-2-macroglobulin-antisense 1 (A2M-AS1) in acute myocardial infarction (AMI). One hundred patients with AMI and eighty patients with chest pain were recruited in the case-control study. A2M-AS1 expression was examined by quantitative real-time polymerase chain reaction (qRT-PCR). Receiver operating characteristic (ROC) analysis was utilized for evaluating the diagnostic value. Pearson's correlation analysis was used to analyze the correlation between A2M-AS1 and conventional AMI biomarkers. AMI-associated risk indicators were identified using logistic regression analysis. A significant reduction of serum A2M-AS1 was measured in AMI patients relative to chest pain patients. A2M-AS1 had an area under the curve (AUC) of 0.927 to distinguish AMI patients from those with chest pain. Pearson's correlation analysis showed that A2M-AS1 was adversely correlated with white blood cell (WBC) (r=-0.6682, Pβ<β0.001), low density lipoprotein cholesterol (LDL-C) (r=-0.5795, Pβ<β0.001), creatine kinase MB (CK-MB) (r=-0.6022, Pβ<β0.001) and cTnl (r=-0.5473; Pβ<β0.001), while positively correlated with high density lipoprotein cholesterol (HDL-C) (rβ=β0.6445, Pβ<β0.001). Relative to non-Major Adverse Cardiovascular Events (non-MACE) group, serum A2M-AS1 was obviously declined in the MACE group of AMI patients with high capacity to distinguish the MACE group from the non-MACE patients (AUCβ=β0.802). Additionally, A2M-AS1 (Pβ=β0.013; ORβ=β0.268; 95%CIβ=β0.095-0.760) was a risk indicator for predicting MACE with AMI patients, as well as age (Pβ=β0.014; ORβ=β3.478; 95%CIβ=β1.285-9.414). A reduction in A2M-AS1 expression was observed in AMI patients, suggesting its potential as an underlying indicator for AMI diagnosis. Show less
The highly organized structures of the immunological synapse (IS) are crucial for T cell activation. PDZ domains might be involved in the formation of the IS by serving as docking sites for protein in Show more
The highly organized structures of the immunological synapse (IS) are crucial for T cell activation. PDZ domains might be involved in the formation of the IS by serving as docking sites for protein interactions. In this study, we investigate the role of the PALS1-associated tight junction protein (PATJ), which contains 10 PDZ domains, in the formation of IS and its subsequent impact on T cell activation. To elucidate the function of PATJ, we generated murine models with conditional T cell-specific knockout of We observed a rapid increase in PATJ expression during T cell activation. Conditional knockout of Our study reveals an important role of PATJ in the formation of IS and provides an approach to improve the efficacy of CAR-T therapy. Show less
Endothelial-to-mesenchymal transition (EndMT) is a biological process that converts endothelial cells to mesenchymal cells with increased proliferative and migrative abilities. EndMT has been implicat Show more
Endothelial-to-mesenchymal transition (EndMT) is a biological process that converts endothelial cells to mesenchymal cells with increased proliferative and migrative abilities. EndMT has been implicated in the development of pulmonary vascular remodeling in pulmonary arterial hypertension (PAH), a fatal and progressive lung vascular disease. Transforming growth factor Ξ² Show less
Atherosclerosis (AS) is a chronic inflammatory disorder characterized by foam cell formation and persistent inflammation as central pathological drivers. Although colchicine (Col) exhibits potent anti Show more
Atherosclerosis (AS) is a chronic inflammatory disorder characterized by foam cell formation and persistent inflammation as central pathological drivers. Although colchicine (Col) exhibits potent anti-inflammatory activities, its clinical application is limited by a narrow therapeutic window. In the present study, we developed phosphatidylserine-exposing nanovesicles (Col@PSVs) that leverage the innate phagocytic capacity of macrophage-derived foam cells by presenting surface "eat-me" signals, thereby enabling targeted immune modulation. The synergistic collaboration between Col and PSVs allows low-dose Col to retain robust anti-inflammatory efficacy while mitigating dose-dependent toxicity. Mechanistically, Col@PSVs potently suppress CCR7-mediated NF-ΞΊB signaling activation in foam cells, leading to a marked downregulation of pro-inflammatory cytokine and disruption of inflammatory cascades. In ApoE Show less
Metabolic dysfunction-associated steatotic liver disease (MASLD) covers a broad spectrum of profile from simple fatty liver, evolving to metabolic dysfunction-associated steatohepatitis (MASH), to hep Show more
Metabolic dysfunction-associated steatotic liver disease (MASLD) covers a broad spectrum of profile from simple fatty liver, evolving to metabolic dysfunction-associated steatohepatitis (MASH), to hepatic fibrosis, further progressing to cirrhosis and hepatocellular carcinoma (HCC). MASLD has become a prevalent disease with 25% in average over the world. MASH is an active stage, and requires pharmacological intervention when there is necroptotic damage with fibrotic progression. Although there is an increased understanding of MASH pathogenesis and newly approved resmetirom, given its complexity and heterogeneous pathophysiology, there is a strong necessity to develop more drug candidates with better therapeutic efficacy and well-tolerated safety profile. With an increased list of pharmaceutical candidates in the pipeline, it is anticipated to witness successful approval of more potential candidates in this fast-evolving field, thereby offering different categories of medications for selective patient populations. In this review, we update the advances in MASH pharmacotherapeutics that have completed phase II or III clinical trials with potential application in clinical practice during the latest 2 years, focusing on effectiveness and safety issues. The overview of fast-evolving status of pharmacotherapeutic candidates for MASH treatment confers deep insights into the key issues, such as molecular targets, endpoint selection and validation, clinical trial design and execution, interaction with drug administration authority, real-world data feedback and further adjustment in clinical application. Show less
Lung adenocarcinoma (LUAD), the predominant histological subtype of non-small cell lung cancer, demonstrates critical regulatory involvement of RNA-binding proteins (RBPs) and circular RNAs (circRNAs) Show more
Lung adenocarcinoma (LUAD), the predominant histological subtype of non-small cell lung cancer, demonstrates critical regulatory involvement of RNA-binding proteins (RBPs) and circular RNAs (circRNAs) in tumorigenic processes. Emerging evidence highlights the circRNA-autophagy regulatory axis as a crucial modulator of cancer progression. This study systematically investigates the functional interplay within the RBP-circRNA-autophagy network in LUAD pathogenesis. Employing RNA pull down, mass spectrometry and RNA immunoprecipitation facilitated the exploration of the circRAPGEF5 binding protein. M6A methylation RNA immunoprecipitation-PCR was utilized for m6A analysis. Immunofluorescence (IF) and fluorescence in situ hybridization (FISH) assays were conducted to ascertain the subcellular localization of target genes. Employing mRFP-GFP-LC3 fluorescent lentivirus labelling facilitated the monitoring of autophagy flow levels. Xenografts in mice were instrumental in affirming the role of circRAPGEF5. Through comprehensive molecular profiling, we identified elevated circRAPGEF5 expression in LUAD cells, which significantly suppressed autophagic flux while promoting malignant phenotypes including enhanced proliferation, migration, and invasion. Mechanistic investigations revealed that circRAPGEF5 directly interacts with the KH3-4 functional domain of Insulin-like Growth Factor 2 mRNA-Binding Protein 2 (IGF2BP2), an m6A reader protein. This interaction facilitated IGF2BP2-mediated stabilization of NUP160 mRNA, a nuclear pore complex component. Genetic ablation of NUP160 through RNA interference effectively restored autophagic activity, thereby attenuating the aggressive biological behaviors of LUAD cells. In vivo validation using xenograft models demonstrated that the circRAPGEF5/IGF2BP2/NUP160 signaling axis promotes tumor growth and metastatic dissemination through autophagy suppression. Our findings reveal a novel epigenetic regulatory mechanism wherein m6A-modified circRAPGEF5 orchestrates autophagy inhibition via IGF2BP2-dependent stabilization of NUP160 transcripts, ultimately driving LUAD progression and metastasis. These results establish the circRAPGEF5/IGF2BP2/NUP160 axis as a potential therapeutic target for LUAD intervention. Show less
Calcific aortic stenosis (CAS) is frequently accompanied by systemic comorbidities, but their causal relationships and shared genetic architecture remain poorly defined. We aimed to map the multisyste Show more
Calcific aortic stenosis (CAS) is frequently accompanied by systemic comorbidities, but their causal relationships and shared genetic architecture remain poorly defined. We aimed to map the multisystem comorbidity network of CAS and clarify underlying genetic mechanisms. In 467β484 participants from the UK Biobank, observational and polygenic phenome-wide association studies evaluated associations between CAS and 1571 phenotypes, integrating disease-trajectory analyses to visualise temporal patterns. Associations replicated across observational and polygenic analyses were tested using two-sample Mendelian randomisation (MR) based on 22 CAS-related variants from FinnGen. Polygenic risk score (PRS) analyses excluding specific genes assessed their contributions, particularly LPA and plasma lipoprotein(a) (Lp(a)) levels. CAS was associated with higher risks of 42 cardiovascular and non-cardiovascular conditions, most prominently metabolic, endocrine, haematological and respiratory disorders. Temporal analyses showed that circulatory and metabolic diseases typically precede other comorbidities in CAS trajectories. MR findings were consistent with causal effects of CAS on multiple cardiovascular diseases, iron-deficiency anaemia, mental disorders and pleural effusion. When LPA variants were removed from the CAS PRS or plasma Lp(a) concentration was adjusted for, most associations lost significance, indicating a shared LPA/Lp(a)-mediated genetic pathway. CAS is embedded within a broad multisystem comorbidity network, driven largely by genetic variation at LPA and elevated Lp(a). These findings highlight pleiotropic mechanisms linking valvular calcification with systemic disease and support LPA-targeted therapies as a promising avenue for reducing the multisystem burden of CAS. Show less
To identify risk factors for heart failure (HF) within one year after percutaneous coronary intervention (PCI) in patients with acute coronary syndrome (ACS) and to develop a predictive nomogram model Show more
To identify risk factors for heart failure (HF) within one year after percutaneous coronary intervention (PCI) in patients with acute coronary syndrome (ACS) and to develop a predictive nomogram model. A retrospective analysis was performed on 492 patients with ACS treated at Suzhou Municipal Hospital between January 2020 and October 2023. Patients were divided into the HF group and the non-HF group according to the occurrence of HF within one year after PCI. 70% of the cases were randomly assigned to the training set and 30% to the validation set. Univariate and multivariate logistic regression analyses were conducted to screen independent predictors, and a nomogram model was subsequently established. Model performance was evaluated using receiver operating characteristic (ROC) curves, calibration curves, and decision curve analysis (DCA). Among the 492 patients, the incidence of HF within one year after PCI was 26.42% (n = 130). Logistic regression identified type 2 diabetes mellitus (T2DM), left ventricular ejection fraction (LVEF), lipoprotein(a) [LP(a)], B-type natriuretic peptide (BNP), and high-sensitivity C-reactive protein (Hs-CRP) as independent predictors of HF, with odds ratios of 5.756, 0.904, 1.427, 1.012, and 1.666, respectively (all P < 0.05). The model demonstrated excellent discrimination, with areas under the ROC curve of 0.946 in the training set and 0.958 in the validation set. DCA indicated that the model provided greater net clinical benefit than the "treat-all" or "treat-none" strategies, and its predictive performance surpassed that of each individual factor (P < 0.05). The nomogram model incorporating T2DM, LVEF, LP(a), BNP and Hs-CRP provides an effective tool for predicting HF risk within one year after PCI in patients with ACS, offering valuable guidance for early clinical identification and risk stratification of high-risk individuals. Show less