Molecular QTL studies quantify whether genetic variants affect molecular traits, but non-linear effects including distributional patterns, variance, and interactions provide mechanistic insights beyon Show more
Molecular QTL studies quantify whether genetic variants affect molecular traits, but non-linear effects including distributional patterns, variance, and interactions provide mechanistic insights beyond mean-level associations. Methods for detecting distributional effects have been developed for eQTL analysis, yet applications have focused on method demonstrations rather than large-scale biological discovery. We comprehensively mapped quantile, variance, and interaction QTLs across 34 data-set from 22 molecular contexts in >2,300 human brain donors, revealing that 48.7% of quantile QTLs (qQTLs) exhibit context-dependent regulation invisible to linear models, with enrichment at phenotypic extremes and in cell-type-specific regulatory elements, chromatin accessibility regions, and long-range chromosomal contacts. qQTL variants explained additional trait heritability beyond linear QTLs for brain-related traits. At Alzheimer's disease (AD) risk loci, qQTL analysis revealed complex regulatory architecture including variance effects at Show less
Atherosclerosis (AS), a chronic inflammatory disease linked to oxidative stress and lipid imbalance, remains a major cardiovascular threat. Traditional herbs Salvia miltiorrhiza and Carthamus tinctori Show more
Atherosclerosis (AS), a chronic inflammatory disease linked to oxidative stress and lipid imbalance, remains a major cardiovascular threat. Traditional herbs Salvia miltiorrhiza and Carthamus tinctorius exhibit multi-target anti-AS potential, yet their compositional complexity limits clinical translation. This study aimed to systematically identify core anti-AS components from these herbs and enhance their anti-AS efficacy via machine learning-aided screening and nanotechnology-driven codelivery. We initially pioneered a machine learning-aided hybrid strategy integrating network pharmacology and quantitative activity relationship (QSAR) modeling to identify four core anti-AS polyphenols (i.e., salvianic acid A, salvianolic acid B, protocatechuic acid, and hydroxysafflor yellow A). Subsequently, a quaternary metal-phenolic network (SSPH-MPN) was engineered for plaque-targeted codelivery, optimized via the median-effect principle for achieving a synergistic effect based on ROS scavenging efficacy. The optimized SSPH-MPN was characterized by a series of studies, including molecular dynamics simulations, UV, DLS, TEM, FTIR, XPS, and ICP-MS. The anti-AS effect of the optimized SSPH-MPN was evaluated by monitoring oxidative status (ROS levels, antioxidant enzymes SOD, GSH-Px, MDA, T-AOC), inflammatory markers (IL-1β, IL-6, TNF-α), lipid metabolism (DiI-oxLDL uptake, cholesterol efflux, blood lipid levels, lipid accumulation), and plaque areas. The results demonstrated that the optimized SSPH-MPN showed great efficiency in inhibiting lipid uptake and accumulation, and mediating cholesterol efflux in RAW 264.7 cells, and exhibited improved lipid metabolism, attenuated oxidative stress and inflammation, thus acquired diminished plaque area in apoE Show less
The existence of a definite direct causal relationship between vitiligo and diverse autoimmune disorders remains unknown due to the influence of confounding factors and potential reverse causality. Me Show more
The existence of a definite direct causal relationship between vitiligo and diverse autoimmune disorders remains unknown due to the influence of confounding factors and potential reverse causality. Mendelian randomization (MR) is a technique employed to explore causal connections between two phenotypes. In our research, bidirectional two-sample MR analyses were utilized to evaluate the causal connections between vitiligo and multiple autoimmune diseases (systemic lupus erythematosus, Graves' disease, inflammatory bowel disease, alopecia areata [AA], type 1 diabetes mellitus [T1MD], and rheumatoid arthritis [RA]). Furthermore, we utilized summary-based Mendelian randomization (SMR) analysis to search for common susceptibility loci between two diseases that reciprocally elevate each other's risk. Finally, colocalization analyses were used to validate the robustness of the selected genes. There was an indication of potential causation between RA and vitiligo (IVW OR = 1.19; 95% CI = 1.05-1.13; p = 0.008). Furthermore, evident causal connections exist between vitiligo and AA (IVW OR = 1.14; 95% CI = 1.04-1.26; p = 0.008), T1MD (IVW OR = 1.14; 95% CI = 1.06-1.23; p < 0.001), and RA (IVW OR = 1.08; 95% CI = 1.03-1.13; p < 0.001). In SMR analyses and colocalization analyses, we identified three shared genes associated with both vitiligo and RA, including: FCRL3, FADS1, and FADS2. Our findings demonstrated that vitiligo and RA mutually act as risk factors for each other. Additionally, vitiligo had significant causal relationships with AA and type 1 diabetes. Show less
Pharmaceutical and personal care products (PPCPs), as ubiquitous emerging contaminants, present undercharacterized neuropsychiatric hazards through environmental exposure. This investigation employs c Show more
Pharmaceutical and personal care products (PPCPs), as ubiquitous emerging contaminants, present undercharacterized neuropsychiatric hazards through environmental exposure. This investigation employs convergent multi-omics strategies - integrating toxicogenomic discovery, disease-associated genomic mapping, and transcriptomic profiling - to elucidate mechanistic linkages between PPCPs bioactivity and depressive pathogenesis. Through systematic analysis of Nanjing's aquatic chemical burden (prioritizing dimenhydrinate, ibuprofen, padimate-O, caffeine, and roxithromycin), we identified 3073 conserved molecular targets bridging PPCPs toxicity and depression etiology via Comparative Toxicogenomics Database and GeneCards interrogation. Functional ontology revealed dysregulated pathways encompassing lipidomic remodeling, IL-17-mediated neuroinflammation, and synaptic transmission deficits. Ensembled machine learning algorithms (Lasso regression, XGBoost, random forest) converged on seven high-fidelity candidate biomarkers (HSPA8, CBX1, CD59, CHAF1A, CUX1, ID2, RPL3) demonstrating stress-adaptive, chromatin regulatory, and immunomodulatory functions. Molecular docking predicted strong binding affinities between PPCPs and depression-related proteins, notably dimenhydrinate with CHAF1A (- 6.1 kcal/mol) and HSPA8 (- 6.1 kcal/mol), suggesting multi-target modulation. This work proposes a computational framework to map molecular interactions between specific PPCPs and depression-associated pathways. Candidate targets highlight testable hypotheses for future experimental validation. These findings suggest selected PPCPs with neuroactive properties may warrant further investigation as environmental modifiers of depression risk. Show less
Several protein convertase subtilisin/kexin type 9 (PCSK9) inhibitors have been shown to significantly reduce low-density lipoprotein cholesterol (LDL-C) levels in statin-intolerant patients, but none Show more
Several protein convertase subtilisin/kexin type 9 (PCSK9) inhibitors have been shown to significantly reduce low-density lipoprotein cholesterol (LDL-C) levels in statin-intolerant patients, but none have been verified in Chinese patients. This study aimed to evaluate the efficacy and safety of ongericimab, a novel PCSK9 monoclonal antibody, in Chinese statin-intolerant patients with primary hypercholesterolemia or mixed dyslipidemia. This was a randomized, multicenter, double-blind, placebo-controlled phase 3 study designed to enroll 120 statin-intolerant adult patients. Eligible patients were randomly assigned in a 2:1 ratio to receive ongericimab 150 mg or placebo subcutaneously every 2 weeks for 12 weeks in the double-blind treatment period, followed by 40 weeks of ongericimab treatment during the open-label period. The primary endpoint was a percentage change in LDL-C from baseline to week 12. The key secondary endpoints included percentage change from baseline to week 12 in non-high density lipoprotein cholesterol (non-HDL-C), apolipoprotein B (ApoB), total cholesterol (TC), and lipoprotein(a) [Lp(a)]. From February 6, 2023, to September 23, 2024, a total of 139 patients were enrolled. The least-squares (LS) mean difference between ongericimab and placebo groups in LDL-C from baseline to week 12 was -66.2 % (95 % CI: 74.2 %, -58.2 %; p < 0.0001), with reductions sustained up to week 52. Ongericimab also significantly reduced levels of non-HDL-C, ApoB, TC, and Lp(a). The overall incidence of treatment-emergent adverse events was comparable between the ongericimab and placebo groups. Ongericimab significantly reduced LDL-C as well as other atherogenic lipid levels and was well tolerated in Chinese statin-intolerant patients with primary hypercholesterolemia or mixed dyslipidemia. http://www. gov; Unique Identifier: NCT05621070. Show less
With the advancement of genomic technologies, precision lifestyle interventions tailored to individual genetic backgrounds have emerged as a novel approach for preventing and managing chronic diseases Show more
With the advancement of genomic technologies, precision lifestyle interventions tailored to individual genetic backgrounds have emerged as a novel approach for preventing and managing chronic diseases such as obesity. Several randomized controlled trials (RCTs) targeting obese or overweight populations have found that individuals with different genotypes exhibit varying responses to the same lifestyle intervention (gene-lifestyle intervention interactions). To date, more than 20 genes, including Show less
Recent advances in human blastoids have opened new avenues for modeling early human development and implantation. Human blastoids can be generated in large numbers, making them well-suited for high-th Show more
Recent advances in human blastoids have opened new avenues for modeling early human development and implantation. Human blastoids can be generated in large numbers, making them well-suited for high-throughput screening. However, automated methods for evaluating and characterizing blastoid morphology are lacking. We developed a deep-learning model-deepBlastoid-for automated classification of live human blastoids using only brightfield images. The model processes 273.6 images per second with an average accuracy of 87%, which is further improved to 97% by integrating a Confidence Rate metric. deepBlastoid outperformed human experts in throughput while matching accuracy in blastoid classification. We demonstrated the utility of the model in two use cases: (i) systematic assessment of the effect of lysophosphatidic acid (LPA) on blastoid formation and (ii) evaluating the impact of dimethyl sulfoxide (DMSO) on blastoid formation. The evaluation results of deepBlastoid using over 10,000 images were consistent with the known drug effects and showed subtle but significant effects that might have been overlooked in manual assessments. The publicly available deepBlastoid model enables researchers to train customized models based on their imaging and protocols, providing an efficient, automated tool for blastoid classification with broad applications in research, drug screening, and Show less
Alzheimer's disease (AD) presents significant challenges due to its intricate pathogenic mechanisms and the limited efficacy of single-target therapies. In this study, we investigated the potential of Show more
Alzheimer's disease (AD) presents significant challenges due to its intricate pathogenic mechanisms and the limited efficacy of single-target therapies. In this study, we investigated the potential of chlorogenic acid (CHA), a multifunctional natural active compound, in AD therapy by developing a trifunctional nanocarrier (MC-H/R/si). CHA was effectively conjugated with iron-based metal-organic frameworks (MIL/Fe-100) through chelation interaction. The resulting nanocomplex (MC) not only enhances the bioavailability of CHA but also facilitates a synergistic antioxidant effect between CHA and MIL/Fe-100. Importantly, CHA can chelate Zn Show less
Meng Xiong, Renjie Luo, Zhijiao Zhang+4 more · 2025 · Inflammation research : official journal of the European Histamine Research Society ... [et al.] · Springer · added 2026-04-24
Acute respiratory distress syndrome (ARDS) is a clinical syndrome characterized by high morbidity and mortality rates. Sepsis-induced ARDS involves excessive inflammatory responses, which are modulate Show more
Acute respiratory distress syndrome (ARDS) is a clinical syndrome characterized by high morbidity and mortality rates. Sepsis-induced ARDS involves excessive inflammatory responses, which are modulated by macrophages. This study aimed to elucidate the effect of Recombinant Mouse IL-27 Protein on macrophage ferroptosis and polarization, as well as its impact on sepsis-induced ARDS. A cecal ligation and puncture (CLP)-induced sepsis model was established using wild-type (WT) or IL27R In vitro, IL-27 alone did not alter the expression of proteins linked to the ferroptosis pathway or macrophage polarization. Contrastingly, the combination of IL-27 with LPS further amplified LPS-induced alterations in the ferroptosis pathway, thereby promoting macrophage M1 polarization and inhibiting M2 polarization. Additionally, IL-27 + LPS increased ROS levels in macrophages. A sepsis-induced ARDS mouse model was then established via CLP. In vivo, IL-27 exacerbated CLP-induced lung injury in WT mice. Additionally, it decreased the expression levels of ferroptosis-related proteins (Nrf2, HO-1, GPX4) and increased those of Ptgs2 in the lung tissue of septic mice. Besides, GSH and SOD levels in lung tissue were also reduced. Moreover, IL-27 also promoted M1 polarization and inhibited M2 polarization in macrophages. In IL27R Oltipraz may alleviate ARDS-related lung injury by up-regulating Nrf2 expression and concurrently inhibiting macrophage ferroptosis. Show less
Post traumatic stress disorder (PTSD) is a serious and persistent mental diseases. Nowadays, Treatment of PTSD patients in clinical practice is mainly based on drug therapy accompanied by psychologica Show more
Post traumatic stress disorder (PTSD) is a serious and persistent mental diseases. Nowadays, Treatment of PTSD patients in clinical practice is mainly based on drug therapy accompanied by psychological therapy. However, the therapeutic effect is unsatisfactory. It is urgent to detect how to treat PTSD patients. Here, we found that ginsenoside can significantly relieve PTSD symptoms in mice model. Rg3, one of the main pharmacological components of ginsenoside, prevents PTSD by promoting alternatively activated M2 phenotype microglia while inhibiting classically activated inflammatory M1 phenotype microglia. Mechanistically, Rg3 up-regulates fibroblast growth factor receptor 1 (FGFR1) expression in microglia to suppress excessive activation of microglia and reduce neuronal apoptosis. Importantly, knocking down FGFR1 expression in BV2 cells promoted a pro-inflammatory phenotype of BV2 cells, while over-expressing FGFR1 reversed this effect. In vivo PTSD mice model results showed that knockdown FGFR1 prevents the therapeutic effect of Rg3, which indicates that FGFR1 is an essential target of PTSD. Our results reveal that Rg3 may be a potential drug to treat PTSD patients. Show less
The transcription factor carbohydrate response element binding protein (ChREBP) activates genes of glucose, fructose, and lipid metabolism in response to carbohydrate feeding. Integrated transcriptomi Show more
The transcription factor carbohydrate response element binding protein (ChREBP) activates genes of glucose, fructose, and lipid metabolism in response to carbohydrate feeding. Integrated transcriptomic and metabolomic analyses in rats with GalNac-siRNA-mediated suppression of ChREBP expression in liver reveal other ChREBP functions. GalNac-siChREBP treatment reduces expression of genes involved in coenzyme A (CoA) biosynthesis, with lowering of CoA and short-chain acyl-CoA levels. Despite suppression of pyruvate kinase, pyruvate levels are maintained, possibly via increased expression of pyruvate and amino acid transporters. In addition, expression of multiple anaplerotic enzymes is decreased by GalNac-siChREBP treatment, affecting TCA cycle intermediates. Finally, GalNAc-siChREBP treatment suppresses late steps in purine and NAD synthesis, with increases in precursors and lowering of end products in both pathways. In sum, our study reveals functions of ChREBP beyond its canonical roles in carbohydrate and lipid metabolism to include regulation of substrate transport, mitochondrial function, and energy balance. Show less
The lack of standardized objective approaches hinders the accurate diagnosis and treatment of depression. Herein, a novel electrochemical platform was created utilizing cost-effective and rapid 3D pri Show more
The lack of standardized objective approaches hinders the accurate diagnosis and treatment of depression. Herein, a novel electrochemical platform was created utilizing cost-effective and rapid 3D printing technology to overcome the constraints of conventional diagnostic methods. This method allows for highly sensitive detection of Apolipoprotein A4 (Apo-A4), an important biomarker for depression, using dual-signal outputs. The electrode material utilized in this setup consisted of a combination of carbon black/polylactic acid (CB/PLA) and ferrocene-chitosan-gold nanoparticles (Fc-CS-AuNPs). On the other hand, the signal label was composed of gold nanoparticles-thionine-secondary antibody (AuNPs-Thi-Ab Show less
Diabetic cardiomyopathy (DCM) in type 2 diabetes (T2D) may lead to heart failure and patient death. Fibroblast growth factor 21 (FGF21) is a therapeutic candidate for treating this disease. However, o Show more
Diabetic cardiomyopathy (DCM) in type 2 diabetes (T2D) may lead to heart failure and patient death. Fibroblast growth factor 21 (FGF21) is a therapeutic candidate for treating this disease. However, one impediment to its clinical use is its weak ability to activate downstream signaling pathways. In this study, based on our in-depth understanding of the binding properties of fibroblast growth factor receptor 1c (FGFR1c) with paracrine FGF1 and endocrine FGF21, we engineered a novel FGF21 analog named FGF21 Show less
Acute respiratory distress syndrome (ARDS) is a severe clinical condition characterized by widespread inflammation and fluid accumulation in the lungs. Endothelial cell (EC) metabolic changes in acute Show more
Acute respiratory distress syndrome (ARDS) is a severe clinical condition characterized by widespread inflammation and fluid accumulation in the lungs. Endothelial cell (EC) metabolic changes in acute lung injury (ALI) and their relationship to injury remain unclear. Transcriptomic and lipidomic analyses revealed downregulation of PUFA synthesis pathways, particularly omega-3 PUFAs, in pulmonary ECs during LPS-induced ALI. Activation of the PUFA metabolic pathway, through FADS1/2 overexpression or omega-3 fatty acid supplementation, protected ECs from ferroptosis and restored barrier function. In vivo, pulmonary EC-specific overexpression of FADS1/2 contributed to the alleviation of ALI. Overexpression of whole lung FADS1/2, combined with alpha-linolenic acid (ALA) supplementation, also significantly mitigated ALI. PARK7 is identified as an endogenous regulator of FADS1/2, acting through the BMP-BMPR-SMAD1/5/9 signaling. Driven by histone H3K14 lactylation, which is also promoted by the downregulation of FADS1/2, PARK7 upregulation restored FADS1/2 expression and counteracted ferroptosis, thereby forming a protective feedback loop. This study elucidates a novel regulatory axis involving the two major metabolic changes-downregulation of PUFA synthesis and upregulation of histone lactylation-in ALI pathogenesis, which are interconnected through the PARK7-BMP signaling pathway. Targeting this axis offers potential therapeutic strategies for mitigating endothelial dysfunction and ferroptosis in ARDS/ALI. Show less
Accelerated population aging and rising incidence of bone defects have intensified the need for advanced bone regeneration strategies. While tissue-engineered scaffolds fabricated via 3D printing offe Show more
Accelerated population aging and rising incidence of bone defects have intensified the need for advanced bone regeneration strategies. While tissue-engineered scaffolds fabricated via 3D printing offer promising alternatives to conventional grafts, most techniques fail to replicate the multi-scale fibrous architecture of native bone extracellular matrix, limiting their biofunctionality. To address this, we developed a hybrid manufacturing strategy integrating low-temperature thermally induced phase separation with extrusion-based 3D printing of polylactic acid (PLA) scaffolds. By optimizing solvent ratios (THF: DMF = 3:1) and freezing temperatures (-196 °C-4 °C), we produced scaffolds with tunable micro-nano fibrous surfaces and macroporous structures. Key findings revealed that scaffolds processed at -196 °C (PLA-196) exhibited the highest porosity (pore size: 6.01 ± 2.06 μm), superior hydrophilicity, and enhanced compressive modulus. These scaffolds significantly promoted BMSC adhesion, proliferation, and osteogenic differentiation via activation of Show less
Graphical Abstract Lipoprotein lipase (LPL) mediates peripheral tissue triglyceride (TG) uptake. Hepatic ANGPTL3 (A3) and ANGPTL8 (A8) form a complex and inhibit LPL activity in the white adipose tiss Show more
Graphical Abstract Lipoprotein lipase (LPL) mediates peripheral tissue triglyceride (TG) uptake. Hepatic ANGPTL3 (A3) and ANGPTL8 (A8) form a complex and inhibit LPL activity in the white adipose tissue (WAT) via systematic circulation. ANGPTL4 (A4) is expressed in WAT and inhibits LPL activity locally. Feeding increases hepatic A8 expression and increases its inhibition for WAT LPL activity together with A3, while feeding suppresses WAT A4 expression and releases its inhibition on LPL. At room temperature, the feeding-suppressed A4 overrides the feeding-increased A3/A8, resulting in increased LPL activity in WAT by food intake. Browning improves hepatic insulin sensitivity and increases postprandial A8 expression. The feeding-increased A3/A8 overrides the feeding-suppressed A4, resulting in suppressed LPL activity in WAT by food intake. This reprogrammed LPL regulation plays an important role in reprogramming TG metabolism during adipose tissue browning. Show less
Biomarker profiling from biofluids such as blood are widely measured in clinical research, using for example Olink proteomics panels. One such research focus area is cardiovascular disease (CVD), for Show more
Biomarker profiling from biofluids such as blood are widely measured in clinical research, using for example Olink proteomics panels. One such research focus area is cardiovascular disease (CVD), for which chronic sleep restriction (SR) is a risk factor. However, it remains unclear whether blood levels of commonly measured CVD biomarkers are sensitive to acute dynamic factors such as SR, physical exercise (PEx), and time of day. In this crossover design, 16 normal-weight, healthy men underwent three highly standardized in-lab nights of SR (4.25 h/night) and normal sleep (NS, 8.5 h/night) in randomized order, with 88 CVD blood protein biomarkers quantified using the Olink technology (and selected validation using ELISA) in the morning, evening, and immediately before and repeatedly after 30 min of high-intensity exercise. We found significant time-of-day-dependent changes in several CVD biomarkers. Whereas several proteins were exercise-induced across sleep conditions (such as the canonical exerkines IL- 6 and BDNF), exercise-induced proteomic dynamics differed in response to recurrent SR, compared with following NS. Moreover, SR compared with NS resulted in a biomarker profile previously associated with increased prospective risk of several CVDs across large-scale cohorts (such as higher circulating levels of IL-27 and LGALS9). Our findings highlight how dynamic physiology can modulate CVD biomarker levels. These results also underscore the need to consider sleep duration as a key determinant of cardiovascular health-an emphasis reflected in recent American Heart Association guidelines. Further studies in women, older individuals, and patients with prior CVD, and across different chronotypes and dietary schedules are warranted. Show less
Homologous recombination repair (HRR) is crucial for maintaining genomic stability by repairing DNA damage. Despite its importance, HRR's role in cancer progression is not fully elucidated. Here, this Show more
Homologous recombination repair (HRR) is crucial for maintaining genomic stability by repairing DNA damage. Despite its importance, HRR's role in cancer progression is not fully elucidated. Here, this work shows that nuclear-localized branched-chain α-ketoacid dehydrogenase kinase (BCKDK) acts as a modulator of HRR, promoting cell resistance against DNA damage-inducing therapy in breast cancer. Mechanistically, this work demonstrates that BCKDK is localized in the nucleus and phosphorylates RNF8 at Ser157, preventing the ubiquitin-mediated degradation of RAD51, thereby facilitating HRR-mediated DNA repair under replication stress. Notably, aberrant expression of the BCKDK/p-RNF8/RAD51 axis correlates with breast cancer progression and poor patient survival. Furthermore, this work identifies a small molecule inhibitor of BCKDK, GSK180736A, that disrupts its HRR function and exhibits strong tumor suppression when combined with DNA damage-inducing drugs. Collectively, this study reveals a new role of BCKDK in regulating HRR, independent of its metabolic function, presenting it as a potential therapeutic target and predictive biomarker in breast cancer. Show less
Glucose homeostasis, essential for metabolic health, requires coordinated insulin and glucagon activity to maintain blood glucose balance. Dysregulation of glucose homeostasis causes hyperglycaemia an Show more
Glucose homeostasis, essential for metabolic health, requires coordinated insulin and glucagon activity to maintain blood glucose balance. Dysregulation of glucose homeostasis causes hyperglycaemia and glucose intolerance, hallmark features of type 2 diabetes. While SEC16 homologue B (SEC16B), an endoplasmic reticulum export factor, has been linked to obesity, type 2 diabetes and lipid metabolism, its role in glucose regulation remains poorly defined. This study aims to investigate SEC16B's contribution to glucose homeostasis by systematically dissecting its conserved physiological mechanisms across species. To interrogate SEC16B's role, we combined Drosophila genetics (RNA interference-mediated dSec16 knockdown) with murine models (Sec16b deletion) under standard or high-fat diet conditions. Glucose and insulin tolerance tests assessed glucose homeostasis. Mechanistic insights into beta cell dysfunction were derived from immunostaining, glucose-stimulated insulin secretion assays and RNA-seq profiling of murine pancreatic islets. Both disruption of dSec16 in Drosophila and Sec16b deletion in mice triggered glucose intolerance under standard diet conditions, recapitulating conserved metabolic dysfunction. In addition, Sec16b loss impaired glycaemic control in mice fed a high-fat diet. Mechanistically, Sec16b deficiency impairs insulin secretion by downregulating cholinergic signalling and compromising intracellular Ca Our study reveals SEC16B, a genome-wide association study-identified obesity risk gene, as an evolutionarily conserved regulator of glucose homeostasis. By linking SEC16B to cholinergic-driven insulin secretion and calcium dynamics, we resolve a mechanistic gap in beta cell dysfunction and metabolic disease. This finding provides novel insights into the mechanisms underlying glucose homeostasis and may enhance our understanding of potential treatments for metabolic diseases. Show less
Interleukin-27 receptor alpha (IL27RA), a key subunit of the interleukin-27 receptor, plays an essential role in T cell-mediated immunity. However, its relevance in breast cancer and response to immun Show more
Interleukin-27 receptor alpha (IL27RA), a key subunit of the interleukin-27 receptor, plays an essential role in T cell-mediated immunity. However, its relevance in breast cancer and response to immunotherapy remains unexplored. We integrated bulk and single-cell RNA sequencing data from TCGA, GEO, and scRNA-seq datasets to analyze IL27RA expression, prognosis, immune infiltration, and treatment response. TIDE and immune checkpoint-treated clinical cohorts were used to assess immunotherapy responsiveness. Chemotherapy sensitivity was predicted using GDSC data, and IL27RA protein expression was validated by Western blot. IL27RA was downregulated in breast cancer but high expression correlated with favorable survival. It was primarily expressed in T cells, particularly CD8⁺ subsets, and associated with enriched immune infiltration and elevated checkpoint gene expression. IL27RA high-expression patients showed lower TIDE scores, better outcomes in ICI-treated cohorts, and higher sensitivity to multiple chemotherapeutic agents. IL27RA is a potential immune biomarker that reflects an inflamed tumor microenvironment and predicts benefit from immunotherapy and chemotherapy in breast cancer. These findings provide novel insights into immune-based stratification using single-cell transcriptomic data. Show less
The existing evidence regarding the impact of tamoxifen on lipoprotein(a) and apolipoproteins remains inconsistent. Therefore, this updated meta-analysis of randomized controlled trials (RCTs) aims to Show more
The existing evidence regarding the impact of tamoxifen on lipoprotein(a) and apolipoproteins remains inconsistent. Therefore, this updated meta-analysis of randomized controlled trials (RCTs) aims to enhance the quality of evidence concerning the effects of tamoxifen on these lipid parameters. Eligible RCTs published up to October 2024 were meticulously selected through a comprehensive search. A meta-analysis was then performed using a random-effects model, and results were presented as the weighted mean difference (WMD) with a 95% confidence interval (CI). Findings from the random-effects model revealed an increase in ApoA-I (WMD: 15.22 mg/dL, 95% CI: 6.43-24.01, P = 0.001), alongside decreases in ApoB (WMD: -9.33 mg/dL, 95% CI: -15.46 to -3.19, P = 0.003) and lipoprotein(a) (WMD: -3.35 mg/dL, 95% CI: -5.78 to -0.91, P = 0.007) levels following tamoxifen treatment in women. Subgroup analyses indicated a more significant reduction in lipoprotein(a) levels in RCTs with a duration of ≤24 weeks (WMD: -3.65 mg/dL) and in studies using tamoxifen doses of ≥20 mg/day (WMD: -4.53 mg/dL). This meta-analysis provides evidence that tamoxifen leads to a decrease in lipoprotein(a) levels, along with reductions in ApoB and increases in ApoA-I among women. Show less
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
Osteosarcoma is the most prevalent primary malignant bone tumor in children and adolescents. However, its underlying pathogenesis and mechanisms driving metastasis remain poorly understood. Here, we i Show more
Osteosarcoma is the most prevalent primary malignant bone tumor in children and adolescents. However, its underlying pathogenesis and mechanisms driving metastasis remain poorly understood. Here, we identified a novel super-enhancer-associated long noncoding RNA (SE-lncRNA), Zinc Finger MIZ-Type Containing 1 Antisense RNA 1 (ZMIZ1-AS1), which is highly expressed in osteosarcoma and promoted tumor cell proliferation, migration, and invasion. Mechanistically, the m⁶A demethylase ALKBH5 post-transcriptionally stabilized ZMIZ1-AS1 through m⁶A demethylation. Furthermore, ZMIZ1-AS1 directly bound to the RNA-binding protein Polypyrimidine Tract Binding Protein 1 (PTBP1), facilitating the translocation of PTBP1 from the nucleus to the cytoplasm. The relocalized PTBP1 then bound to and stabilized fibroblast growth factor receptor 1 (FGFR1) mRNA. In nude mouse models, ZMIZ1-AS1 overexpression promoted tumor growth and lung metastasis. Notably, combined inhibition of ALKBH5 (using ALKBH5-IN-5) and FGFR1 (using BGJ398/infigratinib) synergistically suppressed ZMIZ1-AS1-driven oncogenesis in vivo. Our study establishes the ALKBH5/ZMIZ1-AS1/PTBP1/FGFR1 signaling axis as a key driver of osteosarcoma progression and a promising target for therapeutic intervention. Show less
Despite the increasing approval and ongoing clinical trials of FGFR-targeted therapies, accurately detecting FGFR fusions remains a challenge due to limited research, low incidence rates, complex fusi Show more
Despite the increasing approval and ongoing clinical trials of FGFR-targeted therapies, accurately detecting FGFR fusions remains a challenge due to limited research, low incidence rates, complex fusion partner distribution, and unique kinase domain distribution. We conducted a multicenter study to comprehensively profile FGFR fusions in the largest Chinese pan-cancer cohort to date, comprising 118 FGFR fusions from 114 individuals. Both DNA- and RNA-based sequencing approaches were utilized to reveal novel and fundamental features of FGFR fusion. Our research reveals an incidence rate of 0.96% for FGFR rearrangements within this Chinese cohort, including a high incidence rate of FGFR fusions (40%) in parotid gland carcinoma. However, this is based on a small sample size of 5 tumors and should be interpreted cautiously pending validation in larger cohorts. We also uncovered distinct breakpoint distribution patterns across various FGFR rearrangements. For example, a primary breakpoint in intron17 of FGFR2 was predominant (21/22), while FGFR1/3 breakpoints displayed substantial diversity. For the first time, we identified "hot" breakpoints in FGFR1 intron17, exon18, and FGFR3's 3' untranslated region. These findings underline the importance of incorporating these regions in targeted sequencing to ensure comprehensive detection of FGFR1/3 fusions. Notably, we observed a predilection for intrachromosomal distribution in common FGFR1/2/3 fusions. In contrast, most novel fusions (12/15) exhibited an interchromosomal distribution pattern, indicating variations in the fusion formation mechanism. Importantly, our study demonstrates the substantial incremental value of RNA-NGS or other orthogonal methods in confirming the functionality of FGFR rearrangements initially identified by DNA sequencing. In our cohort, 46% (6/13) of rare FGFR1/2/3 fusions lacked detectable RNA transcripts; however, this does not definitively indicate non-functionality as factors such as low RNA quality, expression below detection limits, or nonsense-mediated decay may contribute. Therefore, RNA-based validation is critical for accurately identifying potentially targetable FGFR fusions and guiding therapy. Our findings offer critical novel insights into functional FGFR fusions and bear considerable clinical implications for identifying individuals whose tumors are most likely to respond favorably to FGFR-targeted therapies. Show less
This study aimed to explore the effects of chili meal (CM), a by-product of chili pepper oil extraction, on the productive performance, intestinal health, and lipid metabolism of laying hens fed low-p Show more
This study aimed to explore the effects of chili meal (CM), a by-product of chili pepper oil extraction, on the productive performance, intestinal health, and lipid metabolism of laying hens fed low-protein (LP) diets. A total of 384 Hy-Line brown laying hens (32 weeks old) were divided into six groups: control (CON) diet with 16.5 % crude protein (CP), LP diet with 15 % CP, and LP diets supplemented with 3 %, 5 %, 7 %, and 9 % CM. Results showed that dietary CM supplementation of up to 5 % did not negatively affect the productive performance of laying hens fed LP diets. However, the groups receiving 7 % and 9 % CM exhibited a significant increase in the feed-to-egg ratio (P < 0.05). Additionally, dietary CM supplementation effectively enhanced egg yolk color in a dose-dependent manner (P < 0.05). Intestinal morphology analysis indicated that the 5 % CM group had a higher villus height-to-crypt depth ratio than the LP and 9 % CM groups (P < 0.05), with no significant differences among the other groups. Dietary supplementation with 3 %-7 % CM did not significantly affect serum and jejunal antioxidant capacity, and the 9 % CM group exhibited the highest levels of serum and jejunal malondialdehyde among the groups (P < 0.05). Dietary CM supplementation significantly increased anti-inflammatory cytokines (IL-4 and IL-10) and decreased pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α) in the serum and jejunal tissue of laying hens (P < 0.05). Moreover, CM supplementation significantly altered the cecal microbiota composition in laying hens, increasing the abundance of beneficial bacteria, such as Desulfovibrio and Megamonas. Furthermore, dietary CM supplementation significantly decreased serum triglyceride levels; downregulated liver mRNA levels of ACC, FAS, and SREBP-1C/2; and upregulated the mRNA levels of ACOX1, PPAR-α, Apob, and CPT in laying hens fed LP diets. In conclusion, CM supplementation should not exceed 5 % to avoid negative impacts on performance while supporting intestinal health and lipid metabolism. 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 (PPARγ, C/EBPβ, FASN and FABP4) in DUSP6 knockdown cells. Our results demonstrate that DUSP6 is required for white adipocyte adipogenesis in pigs. Show less
To explore the correlation between different traditional Chinese medicine (TCM) constitution types and apolipoprotein B (ApoB) in patients with hyperuricemia (HUA) and to investigate the relationships Show more
To explore the correlation between different traditional Chinese medicine (TCM) constitution types and apolipoprotein B (ApoB) in patients with hyperuricemia (HUA) and to investigate the relationships between TCM constitutions, uric acid levels, and various cardiovascular risk factors. A cross-sectional study involving 683 patients diagnosed with HUA was conducted. Patients' TCM constitutions were classified using the standardise "Classification and Determination of TCM Constitution" questionnaire. Serum uric acid (UA), lipid profiles, ApoB, and homocysteine (Hcy) levels were measured. Among 683 HUA patients, phlegm-dampness (22.99% ) and damp-heat constitution (20.06% ) were the most common TCM constitution types. UA, ApoB, and Hcy levels in patients with phlegm-damp constitution were significantly higher than those in other constitutions (P< 0.05). UA levels were negatively correlated with HDL-C (r=-0.472, P= 0.027) and positively correlated with ApoB (r= 0.618, P= 0.012) and Hcy (r= 0.492, P= 0.018). Phlegm-damp and damp-heat constitutions are the most common TCM constitution types in HUA patients and are associated with higher levels of UA, ApoB, and Hcy. These constitutional types are independently associated with increased cardiovascular risk. Show less