Integration of human genomics and other omics across different ancestries provides novel, affordable, and systematic approach for target identification. We used Mendelian randomization approaches to u Show more
Integration of human genomics and other omics across different ancestries provides novel, affordable, and systematic approach for target identification. We used Mendelian randomization approaches to unravel causal associations between 2,940 circulating proteins and 19 CVD. We found 218 proteins that impacted risk of one or more CVDs through forward MR (106 and 182 using cis-pQTLs only and cis- + trans-pQTLs, respectively), among which 107 were previously reported as associated with CVD or CVD-related traits. There were 102 proteins replicated (FDR < 5%, 53 with cis-pQTLs only and 88 with cis- + trans-pQTLs) using the FinnGen Olink data. BTN3A2 was highlighted as a novel candidate gene for ischemic stroke, suggesting a crosstalk between immune modulation and stroke pathogenesis. Single cell integration prioritized PAM for stable angina pectoris and ventricular arrhythmia and LPL for peripheral artery disease, whose transcriptional expressions were enriched in cardiomyocytes. Forward and reverse MR found largely non-overlapping proteins (only 2 overlapped: LGALS4 and MMP12), suggesting distinct proteomic causes and consequences of CVD. Our study provides human genetics-based evidence of novel candidate genes, a foundational step towards full-scale causal human biology-based drug discovery for CVD. Show less
Given the lack of evidence, we cannot definitively determine the relationship between attachment networks and problematic mobile phone use, hindering effective intervention strategies. Therefore, a th Show more
Given the lack of evidence, we cannot definitively determine the relationship between attachment networks and problematic mobile phone use, hindering effective intervention strategies. Therefore, a three-wave longitudinal study was designed to explore the heterogeneity of parent-child attachment networks using latent profile analysis (LPA) and random intercept latent transition analysis (RI-LTA). Participants included 2116 adolescents (ages 14-21; 53.8% girls). Results identified five stable parent-child attachment network profiles, each showing moderate but decreasing stability. Notably, adolescents who were grouped into an attachment network characterized by secure maternal attachment but insecure paternal attachment, similar to those in attachment networks with both insecure maternal and paternal attachment, scored higher levels of problematic mobile phone use than those who were grouped into attachment networks with both secure maternal and paternal attachment. Our findings fill empirical gaps and provide strong evidence supporting attachment-based interventions to reduce problematic mobile phone use. Show less
SLC35B4, a nucleotide sugar transporter that mediates the transport of UDP-GlcNAc and UDP-xylose, was found to be required for the replication of influenza A virus (IAV) of the H5N1 subtype in our gen Show more
SLC35B4, a nucleotide sugar transporter that mediates the transport of UDP-GlcNAc and UDP-xylose, was found to be required for the replication of influenza A virus (IAV) of the H5N1 subtype in our genome-wide siRNA library screen. We found that defective IAV replication in SLC35B4-deficient A549 cells was independent of virus strain specificity, and the virulence of IAV in Slc35b4 knockdown mice was also decreased. By examining the individual stages of the IAV replication cycle, we discovered that the amount of internalized IAV was significantly reduced in SLC35B4-knockout A549 cells. Mechanistically, SLC35B4 facilitated IAV replication by transporting UDP-xylose, which attaches to the serine residue of heparan sulfate proteoglycans (HSPGs) in the heparan sulfate (HS) biosynthesis pathway. Knockdown of associated host factors (i.e., XYLT2, B4GALT7, EXT1, and EXT2) in the HS biosynthesis pathway also impaired IAV replication. Furthermore, we revealed that AGRN, a unique HSPG family member, was important for the endocytosis of IAV in A549 cells. Moreover, we found that the homeostasis of the AGRN protein was regulated by HS modification mediated by the initial UDP-xylose transporter SLC35B4, thereby affecting the expression level of endocytic adapter AP2B1 to influence IAV internalization. Collectively, these findings establish that SLC35B4 is an important regulator of IAV replication and uncover the underlying mechanisms by which SLC35B4 employs UDP-xylose transport activity to promote IAV internalization.IMPORTANCEThe entry process of IAV represents a favorable target for drug development. In this study, we identified SLC35B4 as an important host factor for the efficient replication of different subtypes of IAV Show less
To investigate the effects and the underlying mechanism(s) of conbercept on the phagocytosis of hard exudates (HEs) by Müller glia in diabetic retinopathy (DR). Twenty-one eyes from 17 patients with d Show more
To investigate the effects and the underlying mechanism(s) of conbercept on the phagocytosis of hard exudates (HEs) by Müller glia in diabetic retinopathy (DR). Twenty-one eyes from 17 patients with diabetic macular edema (DME) underwent optical coherence tomography (OCT) imaging to examine the changes of HEs before and after intravitreal conbercept injection (IVC). The area of HEs showed minimal change after the first IVC (1.39±1.41 to 1.38±1.3 mm Conbercept reduces HEs in DR by enhancing Müller glia phagocytosis possibly through activating PPARγ-CD36 axis, which is mediated by inhibition of VEGF signaling. Modulation of Müller glia phagocytic capacity might provide a novel therapeutic strategy to treat DR and DME. Show less
Abnormal lipid accumulation is an important cause of metabolic dysfunction-associated fatty liver disease (MAFLD) progression and can induce several stress responses within cells. This study is the fi Show more
Abnormal lipid accumulation is an important cause of metabolic dysfunction-associated fatty liver disease (MAFLD) progression and can induce several stress responses within cells. This study is the first to explore the role and molecular mechanism of stress granules (SGs) in MAFLD. A gene knock-down model of G3BP1, a core SG molecule in mice and HepG2 cells, was constructed to explore the role of SGs in MAFLD induced in vivo by a high-fat diet or in vitro by palmitic acid (PA). Methods included metabolic phenotyping; western blotting; qPCR; and immunofluorescence, haematoxylin/eosin and masson staining. The downstream molecules of G3BP1 and its specific molecular mechanism were screened using RNA sequencing (RNA-seq). G3BP1 and TIA1 expression were upregulated in high-fat diet-fed mouse liver tissues and PA-induced HepG2 cells, and the two molecules showed significantly increased colocalisation. G3BP1 knock-down slightly increased TIA1 expression in the livers of obese mice but not in lean mice. G3BP1 deficiency aggravated liver lipid deposition and insulin resistance in obese mice, and this phenotype was confirmed in vitro in PA-induced hepatocytes. RNA-seq demonstrated that G3BP1 slowed down MAFLD progression by inhibiting APOC3, possibly through a mechanistic suppression of APOC3 entry into the nucleus. This study reveals for the first time a protective role for SGs in MAFLD. Specifically, knocking down the core G3BP1 molecule in SGs aggravated the progression of fatty acid-induced MAFLD through a mechanism that may involve the nuclear entry of APOC3. These findings provide a new therapeutic direction for MAFLD. Show less
Familial Hypercholesterolaemia (FH) is characterised by high cholesterol and premature cardiovascular disease. While hypercholesterolaemia and inflammation are both key drivers in the formation of ath Show more
Familial Hypercholesterolaemia (FH) is characterised by high cholesterol and premature cardiovascular disease. While hypercholesterolaemia and inflammation are both key drivers in the formation of atherosclerotic plaques, inflammation remains understudied in FH. Inflammatory (M1) macrophages contribute to plaque destabilisation and macrophage precursors, monocytes, can be skewed towards an inflammatory state. Aims: Determine; whether monocytes of FH individuals are inflammatory, if they readily form inflammatory macrophages, and whether this remains so in statin-treated individuals. Blood samples were collected from people with FH (statin-treated and untreated) and healthy controls. Lipid profile was obtained and monocyte inflammatory marker expression was determined by whole blood flow cytometry. Monocytes were cultured with autologous serum and resultant macrophage profile determined by flow cytometry. Total cholesterol and low-density lipoprotein cholesterol (LDL-C) were higher in the Untreated-FH group compared to the Treated-FH group and controls. In both Treated-FH and Untreated-FH groups, monocytes were inflammatory with high CD86 (M1). The ratio of inflammatory/anti-inflammatory markers (CD86/CD163) significantly correlated with LDL-C and ApoB/ApoA1 ratio across the cohort, indicating the high LDL-C of FH may promote an inflammatory monocyte profile. Monocyte-derived-macrophages from (Treated) FH individuals also had a more inflammatory profile (CD86 and CD86/CD163). Overall, monocytes show inflammatory skewing in FH individuals, even those with moderately-reduced cholesterol levels. These monocytes readily become inflammatory macrophages. This, along with subsequent inflammatory macrophage formation, could contribute to plaque destabilisation and downstream clinical events. This supports inflammatory monocyte targeting as a potential approach to reduce residual risk in FH individuals. Show less
The beak bean, found only in waterfowl and Galliformes, aids in foraging, self-defense and pecking hard objects. Its rich coloration results from prolonged evolutionary adaptation. This study analyzed Show more
The beak bean, found only in waterfowl and Galliformes, aids in foraging, self-defense and pecking hard objects. Its rich coloration results from prolonged evolutionary adaptation. This study analyzed beak bean phenotypes of duck at 10, 20, 30 and 40 days of age, revealing that the most common type is the black beak bean, characterized by melanin deposition on the beak surface. This study performed single nucleotide polymorphism (SNP)-based genome-wide association studies (GWASs) to investigate the genetic basis of beak bean color, identifying signals on chromosome 1. The copy number variation region-based GWAS revealed a consistent candidate region overlapping with the SNP-based GWAS signals, further supporting the importance of this genomic region. Locus zoom analysis further refined the candidate regions to 48.5-50.5 and 50.8-52.8 Mb. Functional enrichment analysis highlighted six candidate genes within these regions: KITLG, DUSP6, GALNT4, MGAT4C, ATP2B1 and NTS. Notably, KITLG and DUSP6, which are linked to melanin production, were identified as key candidate genes for beak bean color. Our finding revealed the genetic basis of the bean color traits for the first time in ducks, providing a theoretical foundation and technological framework for enhancing duck beak coloration. Show less
Hyperglycemia accelerates Alzheimer's disease (AD) progression, yet the role of monosaccharides remains unclear. Here, it is demonstrated that mannose, a hexose, closely correlates with the pathologic Show more
Hyperglycemia accelerates Alzheimer's disease (AD) progression, yet the role of monosaccharides remains unclear. Here, it is demonstrated that mannose, a hexose, closely correlates with the pathological characteristics of AD, as confirmed by measuring mannose levels in the brains and serum of AD mice, as well as in the serum of AD patients. AD mice are given mannose by intra-cerebroventricular injection (ICV) or in drinking water to investigate the effects of mannose on cognition and AD pathological progression. Chronic mannose overload increases β-amyloid (Aβ) burdens and exacerbates cognitive impairments, which are reversed by a mannose-free diet or mannose transporter antagonists. Mechanistically, single-cell RNA sequencing and metabolomics suggested that mannose-mediated N-glycosylation of BACE1 and Nicastrin enhances their protein stability, promoting Aβ production. Additionally, reduced mannose intake decreased BACE1 and Nicastrin stability, ultimately lowering Aβ production and mitigating AD pathology. this results highlight that high-dose mannose consumption may exacerbate AD pathogenesis. Restricting dietary mannose may have therapeutic benefits. Show less
Central nervous system (CNS) tumors often harbor alterations in genes regulating key cellular pathways, including fibroblast growth factor receptor (FGFR) genes. Here, we report the efficacy and safet Show more
Central nervous system (CNS) tumors often harbor alterations in genes regulating key cellular pathways, including fibroblast growth factor receptor (FGFR) genes. Here, we report the efficacy and safety of treatment with pemigatinib, an oral, potent, selective FGFR1-3 inhibitor, in patients with advanced FGFR-altered CNS tumors. FIGHT-207 was a single-arm, open-label, phase 2 study of pemigatinib in patients with advanced solid tumors harboring FGFR fusions/rearrangements or other mutations. Patients received pemigatinib 13.5 mg once daily until disease progression or unacceptable toxicity. Endpoints included tumor response and safety. Of the 13 patients with CNS tumors in FIGHT-207, 10 had glioblastoma. Fibroblast growth factor receptor alterations were FGFR3-TACC3 fusions (n = 9), FGFR1 K656E mutations (n = 2), FGFR1 N546K mutation (n = 1), and FGFR1-MITF fusion (n = 1). Three patients (23%) displayed objective responses (1 complete, 2 partial). Safety was consistent with the overall FIGHT-207 population. Pemigatinib had antitumor activity and a manageable safety profile in patients with CNS tumors. Show less
Heart failure (HF) as the terminal stage of various cardiac diseases, its underlying molecular mechanisms still remain elusive. Emerging evidence have implicated long noncoding RNAs (lncRNAs) play a m Show more
Heart failure (HF) as the terminal stage of various cardiac diseases, its underlying molecular mechanisms still remain elusive. Emerging evidence have implicated long noncoding RNAs (lncRNAs) play a multifaceted role in the progression of cardiac hypertrophy and HF. Here, it is identified that a lncRNA forkhead box O6, opposite strand (Foxo6os) is significantly downregulated in murine HF model induced using transverse aortic constriction (TAC). Knockdown of Foxo6os accelerates cardiomyocyte hypertrophy, reflects as elevated expression of atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and myosin heavy chain 7 (MYH7). Conversely, Foxo6os overexpression can improve cardiac function and alleviate adverse cardiac remodeling. Mechanistically, Foxo6os directly interacts with myosin-binding protein-C (MYBPC3), which then recruits protein kinase C alpha (PKC-α) to facilitate MYBPC3 phosphorylation, resulting in maintaining myocardial contractility and postponing HF progression. Therefore, these findings underscore the critical role of Foxo6os in preserving cardiomyocyte contractile function, suggesting a potential for Foxo6os as a novel therapeutic target of HF. Show less
Gentidelasides A-G (1-7) seven unreported loganin derivatives and fourteen known compounds (8-21) were isolated from the flowers of Gentiana delavayi Franch. Their structures including absolute config Show more
Gentidelasides A-G (1-7) seven unreported loganin derivatives and fourteen known compounds (8-21) were isolated from the flowers of Gentiana delavayi Franch. Their structures including absolute configurations were unambiguously elucidated by analysis of extensive NMR spectroscopy, ECD, and HRESIMS, as well as enzymatic hydrolysis. In vitro bioassay, compound 7 showed obvious inhibitory effects on the production of Aβ40 and Aβ42, with IC Show less
Arsenic (As) is a toxic metalloid widespread in the environment, and its exposure has been associated with a variety of adverse health outcomes. As exposure is demonstrated to cause nonalcoholic fatty Show more
Arsenic (As) is a toxic metalloid widespread in the environment, and its exposure has been associated with a variety of adverse health outcomes. As exposure is demonstrated to cause nonalcoholic fatty liver disease (NAFLD), and the underlying epigenetic mechanisms remain largely unknown. This study aimed to investigate the roles of histone modifications in low-level As exposure-induced NAFLD in rats. The results showed that exposure to As caused lipid accumulation and upregulated the expression of lipid metabolism-related genes Show less
Impaired glucose-stimulated insulin secretion (GSIS) is a hallmark of β cell dysfunction in diabetes. Epigenetic mechanisms govern cellular glucose sensing and GSIS by β cells, but they remain incompl Show more
Impaired glucose-stimulated insulin secretion (GSIS) is a hallmark of β cell dysfunction in diabetes. Epigenetic mechanisms govern cellular glucose sensing and GSIS by β cells, but they remain incompletely defined. Here, we found that BAF60a functions as a chromatin regulator that sustains biphasic GSIS and preserves β cell function under metabolic stress conditions. BAF60a was downregulated in β cells from obese and diabetic mice, monkeys, and humans. β cell-specific inactivation of BAF60a in adult mice impaired GSIS, leading to hyperglycemia and glucose intolerance. Conversely, restoring BAF60a expression improved β cell function and systemic glucose homeostasis. Mechanistically, BAF60a physically interacted with Nkx6.1 to selectively modulate chromatin accessibility and transcriptional activity of target genes critical for GSIS coupling in islet β cells. A BAF60a V278M mutation associated with decreased β cell GSIS function was identified in human donors. Mice carrying this mutation, which disrupted the interaction between BAF60a and Nkx6.1, displayed β cell dysfunction and impaired glucose homeostasis. In addition, GLP-1R and GIPR expression was significantly reduced in BAF60a-deficient islets, attenuating the insulinotropic effect of GLP-1R agonists. Together, these findings support a role for BAF60a as a component of the epigenetic machinery that shapes the chromatin landscape in β cells critical for glucose sensing and insulin secretion. Show less
Accumulation of amyloid-β (Aβ) peptides and hyperphosphorylated tau proteins in the hippocampus triggers cognitive memory decline in Alzheimer's disease (AD). The incidence and mortality of sporadic A Show more
Accumulation of amyloid-β (Aβ) peptides and hyperphosphorylated tau proteins in the hippocampus triggers cognitive memory decline in Alzheimer's disease (AD). The incidence and mortality of sporadic AD were tightly associated with diabetes and hyperlipidemia, while the exact linked molecular mechanism is uncertain. Here, the present investigation identified significantly elevated serum Kallistatin levels in AD patients concomitant with hyperglycemia and hypertriglyceridemia, suggesting potential crosstalk between neuroendocrine regulation and metabolic dysregulation in AD pathophysiology. In addition, the constructed Kallistatin-transgenic (KAL-TG) mice defined its cognitive memory impairment phenotype and lower long-term potentiation in hippocampal CA1 neurons accompanied by increased Aβ deposition and tau phosphorylation. Mechanistically, Kallistatin could directly bind to the Notch1 receptor and thereby upregulate BACE1 expression by inhibiting PPARγ signaling, resulting in Aβ cleavage and production. Besides, Kallistatin could promote the phosphorylation of tau by activating GSK-3β. Fenofibrate, a hypolipidemic drug, could alleviate cognitive memory impairment by downregulating Aβ and tau phosphorylation of KAL-TG mice. Collectively, the experiments clarified a novel mechanism for Aβ accumulation and tau protein hyperphosphorylation regulation by Kallistatin, which might play a crucial role in linking metabolic syndromes and cognitive memory deterioration, and suggested that fenofibrate might have the potential for treating metabolism-related AD. Show less
The Tibetan sheep is a typical hypoxia-tolerant mammal, which lives on the plateau, at an altitude of between 2500 and 5000 m above sea level; the study of its hypoxic adaptation mechanism provides a Show more
The Tibetan sheep is a typical hypoxia-tolerant mammal, which lives on the plateau, at an altitude of between 2500 and 5000 m above sea level; the study of its hypoxic adaptation mechanism provides a reference for exploring the hypoxic adaptation mechanism of other animals. To grope for the genetic mechanism of adaptation to the hypoxic environment at the transcriptional level in Tibetan sheep testicular tissue, and to identify candidate genes and key pathways related to sheep adaptation, histological observation of testicular tissues from two sheep breeds was carried out using haematoxylin-eosin (HE) conventional staining. A total of 103 differentially expressed genes (DEGs) were authenticated in high altitude Tibetan sheep (ZYH) and low altitude Tibetan sheep (ZYM) by RNA sequencing technology (RNA-Seq), which included 50 up-regulated genes and 53 down-regulated genes. Functional analyses revealed several terms and pathways that were closely related to testis adaptation to the plateau. Several genes (including GGT5, AGTR2, EDN1, LPAR3, CYP2C19, IGFBP3, APOC3 and PKC1) were remarkably enriched in several pathways and terms, which may impact the Plateau adaptability of sheep by adjusting its reproductive activity and sexual maturation, and protecting Sertoli cells, various spermatocytes, and spermatogenesis processes. The results make a reasonable case for a better understanding of the molecular mechanisms of adaptation to altitude in sheep. Show less
Dyslipidemia exacerbates pancreatic β-cell apoptosis, heightening the risk of type 2 diabetes (T2DM). Kansuinine A (KA), a diterpene from Euphorbia roots, exhibits antiapoptotic properties, suggestive Show more
Dyslipidemia exacerbates pancreatic β-cell apoptosis, heightening the risk of type 2 diabetes (T2DM). Kansuinine A (KA), a diterpene from Euphorbia roots, exhibits antiapoptotic properties, suggestive of its therapeutic potential against T2DM. In this study, we evaluated the protective effects of KA against apolipoprotein C3 (ApoC3)-rich low-density lipoprotein (LDL) (AC3RL)-induced β-cell apoptosis and its underlying mechanism of action. ApoE Show less
The Huainan pig (HN) is known for its impressive litter size and exquisite meat quality. However, it also exhibits certain drawbacks such as excessive fat deposition, a relatively low percentage of le Show more
The Huainan pig (HN) is known for its impressive litter size and exquisite meat quality. However, it also exhibits certain drawbacks such as excessive fat deposition, a relatively low percentage of lean meat percentage, and a slower growth rate. Crossbreeding with lean-type breeds, such as Large White, Landrace, and Berkshire can enhance offspring traits, and increase genetic diversity. In this study we employed RNA-seq technology to identify differentially expressed genes (DEGs) in subcutaneous adipose tissue (SAT) samples from HN pigs and their crosses with multiple breeds (with three replicates per group). In the SAT of Huainan × Berkshire pigs (BH), Huainan × Yorkshire pigs (YH), and Huainan × Landrace pigs (LH), numerous key functional genes were identified, including In conclusion, these findings offer valuable insights and provide a foundation for future research on the molecular mechanisms underlying fat deposition in pigs. Show less
The color of rice leaves are important agronomic traits that directly influence the proportion of sunlight energy utilization and ultimately affect the yield and quality, so it is crucial to excavate Show more
The color of rice leaves are important agronomic traits that directly influence the proportion of sunlight energy utilization and ultimately affect the yield and quality, so it is crucial to excavate the mechanism of regulating rice leave color. To investigate the molecular mechanism that triggers the purple color in rice leaf, phenotypic characterization and genome-wide transcriptome analysis were conducted using the japonica rice cultivar nipponbare (Nip) and its two purple leaf mutants, A total of 2247, 5484, 4525, 2103, 4375 and7029DEGs (differentially expressed genes) were identified in nip-a vs These results not only revealed the molecular mechanism triggering leaf purple color in the rice mutants Show less
Inflammatory bowel disease (IBD) is a chronic, immune-mediated intestinal disorder driven by dysregulated immune responses in genetically susceptible individuals. Despite recent advances in treatment, Show more
Inflammatory bowel disease (IBD) is a chronic, immune-mediated intestinal disorder driven by dysregulated immune responses in genetically susceptible individuals. Despite recent advances in treatment, more than 30% of patients either fail to respond initially or lose response over time, underscoring the need for a deeper mechanistic understanding of immunogenetic pathways and the development of individualized therapeutic strategies. We first discuss how newly identified susceptibility genes (e.g., IL23R, NOD2, BDNF, SLC) and their polymorphisms influence immune cell function and epithelial barrier integrity. Single-cell technologies have further revealed novel cell subsets and interactions underlying disease heterogeneity. We then explore the clinical efficacy of classical and emerging targeted therapies, including cytokine-specific biologics, JAK inhibitors, and novel strategies aimed at restoring regulatory T-cell function or blocking integrin-mediated lymphocyte trafficking. Additionally, we highlight promising therapeutic approaches such as fecal microbiota transplantation, microbial metabolite-based interventions, and nanotherapeutics. We further discuss how genetic insights and immune biomarkers can facilitate treatment personalization and improve prognostic stratification. Ultimately, this review emphasizes the transition from broad immunosuppression to precision medicine and proposes integrated approaches-combining multiomics profiling, immune monitoring, and novel therapeutics-to achieve sustained remission and improve long-term outcomes in IBD patients. Show less
Yolk percentage is a critical index in the egg product industry, reflecting both nutritional value and economic benefits. To elucidate the underlying mechanisms that contribute to variations in egg yo Show more
Yolk percentage is a critical index in the egg product industry, reflecting both nutritional value and economic benefits. To elucidate the underlying mechanisms that contribute to variations in egg yolk percentage, we performed integrated transcriptome and metabolome analyses on the liver, ovary, and magnum tissues of Rhode Island Red chickens with high and low yolk percentages. A total of 322 differentially expressed genes (DEGs) and 128 significantly differential metabolites (SDMs) (VIP>1, P < 0.05) were identified in the liver, whereas 419 DEGs and 215 SDMs were detected in the ovary, and 238 DEGs along with 47 SDMs were found in the magnum. In the liver, genes such as HMGCR, DHCR7, MSMO1, and CYP7A1 were linked to cholesterol metabolism, essential for steroid hormone synthesis and yolk formation, while ACACB, ACSL1, ACSL4, LPL, and SGPP2 were involved in fatty acid biosynthesis, a key process for supplying energy and structural components of the yolk. In the ovary, COL6A6, COMP, CHAD, ITGA7, THBS2, and TNC contributed to extracellular matrix-receptor interactions, which are fundamental for follicle development and oocyte maturation. In the magnum, UGT1A1, MAOB, and ALDH3B2 participated in drug metabolism-cytochrome P450 and amino acid metabolism, ensuring a proper environment for egg white formation and potentially influencing nutrient allocation to the yolk. Metabolic pathway enrichment revealed that steroid hormone biosynthesis, glycerophospholipid metabolism, and betaine metabolism were predominant in the liver; pyruvate, taurine, and hypotaurine metabolism in the ovary; and phenylalanine metabolism in the magnum. Moreover, integrated analysis highlighted key metabolites and genes potentially regulating yolk deposition, including 7,8-dihydroneopterin and Pg 38:4 in the liver (related to immune modulation and lipid metabolism, respectively), thalsimine in the ovary, as well as DL-glutamine in the magnum, all of which may be crucial for maintaining metabolic homeostasis and supporting egg formation. Collectively, these findings deepen our understanding of how distinct molecular and metabolic pathways in the liver, ovary, and magnum orchestrate yolk proportion and deposition. Such insights may advance future strategies to improve egg quality and productivity in poultry breeding programs. Show less
Palmitic acid (PA), being the most prevalent free fatty acid in the human, holds significant implications as a risk factor for atherosclerosis (AS) due to its ability to induce physiological dysfuncti Show more
Palmitic acid (PA), being the most prevalent free fatty acid in the human, holds significant implications as a risk factor for atherosclerosis (AS) due to its ability to induce physiological dysfunction in endothelial cells (ECs). Endothelial cell-specific molecule 1 (ESM1), has been identified as a marker for activated ECs. Nevertheless, the mechanisms underlying ESM1-induced endothelial cell proliferation remain elusive. The expression of ESM1, ANGPTL4 and autophagy related protein were confirmed by western blot. Proliferation ability was tested by MTT and EdU. Lipids level was confirmed by Oil red staining. Autophagic flux was confirmed by Monodansylcadaverine (MDC) staining and pCMV-mCherry-GFP-LC3B fluorescence staining assay. The mouse model of AS was used to observe the effect of PA on the ESM1-ANGPTL4-autophagy signaling axis. This study elucidates ESM1-ANGPTL4 axis in maintaining proliferation of ECs and lipid reprogramming. Furthermore, it has been observed that PA has the ability to stimulate EC to autonomously increase the expression of ESM1, which in turn can counteract the detrimental effects of PA on ECs. Conversely, when ESM1 is suppressed, the damaging effects of PA on ECs are exacerbated. Mechanistically, our findings indicate that ESM1 facilitates EC proliferation and lipids homeostasis by up-regulating autophagy through ANGPTL4. This effect of ESM1 on ECs can be attenuated by ATG7 inhibiting. Additionally, the serum levels of ESM1 were found to be elevated in AS mice. ESM1 was found to enhance ECs proliferation and mitigate endothelial cell injury induced by PA through the upregulation of autophagy. This mechanism potentially serves as a protective factor against atherosclerosis progression. Show less
Salmonella enterica serovar Typhimurium (S. Typhimurium) is a facultative intracellular bacterial pathogen that grows within a specialized membrane-bound compartment known as the Salmonella-containing Show more
Salmonella enterica serovar Typhimurium (S. Typhimurium) is a facultative intracellular bacterial pathogen that grows within a specialized membrane-bound compartment known as the Salmonella-containing vacuole (SCV). The molecular composition and regulatory mechanisms governing SCV dynamics remain incompletely understood. In this study, we employed proximity-dependent biotin identification (BioID) to analyze the SCV proteome during infection. For this, we targeted the UltraID biotin ligase to the SCV by fusing it to a type 3 secreted effector. We demonstrate that the bacteria express and translocate the effector-UltraID fusion protein directly into host cells for labeling of the cytosolic face of the SCV surface. Proteomic analysis of biotinylated proteins revealed previously undescribed proteins associated with the SCV, including regulators of vesicular trafficking, cellular metabolism and lipid transport. Among these, VPS13C, a lipid transporter and membrane contact site protein, was identified as a critical regulator of SCV morphology and fission. Functional studies revealed that VPS13C also promotes ER-SCV contact formation, controls SCV positioning in host cells, and facilitates cell-to-cell spread by the bacteria. Together, our findings highlight the utility of BioID as a tool to study host-pathogen interactions in the context of infection and characterize VPS13C as a novel modulator of the intracellular life cycle of S. Typhimurium. Show less
Fibroblast Growth Factor (FGF) ligands and their receptor have been identified as the potent target in non-small cell lung cancer (NSCLC). However, the clinicopathological and microenvironmental chara Show more
Fibroblast Growth Factor (FGF) ligands and their receptor have been identified as the potent target in non-small cell lung cancer (NSCLC). However, the clinicopathological and microenvironmental characteristics of FGF/FGFR in NSCLC remain poorly elucidated. Here, we summarize 4656 NSCLCs and analyze clinicopathological features in 478 FGF/FGFR altered cases. AI analysis and multiplex immunofluorescence staining are used to reveal microenvironment features. First, around 10.27% NSCLC carry FGF/FGFR variant. Squamous cell carcinoma (41.95%) is much more than adenocarcinoma (8.32%). In 118 pathogenic variant (PV) cases, the most frequent variant is FGF/FGFR copy number increase (83.05%), the second is FGFR gene fusion (11.86%). Surprisingly, CCND1 always co-amplifies with FGF19 (100.00%). Furthermore, FGF PV is an independent risk factor for poor outcomes (overall survival: HR = 3.781, disease-free survival: HR = 3.340). And one-third of FGFR3-TACC3 fusion cases show clear cytoplasm in histology. Either CCND1/FGF19 co-amplification or KRAS co-mutation is closely related to cigarette exposure, and KRAS co-mutation acts as an independent factor of poor prognosis. Finally, the FGF/FGFR1/NOTCH1 within RB1 variant group has a remarkably high ratio of inner-tumor CD8+ T cell infiltration, non-exhausted T cells, exhausted T Show less
Qianzhu Jiang, Huiting Li · 2025 · Journal of bioenergetics and biomembranes · Springer · added 2026-04-24
Myocardial fibrosis (MF) is a key pathological process driving heart failure, characterized by excessive extracellular matrix (ECM) deposition and impaired cardiac function. Although myocyte-specific Show more
Myocardial fibrosis (MF) is a key pathological process driving heart failure, characterized by excessive extracellular matrix (ECM) deposition and impaired cardiac function. Although myocyte-specific enhancer factor 2 A (MEF2A) is implicated in cardiac fibroblast activation, its role in MF remains unclear. We manipulated MEF2A expression in cardiac fibroblasts (CFs) through knockdown and overexpression, and assessed fibrosis markers, migration, and RhoA signaling. Binding of MEF2A to the Snail1 promoter was predicted using JASPAR and validated by chromatin immunoprecipitation (ChIP) and luciferase reporter assays. Rescue experiments with Snail1 overexpression and RhoA inhibition were performed. An angiotensin II (Ang II)-induced MF mouse model was used to evaluate cardiac function by echocardiography and to assess collagen deposition through picrosirius red (PSR) staining. MEF2A was significantly upregulated in Ang II-induced fibrotic hearts and CFs. MEF2A knockdown reduced α-SMA and Col1a1 expression, inhibited CF migration, and suppressed activation of the Snail1/RhoA/α-SMA pathway. ChIP and luciferase assays confirmed the direct binding of MEF2A to the Snail1 promoter. Inhibition of RhoA signaling reversed MEF2A-induced myofibroblast activation and migration. Rescue experiments showed that Snail1 overexpression restored the fibrotic phenotype suppressed by MEF2A knockdown. In vivo, MEF2A knockdown improved left ventricular function, reduced collagen deposition (PSR staining), and lowered heart weight/tibia length ratios. MEF2A promotes myocardial fibrosis by directly activating Snail1 and engages the RhoA/α-SMA pathway. Targeting MEF2A offers a promising therapeutic strategy to attenuate MF and improve heart function. Show less
To investigate the impact of obesity on brain structure and cognition using large neuroimaging and genetic data. Associations between body mass index (BMI), gray matter volume (GMV), whiter matter hyp Show more
To investigate the impact of obesity on brain structure and cognition using large neuroimaging and genetic data. Associations between body mass index (BMI), gray matter volume (GMV), whiter matter hyper-intensities (WMH), and fluid intelligence score (FIS) were estimated in 30283 participants from the UK Biobank. Longitudinal data analysis was conducted. Genome-wide association studies were applied to explore the genetic loci associations among BMI, GMV, WMH, and FIS. Mendelian Randomization analyses were applied to further estimate the effects of obesity on changes in the brain and cognition. The observational analysis revealed that BMI was negatively associated with GMV (r = -0.15, p < 1 The phenotypic and genetic association between obesity and aging brain and cognitive decline suggested that weight control could be a promising strategy for slowing the aging brain. Show less
The β-site amyloid precursor protein-cleaving enzyme 1 (BACE1) gene polymorphism (rs638405) has been widely reported to be associated with Alzheimer's disease (AD) risk. However, studies on the relati Show more
The β-site amyloid precursor protein-cleaving enzyme 1 (BACE1) gene polymorphism (rs638405) has been widely reported to be associated with Alzheimer's disease (AD) risk. However, studies on the relationship between BACE1 gene polymorphism (rs638405), brain volume, and cognition in AD patients remain scarce. To investigate the effect of genetic polymorphism in BACE1 on gray matter volume (GMV) and cognition in AD, this study recruited 111 cognitively unimpaired (CU) controls and 144 AD patients. The effect of BACE1 rs638405 polymorphism on cognition was explored in CU and AD groups. Then the interaction effect of the diagnosis and BACE1 rs638405 polymorphism on GMV was performed, following the post-hoc analysis of regions of interest (ROIs) in interaction analysis. Mediation analysis was used to elucidate the relationship among genotypes, ROIs and cognition. BACE1 rs638405 G carriers (BACE1 G+) showed significantly lower scores in global cognition and memory function than noncarriers (BACE1 G-) in AD group. Genotypes (G+/G-) and diagnosis (CU/AD) have interaction on GMV of medial temporal lobe (MTL) including the left parahippocampus and right hippocampus. Post-hoc analysis revealed that BACE1 G+ exhibited significantly lower GMV in ROIs compared to BACE1 G- in AD. Finally, mediation analysis further demonstrated that the GMV of ROIs mediated the effect of BACE1 rs638405 polymorphism on cognition in AD. Our results emphasize the BACE1 rs638405 gene polymorphisms may affect the GMV of MTL and cognition in AD, deepening the understanding of AD pathogenesis. Show less
Melatonin (MLT) can improve mitophagy, thereby ameliorating cognitive deficits in Alzheimer's disease (AD) patients. Hence, our research focused on the potential value of MLT-related genes (MRGs) in A Show more
Melatonin (MLT) can improve mitophagy, thereby ameliorating cognitive deficits in Alzheimer's disease (AD) patients. Hence, our research focused on the potential value of MLT-related genes (MRGs) in AD through bioinformatic analysis. First, the key cells in the single-cell dataset GSE138852 were screened out based on the proportion of annotated cells and Fisher's test between the AD and control groups. The differentially expressed genes (DEGs) in the key cell and GSE5281 datasets were identified, and the MRGs in GSE5281 were selected via weighted gene coexpression network analysis. After intersecting two sets of DEGs and MRGs, we performed Mendelian randomization analysis to identify the MRGs causally related to AD. Biomarkers were further ascertained through receiver operating characteristic curve (ROC) and expression analysis in GSE5281 and GSE48350. Furthermore, gene set enrichment analysis, immune infiltration analysis and correlation analysis with metabolic pathways were conducted, as well as construction of a regulator network and molecular docking. According to the Fisher test, oligodendrocytes were regarded as key cells due to their excellent abundance in the GSE138852 dataset, in which there were 281 DEGs between the AD and control groups. After overlapping with 3,490 DEGs and 550 MRGs in GSE5281, four genes were found to be causally related to AD, namely, G protein-coupled receptor, family C, group 5, member B (GPRC5B), Methyltransferase-like protein 7 A (METTL7A), NF-κB inhibitor alpha (NFKBIA) and RAS association domain family 4(RASSF4). Moreover, GPRC5B, NFKBIA and RASSF4 were deemed biomarkers, except for METTL7A, because of their indistinctive expression between the AD and control groups. Biomarkers might be involved in oxidative phosphorylation, adipogenesis and heme metabolism. Moreover, T helper type 17 cells, natural killer cells and CD56dim natural killer cells were significantly correlated with biomarkers. Transcription factors (GATA2, POU2F2, NFKB1, etc.) can regulate the expression of biomarkers. Finally, we discovered that all biomarkers could bind to MLT with a strong binding energy. Our study identified three novel biomarkers related to MLT for AD, namely, GPRC5B, NFKBIA and RASSF4, providing a novel approach for the investigation and treatment of AD patients. Show less
Inflammation is crucial in regulating coagulation and hemostasis. While prior research shows that apolipoprotein A-IV (ApoA-IV) has anti-inflammatory and antiplatelet effects, its specific impact on c Show more
Inflammation is crucial in regulating coagulation and hemostasis. While prior research shows that apolipoprotein A-IV (ApoA-IV) has anti-inflammatory and antiplatelet effects, its specific impact on coagulation remains unclear. To investigate the effects of ApoA-IV on the coagulation system, including its interactions with potential targets and the underlying mechanisms. Plasma ApoA-IV levels in deep vein thrombosis patients were tested by enzyme-linked immunosorbent assay. The effects of ApoA-IV on coagulation were assessed through thromboelastography. Potential interactions and mechanisms were analyzed using surface plasmon resonance and AlphaFold 3. Mice bleeding and stroke models were employed to evaluate the effects on hemostasis and thrombosis. ApoA-IV levels were reduced in deep vein thrombosis patients and correlated with increased thrombotic risk. Thromboelastography showed that ApoA-IV treatment delayed clot reaction and kinetic times while decreasing thrombus generation angle and maximum amplitude, highlighting its crucial role in inhibiting coagulation and platelet aggregation. We identified ApoA-IV as a functional activator of activated protein C (APC), with critical interactions occurring at residues 144 to 148 within the exosite loop of the APC protease domain. In animal models, anti-ApoA-IV antibody administration shortened bleeding time but exacerbated ischemic stroke outcomes. Notably, inhibitory peptide HE5, which inhibits ApoA-IV-APC interaction, effectively counteracted the anticoagulant activity of ApoA-IV. These findings establish ApoA-IV as a pivotal regulator of coagulation and hemostasis, primarily through enhancing APC activity. This research advances our understanding of the interplay between inflammation, lipid metabolism, and thrombosis, offering insights for developing novel antithrombotic therapies. Show less