👤 Yuqiang Nie

Individuals who experience adverse events during their early life stages are more likely to face negative consequences across various life domains throughout their lifespan. While latent profile analysis has been increasingly applied to adverse childhood experiences (ACEs) worldwide, simultaneous prospective investigations of negative and positive posttraumatic outcomes in Chinese emerging adults remain scarce. The present study aimed to extend prior literature by: (a) assessing the latent profile groupings of ACEs among emerging adults, and (b) analyzing the prospective associations between latent profiles of ACEs and posttraumatic outcomes over a six-month interval, including complex posttraumatic stress disorder (CPTSD) symptoms and posttraumatic growth (PTG). From 3,994 college students who participated in 2 surveys 6 months apart, 1,814 participants (mean age: 18.93 ± 1.45) who reported ACEs were selected. The sample included 901 males (49.7%) and 913 females (50.3%). Data were collected through a two-wave online survey measuring ACEs, CPTSD symptoms, and PTG. The Latent Profile Analysis identified five ACE profiles: High neglect (14.9%), Moderate family dysfunction (46.3%), Moderate abuse (25.1%), High risk (8.5%), and Moderate maltreatment/High family dysfunction (5.2%). Moderate family dysfunction (Profile 2) and Moderate maltreatment/High family dysfunction showed better posttraumatic adaptation than others. The High-risk group had the worst outcomes, while the High neglect and Moderate abuse groups fared better than the High-risk group. This study provides valuable insights into the concurrent examination of ACEs and their impact on the CPTSD symptoms and PTG of emerging adults. It offers a foundation for developing tailored intervention strategies for affected groups. Show less

Inflammation is a complex factor in the pathogenesis of intracranial aneurysms (IA), but its specific cellular inflammatory factors remain uncertain. We collected two cohorts and measured the representation of vascular inflammation-related proteins using the Olink CVD II Vascular Inflammation Panel. We subsequently validated our findings using ELISA and RT-qPCR. Our proteomic analysis identified 11 vascular inflammation-related markers that were significantly differentially represented between the IA and control groups. These markers were implicated in leukocyte migration, immune response, triglyceride and lipoprotein metabolism, acute phase response, T cell regulation, and several key biological pathways, including PPAR, HIF-1, cytokine-cytokine interactions, and PI3K-AKT signaling. Further validation with ELISA and RT-qPCR confirmed the differential representation of IL6, PTX3, LPL, and OLR1 between the two groups. Notably, a combination marker incorporating these four factors demonstrated high diagnostic potential for the early detection of IA. Our study has identified a set of informative biomarkers (IL6, PTX3, LPL, and OLR1) that could be valuable for the early diagnosis of IA. Importantly, this is the first report of significantly elevated OLR1 representation in the plasma of IA patients. Further investigation into the role of OLR1 in the pathogenesis of IA is warranted. SIGNIFICANCE: This study significantly advances our understanding of the molecular mechanisms underlying intracranial aneurysm (IA) pathogenesis. By identifying a panel of novel biomarkers, including the previously unreported elevated expression of OLR1 in IA patients, we provide crucial insights into the inflammatory processes involved in aneurysm formation and development. These findings have important clinical implications, as the identified biomarkers could serve as valuable tools for early diagnosis and potentially targeted therapeutic interventions. Furthermore, the study highlights the complex interplay of inflammatory pathways in IA, suggesting that a multi-faceted approach may be necessary for effective management. Show less

Sex differences in patients with hypertrophic cardiomyopathy have been elaborated by many studies. However, large studies of the association of patient sex with outcomes after surgical myectomy are scarce. This study evaluated sex disparities in a large Chinese cohort undergoing hypertrophic cardiomyopathy surgery. The cohort encompassed 1613 patients, including 627 (38.9%) women who underwent septal myectomy between 2009 and 2018. At the time of surgery, women were 6 years older and had 1 year longer disease onset-to-surgery delay than men. They were more frequently in New York Heart Association class III/IV and had more severe left ventricular outflow tract obstruction. Compared with men, women had a notably higher left ventricular wall thickness index and a lower extent of late gadolinium enhancement. Women also had more mutations in In patients with obstructive hypertrophic cardiomyopathy, women had a similar fatal outcome but a worse nonfatal outcome than men after surgery. Measures improving quality of life may further enhance the event-free survival of female patients. Close monitoring and follow-up are warranted, especially in younger men and older women. Show less

Nucleoporins, as major components of nuclear pore complex, have been recently discovered to participate in organ development. Here, we report a young female patient with nephrotic proteinuria resistant to immune suppressant treatment and congenital ovarian insufficiency. Renal pathology confirmed focal segmental glomerulosclerosis and whole-exome sequencing revealed compound heterozygous mutations in Nucleoporin 160 ( Show less

The effect of coiled-coil domain-containing 154 (CCDC154) in liver cancer (LC) remains unexplored. The objective of this study was to investigate the role of CCDC154 in LC and its underlying mechanism. The analysis of CCDC154 expression and prognosis was performed using UALCAN, Human Protein Atlas and Kaplan-Meier plotter websites. Protein expression was measured using Western blotting assay. Lentivirus was used to silence CCDC154 expression in LC cells. The proliferation and apoptosis of LC cells was evaluated by cell counting assay, colony formation assay and flow cytometry. The migration and invasion of LC cells were investigated using scratch wound-healing assay and Transwell assay. The results showed that CCDC154 was highly expressed in LC and related to tumor grade and stage. High CCDC154 expression was associated with to poor outcomes in LC patients. Silencing of CCDC154 inhibited proliferation, migration and invasion of LC cells. It also increased apoptosis in LC cells. After CCDC154 knockdown, the expression of Twist, Vimentin and Snail was down-regulated. Overexpression of Snail abated the inhibitory caused by CCDC154 knockdown on LC cell growth. CCDC154 knockdown suppressed LC development through reducing Snail expression. Show less

Chronic stress disrupts the emotional and energetic balance, which may lead to abnormal behaviors such as binge eating. This overeating behavior alleviating the negative emotions is called emotional eating, which may exacerbate emotional instability and lead to obesity. It is a complex and multifaceted process that has not yet been fully understood. In this study, we constructed an animal model of chronic mild stress (CMS)-induced emotional eating. The emotional eating mice were treated with tryptophan for 21 days to reveal the key role of tryptophan. Furthermore, serum-targeted metabolomics, immunohistochemical staining, qPCR and ELISA were performed. The results showed that CMS led to the binge eating behavior, accompanied by the disturbed intestinal tryptophan-derived serotonin (5-hydroxytryptamine; 5-HT) metabolic pathways. Then we found that tryptophan supplementation improved depression and anxiety-like behaviors as well as abnormal eating behaviors. Tryptophan supplementation improved the abnormal expression of appetite regulators (e.g., AgRP, OX1R, MC4R), and tryptophan supplementation also increased the tryptophan hydroxylase 2 (tph2) and 5-HT receptors in the hypothalamus of CMS mice, which indicates that the 5-HT metabolic pathway influences feeding behavior. Show less

The hypoxic microenvironment in esophageal carcinoma is an important factor promoting the rapid progression of malignant tumor. This study was to investigate the lactylation of Axin1 on glycolysis in esophageal carcinoma cells under hypoxia exposure. Hypoxia treatment increases pan lysine lactylation (pan-kla) levels of both TE1 and EC109 cells. Meanwhile, ECAR, glucose consumption and lactate production were also upregulated in both TE1 and EC109 cells. The expression of embryonic stem cell transcription factors NANOG and SOX2 were enhanced in the hypoxia-treated cells. Axin1 overexpression partly reverses the induction effects of hypoxia treatment in TE1 and EC109 cells. Moreover, lactylation of Axin1 protein at K147 induced by hypoxia treatment promotes ubiquitination modification of Axin1 protein to promote glycolysis and cell stemness of TE1 and EC109 cells. Mutant Axin1 can inhibit ECAR, glucose uptake, lactate secretion, and cell stemness in TE1 and EC109 cells under normal or hypoxia conditions. Meanwhile, mutant Axin1 further enhanced the effects of 2-DG on inhibiting glycolysis and cell stemness. Overexpression of Axin1 also inhibited tumor growth in vivo, and was related to suppressing glycolysis. In conclusion, hypoxia treatment promoted the glycolysis and cell stemness of esophageal carcinoma cells, and increased the lactylation of Axin1 protein. Overexpression of Axin1 functioned as a glycolysis inhibitor, and suppressed the effects of hypoxia exposure in vitro and inhibited tumor growth in vivo. Mechanically, hypoxia induces the lactylation of Axin1 protein and promotes the ubiquitination of Axin1 to degrade the protein, thereby exercising its anti-glycolytic function. Show less

Tumour metabolic reprogramming is pivotal for tumour survival and proliferation. Investigating potential molecular mechanisms within the heterogeneous and clinically aggressive triple-negative breast cancer (TNBC) subtype is essential to identifying novel therapeutic targets. Accordingly, we investigated the role of branched-chain α-keto acid dehydrogenase kinase (BCKDK) in promoting tumorigenesis in TNBC. We analysed The Cancer Genome Atlas dataset and immunohistochemically stained surgical specimens to investigate BCKDK expression and its prognostic implications in TNBC. The effects of BCKDK on tumorigenesis were assessed using cell viability, colony formation, apoptosis, and cell cycle assays, and subsequently validated in vivo. Metabolomic screening was performed via isotope tracer studies. The downstream target was confirmed using mass spectrometry and a co-immunoprecipitation experiment coupled with immunofluorescence analysis. Upstream transcription factors were also examined using chromatin immunoprecipitation and luciferase assays. BCKDK was upregulated in TNBC tumour tissues and associated with poor prognosis. BCKDK depletion led to reduced cell proliferation both in vitro and vivo. MYC-associated zinc finger protein (MAZ) was confirmed as the major transcription factor directly regulating BCKDK expression in TNBC. Mechanistically, BCKDK interacted with glucose-6-phosphate dehydrogenase (G6PD), leading to increased flux in the pentose phosphate pathway for macromolecule synthesis and detoxification of reactive oxygen species. Forced expression of G6PD rescued the growth defect in BCKDK-deficient cells. Notably, the small-molecule inhibitor of BCKDK, 3,6-dichlorobenzo(b)thiophene-2-carboxylic acid, exhibited anti-tumour effects in a patient-derived tumour xenograft model. Our findings hold significant promise for developing targeted therapies aimed at disrupting the MAZ/BCKDK/G6PD signalling pathway, offering potential advancements in treating TNBC through metabolic reprogramming. Show less

Atherosclerosis (AS) is a leading cause of cardiovascular morbidity and mortality. Atherosclerotic lesions show increased levels of proteins associated with the fibroblast growth factor receptor (FGFR) pathway. However, the functional significance and mechanisms governed by FGFR signalling in AS are not known. In the present study, we investigated fibroblast growth factor receptor 1 (FGFR1) signalling in AS development and progression. Examination of human atherosclerotic lesions and aortas of Apoe-/- mice fed a high-fat diet (HFD) showed increased levels of FGFR1 in macrophages. We deleted myeloid-expressed Fgfr1 in Apoe-/- mice and showed that Fgfr1 deficiency reduces atherosclerotic lesions and lipid accumulations in both male and female mice upon HFD feeding. These protective effects of myeloid Fgfr1 deficiency were also observed when mice with intact FGFR1 were treated with FGFR inhibitor AZD4547. To understand the mechanistic basis of this protection, we harvested macrophages from mice and show that FGFR1 is required for macrophage inflammatory responses and uptake of oxidized LDL. RNA sequencing showed that FGFR1 activity is mediated through phospholipase-C-gamma (PLCγ) and the activation of nuclear factor-κB (NF-κB) but is independent of FGFR substrate 2. Our study provides evidence of a new FGFR1-PLCγ-NF-κB axis in macrophages in inflammatory AS, supporting FGFR1 as a potentially therapeutic target for AS-related diseases. Show less

Synthetic signaling receptors enable programmable cellular responses coupling with customized inputs. However, engineering a designer force-sensing receptor to rewire mechanotransduction remains largely unexplored. Herein, we introduce nongenetically engineered artificial mechanoreceptors (AMRs) capable of reprogramming non-mechanoresponsive receptor tyrosine kinases (RTKs) to sense user-defined force cues, enabling de novo-designed mechanotransduction. AMR is a modular DNA-protein chimera comprising a mechanosensing-and-transmitting DNA nanodevice grafted on natural RTKs via aptameric anchors. AMR senses intercellular tensile force via an allosteric DNA mechano-switch with tunable piconewton-sensitive force tolerance, actuating a force-triggered dynamic DNA assembly to manipulate RTK dimerization and activate intracellular signaling. By swapping the force-reception ligands, we demonstrate the AMR-mediated activation of c-Met, a representative RTK, in response to the cellular tensile forces mediated by cell-adhesion proteins (integrin, E-cadherin) or membrane protein endocytosis (CI-M6PR). Moreover, AMR also allows the reprogramming of FGFR1, another RTK, to customize mechanobiological function, for example, adhesion-mediated neural stem cell maintenance. Show less

Fibroblast growth factor receptor 1 ( FGFR1 ) mutations are associated with congenital hypogonadotropic hypogonadism (CHH) through inheritance or spontaneous occurrence. We detected FGFR1 mutations in a Chinese cohort of 210 CHH patients at Peking Union Medical College Hospital (Beijing, China) using next-generation and Sanger sequencing. We assessed missense variant pathogenicity using six bioinformatics tools and compared clinical features and treatment outcomes between inherited and de novo mutation groups. Among 19 patients with FGFR1 mutations, three were recurrent, and 16 were novel variants. Sixteen of the novel mutations were likely pathogenic according to the American College of Medical Genetics and Genomics (ACMG) guidelines, with the prevalent P366L variant. The majority of FGFR1 mutations was inherited (57.9%), with frameshift mutations exclusive to the de novo mutation group. The inherited mutation group had a lower incidence of cryptorchidism, short stature, and skeletal deformities. In the inherited mutation group, luteinizing hormone (LH) levels were 0.5 IU l -1 , follicle-stimulating hormone (FSH) levels were 1.0 IU l -1 , and testosterone levels were 1.3 nmol l -1 . In contrast, the de novo group had LH levels of 0.2 IU l -1 , FSH levels of 0.5 IU l -1 , and testosterone levels of 0.9 nmol l -1 , indicating milder hypothalamus-pituitary-gonadal axis (HPGA) functional deficiency in the inherited group. The inherited mutation group showed a tendency toward higher spermatogenesis rates. In conclusion, this study underscores the predominance of inherited FGFR1 mutations and their association with milder HPGA dysfunction compared to de novo mutations, contributing to our understanding of the genetic and clinical aspects of FGFR1 mutations. Show less

Fibroblast-like synoviocytes (FLSs) contribute to inflammation and joint damage in rheumatoid arthritis (RA). However, the regulatory mechanisms of FLSs in relapse and remission of RA remain unknown. Identifying FLS heterogeneity and their underlying pathogenic roles may lead to discovering novel disease-modifying antirheumatic drugs. Combining single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics, we sequenced six matched synovial tissue samples from three patients with relapse RA and three patients in remission. We analyzed the differences in the transcriptomes of the FLS subsets between the relapse and remitted phases. We validated several key signaling pathways using quantitative real-time PCR (qPCR) and multiplex immunohistochemistry (mIHC). We further targeted the critical signals in vitro and in vivo using the collagen-induced arthritis (CIA) model in rats. Lining and sublining FLS subsets were identified using scRNA-seq. Differential analyses indicated that the fibroblast growth factor (FGF) pathway was highly activated in the lining FLSs from patients with relapse RA for which mIHC confirmed the increased expression of FGF10. Although the type I interferon pathway was also activated in the lining FLSs, in vitro stimulation experiment suggested that it was independent of the FGF10 pathway. FGF10 knockdown by small interfering RNA in FLSs significantly reduced the expression of receptor activator of NF-κB ligand. Moreover, recombinant FGF10 protein enhanced bone erosion in the primary human-derived pannus cell culture, whereas the FGF receptor (FGFR) 1 inhibitor attenuated this process. Finally, administering an FGFR1 inhibitor displayed a therapeutic effect in a CIA rat model. The FGF pathway is a critical signaling pathway in relapse RA. Targeted tissue-specific inhibition of FGF10/FGFR1 may provide new opportunities to treat patients with relapse RA. Show less

Prenatal exposure to perfluorooctane sulfonate (PFOS) is associated with adverse health effects, including congenital heart disease, yet the underlying mechanisms remain elusive. Herein, we aimed to evaluate the embryotoxicity of PFOS using C57BL/6 J mice to characterize fetal heart defects after PFOS exposure, with the induction of human embryonic stem cells (hESC) into cardiomyocytes (CMs) as a model of early-stage heart development. We also performed DNA methylation analysis to clarify potential underlying mechanisms and identify targets of PFOS. Our results revealed that PFOS caused septal defects and excessive ventricular trabeculation cardiomyopathy at 5 mg/kg/day in embryonic mice and inhibited the proliferation and pluripotency of ESCs at concentrations >20 μM. Moreover, it decreased the beating rate and the population of CMs during cardiac differentiation. Decreases were observed in the abundances of NPPA+ trabecular and HEY2+ compact CMs. Additionally, DNA methyl transferases and ten-eleven translocation (TET) dioxygenases were regulated dynamically by PFOS, with TETs inhibitor treatment inducing significant decreases similar as PFOS. 850 K DNA methylation analysis combined with expression analysis revealed several potential targets of PFOS, including SORBS2, FHOD1, SLIT2, SLIT3, ADCY9, and HDAC9. In conclusion, PFOS may reprogram DNA methylation, especially demethylation, to induce cardiac toxicity, causing ventricular defects in vivo and abnormal cardiac differentiation in vitro. Show less

Mitral valve (MV) leaflet elongation is recognized as a primary phenotypic expression of hypertrophic cardiomyopathy (HCM) that contributes to obstruction. This study investigates the correlation between MV length and genotype mutations in the two predominant genes, myosin-binding protein C (MYBPC3), and the β-myosin heavy chain (MYH7) in patients with obstructive HCM (OHCM). Among the 402 OHCM patients, there were likely pathogenic or pathogenic variations in MYH7 (n = 94) and MYBPC3 (n = 76), along with a mutation-negative group (n = 212). Compared to genotype-negative patients, genotype-positive individuals exhibited elongated MV length, thicker interventricular septum, and increased instances of late gadolinium enhancement. Notably, MYH7 mutations were associated with a more severe disease trajectory than MYBPC3 mutations. After adjusting for potential confounders, multivariate linear regression analysis revealed that MYH7 gene mutations and left ventricular volume were independently associated with MV leaflet elongation. The study indicates that mutations in MYH7 and hemodynamics factors are significant risk factors for elongated MV leaflet. Consequently, regular assessment of MV length, especially in patients with MYH7 mutation and enlarged LV volume, is crucial for timely preoperative strategic planning and improved prognosis. Show less

Lysyl oxidase enzymes (LOXs), as extracellular matrix (ECM) protein regulators, play vital roles in tumor progression by remodeling the tumor microenvironment. However, their roles in glioblastoma (GBM) have not been fully elucidated. The genetic alterations and prognostic value of LOXs were investigated GBM patients with altered LOXs had poor survival. Upregulated LOXs were found in IDH1-wildtype and mesenchymal (not Loxl1) GBM subtypes, promoting ECM receptor interactions in GBM. The Loxl1-based nomogram and the PRSM showed high accuracy, reliability, and net clinical benefits. Loxl1 expression was related to tumor invasion and immune infiltration (B cells, neutrophils, and dendritic cells). Loxl1 knockdown suppressed GBM cell proliferation and invasion by inhibiting the EMT pathway (through the downregulation of N-cadherin/Vimentin/Snai1 and the upregulation of E-cadherin). The Loxl1-based nomogram and PRSM were stable and individualized for assessing GBM patient prognosis, and the invasive role of Loxl1 could provide a promising therapeutic strategy. Show less

The relationships of the rs17782313 polymorphism near melanocortin 4 receptor gene (MC4R) and the rs8192678 polymorphism in peroxisome proliferator-activated receptor gamma coactivator 1 alpha gene (PGC1α) with metabolic abnormalities have been explored in many populations around the world, but the findings were not all consistent and sometimes even a bit contradictory. Electronic databases including Medline, Scopus, Embase, Web of Science, CNKI and Google Scholar were checked for studies that met the inclusion criteria. Data were carefully extracted from eligible studies. Standardized mean differences (SMDs) were calculated by using a random-effects model to examine the differences in the indexes of obesity, glucometabolic disorder and dyslipidemia between the genotypes of the rs17782313 and rs8192678 polymorphisms. Cochran's Q-statistic test and Begg's test were employed to identify heterogeneity among studies and publication bias, respectively. Fifty studies (58,716 subjects) and 51 studies (18,660 subjects) were respectively included in the pooled meta-analyses for the rs17782313 and rs8192678 polymorphisms. The C-allele carriers of the rs17782313 polymorphism had a higher average level of body mass index (SMD = 0.21 kg/m The meta-analysis demonstrates that the C allele of the MC4R rs17782313 polymorphism confers a higher risk of obesity and hyperglycemia, and the PGC1α rs8192678 polymorphism is weakly correlated with glucometabolic disorder. These findings may partly explain the relationships between these variants and diabetes as well as cardiovascular disease. https://www.crd.york.ac.uk/prospero/, identifier CRD42022373543. Show less

Mounting evidence has proposed the importance of the Wnt/β-catenin pathway and tripartite motif 31 (TRIM31) in certain malignancies. Our research aimed to clarify the correlation between aberrant TRIM31 expression and the Wnt/β-catenin pathway during gastric cancer (GC) oncogenesis and development. TRIM31 was drastically elevated in GC tissues and was closely associated with aggressive clinical outcomes and poor prognosis. Moreover, TRIM31 downregulation attenuated GC cell proliferation and invasion in vitro. Mechanistically, TRIM31 could bind and ubiquitinate Axin1 protein, thereby facilitating the activation of the Wnt/β-catenin pathway. Additionally, Axin1 knockdown partially abrogated the inhibitory effects on the proliferative, invasive and migratory abilities of GC cells induced by TRIM31 silencing. Furthermore, TRIM31 was negatively correlated with Axin1 protein expression in GC tissues. In summary, we revealed a new TRIM31-Axin1-Wnt/β-catenin axis that contributed greatly to the progression of GC, and targeting this regulatory axis may represent an effective treatment for GC patients. Show less

Alzheimer's disease (AD) is one of the acute degenerative diseases of the brain that occurs in the central nervous system. This disease is caused by the abnormal deposition of insoluble plaques and peptide amyloid beta (Aβ), the formation of nodules, and synaptic disorder. The formation of these nodes disrupts the functioning of neural circuits and changes in behavioral response due to the activation of neurotransmitter receptors. Research in recent years has shown that microRNAs play an effective role in Alzheimer's disease and neurotransmitter factors. Recently, miR-107 is effective in the pathology of Alzheimer's disease (AD) through the regulation of NF-κB signaling pathway. Experiments conducted using the dual luciferase method and western blot analysis also showed that miR-107 in primary neurons affects neurotransmitter factors in Alzheimer's disease through the regulation of the NF-κB signaling pathway. The results showed that the reduction of miR-107 expression through the regulation of the NF-κB signaling pathway leads to the suppression of cell apoptosis in Alzheimer's patients. On the other hand, increasing the expression of miR-107 leads to increasing the breaking process of Amyloid precursor protein (APP). This factor increases the production of amyloid beta (Aβ) peptide plaques and increases the expression of the BACE1 gene, which ultimately leads to the induction of apoptosis and induction of Alzheimer's disease. Show less

Danggui Buxue decoction (DBD) is a classic herbal decoction consisting of Astragali Radix (AR) and Angelica Sinensis Radix (ASR) with a 5:1 wt ratio, which can supplement 'blood' and 'qi' (vital energy) for the treatment of clinical diseases. According to Traditional Chinese Medicine (TCM) theory, dementia is induced by Blood deficiency and Qi weakness, which causes a decline in cognition. However, the underlying mechanisms of DBD improving cognition deficits in neurodegenerative disease are no clear. This study aims at revealing the underlying mechanisms of DBD plays a protective role in the cognitive deficits and pathology process of Alzheimer's disease (AD). The APP/PS1 (Mo/HuAPP695swe/PS1-dE9) double transgenic mice were adopted as an experimental model of AD. Qualitative and quantitative analysis of 3 compounds in DBT was analyzed by HPLC. Morris water maze test, Golgi staining and electrophysiology assays were used to evaluate the effects of DBD on cognitive function and synaptic plasticity in APP/PS1 mice. Western blot, immunofluorescence and Thioflavin S staining were used for the pathological evaluation of AD. Monitoring the level of ATP, mitochondrial membrane potential, SOD and MDA to evaluate the mitochondrial function, and with the usage of qPCR and CHIP for the changes of histone post-translational modification. In the current study, we found that DBD could effectively attenuate memory impairments and enhance long-term potentiation (LTP) with concurrent increased expression of memory-associated proteins. DBD markedly decreased Aβ accumulation in APP/PS1 mice by decreasing the phosphorylation of APP at the Thr668 level but not APP, PS1 or BACE1. Further studies demonstrated that DBD restored mitochondrial biogenesis deficits and mitochondrial dysfunction. Finally, the restored mitochondrial biogenesis and cognitive deficits are under HADC2-mediated histone H4 lysine 12 (H4K12) acetylation at the peroxisome proliferator-activated receptor-gamma coactivator 1α (PGC-1α) and N-methyl-D-aspartate receptor type 2B (GluN2B) promoters. These findings reveal that DBD could ameliorate mitochondrial biogenesis and cognitive deficits by improving H4K12 acetylation. DBD might be a promising complementary drug candidate for AD treatment. Show less

Abdominal fat deposition depends on both the proliferation of preadipocytes and their maturation into adipocytes, which is a well-orchestrated multistep process involving many regulatory molecules. Circular RNAs (circRNAs) have emergingly been implicated in mammalian adipogenesis. However, circRNA-mediated regulation in chicken adipogenesis remains unclear. Our previous circRNA sequencing data identified a differentially expressed novel circRNA, 8:27,886,180|27,889,657, during the adipogenic differentiation of chicken abdominal preadipocytes. This study aimed to investigate the regulatory role of circDOCK7 in the proliferation and adipogenic differentiation of chicken abdominal preadipocytes, and explore its molecular mechanisms of competing endogenous RNA underlying chicken adipogenesis. Our results showed that 8:27,886,180|27,889,657 is an exonic circRNA derived from the head-to-tail splicing of exons 19-22 of the dedicator of cytokinesis 7 (DOCK7) gene, abbreviated as circDOCK7. CircDOCK7 is mainly distributed in the cytoplasm of chicken abdominal preadipocytes and is stable because of its RNase R resistance and longer half-life. CircDOCK7 is significantly upregulated in the abdominal fat tissues of fat chickens compared to lean chickens, and its expression gradually increases during the proliferation and adipogenic differentiation of chicken abdominal preadipocytes. Functionally, the gain- and loss-of-function experiments showed that circDOCK7 promoted proliferation, G0/G1- to S-phase progression, and glucose uptake capacity of chicken abdominal preadipocytes, in parallel with adipogenic differentiation characterized by remarkably increased intracellular lipid droplet accumulation and triglyceride and acetyl coenzyme A content in differentiated chicken abdominal preadipocytes. Mechanistically, a pull-down assay and a dual-luciferase reporter assay confirmed that circDOCK7 interacted with gga-miR-301b-3p, which was identified as an inhibitor of chicken abdominal adipogenesis. Moreover, the ACSL1 gene was demonstrated to be a direct target of gga-miR-301b-3p. Chicken ACSL1 protein is localized in the endoplasmic reticulum and mitochondria of chicken abdominal preadipocytes and acts as an adipogenesis accelerator. Rescue experiments showed that circDOCK7 could counteract the inhibitory effects of gga-miR-301b-3p on ACSL1 mRNA abundance as well as the proliferation and adipogenic differentiation of chicken abdominal preadipocytes. CircDOCK7 serves as a miRNA sponge that directly sequesters gga-miR-301b-3p away from the ACSL1 gene, thus augmenting adipogenesis in chickens. These findings may elucidate a new regulatory mechanism underlying abdominal fat deposition in chickens. Show less

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the main cause of COVID-19, causing hundreds of millions of confirmed cases and more than 18.2 million deaths worldwide. Acute kidney injury (AKI) is a common complication of COVID-19 that leads to an increase in mortality, especially in intensive care unit (ICU) settings, and chronic kidney disease (CKD) is a high risk factor for COVID-19 and its related mortality. However, the underlying molecular mechanisms among AKI, CKD, and COVID-19 are unclear. Therefore, transcriptome analysis was performed to examine common pathways and molecular biomarkers for AKI, CKD, and COVID-19 in an attempt to understand the association of SARS-CoV-2 infection with AKI and CKD. Three RNA-seq datasets (GSE147507, GSE1563, and GSE66494) from the GEO database were used to detect differentially expressed genes (DEGs) for COVID-19 with AKI and CKD to search for shared pathways and candidate targets. A total of 17 common DEGs were confirmed, and their biological functions and signaling pathways were characterized by enrichment analysis. MAPK signaling, the structural pathway of interleukin 1 (IL-1), and the Toll-like receptor pathway appear to be involved in the occurrence of these diseases. Hub genes identified from the protein-protein interaction (PPI) network, including DUSP6, BHLHE40, RASGRP1, and TAB2, are potential therapeutic targets in COVID-19 with AKI and CKD. Common genes and pathways may play pathogenic roles in these three diseases mainly through the activation of immune inflammation. Networks of transcription factor (TF)-gene, miRNA-gene, and gene-disease interactions from the datasets were also constructed, and key gene regulators influencing the progression of these three diseases were further identified among the DEGs. Moreover, new drug targets were predicted based on these common DEGs, and molecular docking and molecular dynamics (MD) simulations were performed. Finally, a diagnostic model of COVID-19 was established based on these common DEGs. Taken together, the molecular and signaling pathways identified in this study may be related to the mechanisms by which SARS-CoV-2 infection affects renal function. These findings are significant for the effective treatment of COVID-19 in patients with kidney diseases. Show less

Membrane fatty acid desaturase (FADS)-like superfamily proteins (FADSs) are essential for the synthesis of unsaturated fatty acids (UFAs). Recently, studies on FADS in fishes have mostly focused on marine species, and a comprehensive analysis of the FADS superfamily, including the FADS, stearoyl-CoA desaturase (SCD), and sphingolipid delta 4-desaturase (DEGS) families, in freshwater economic fishes is urgently required. To this end, we conducted a thorough analysis of the number, gene/protein structure, chromosomal location, gene linkage map, phylogeny, and expression of the FADS superfamily. We identified 156 FADSs genes in the genome of 27 representative species. Notably, FADS1 and SCD5 were lost in most freshwater fish and other teleosts. All FADSs proteins contain 4 transmembrane helices and 2-3 amphipathic α-helices. FADSs in the same family are often linked on the same chromosome; moreover, FADS and SCD or DEGS are frequently collocated on the same chromosome. In addition, FADS, SCD, and DEGS family proteins share similar evolutionary patterns. Interestingly, FADS6, as a member of the FADS family, exhibits a similar gene structure and chromosome location to that of SCD family members, which may be the transitional form of FADS and SCD. This study shed light on the type, structure, and phylogenetic relationship of FADSs in freshwater fishes, offering a new perspective into the functional mechanism analysis of FADSs. Show less

MicroRNAs (miRNAs) have emerged as promising diagnostic biomarkers and therapeutic targets in various diseases. However, there is currently a lack of molecular strategies that can effectively use disease-associated extracellular miRNAs as input signals to drive therapeutic functions. Herein, we present a modular and programmable miRNA-responsive chimeric DNA receptor (miRNA-CDR) capable of biomarker-driven therapy. By grafting a miRNA-responsive DNA nanodevice on a natural membrane receptor via aptamer anchoring, miRNA-CDR can sense extracellular miRNA levels and autonomously induce dimerization-mediated receptor activation via the complementary-mediated strand displacement reaction-induced dynamic DNA assembly. The sequence programmability of miRNA-CDR allows it to sense and respond to a user-defined miRNA with tunable sensitivity. Moreover, the miRNA-CDR is versatile and customizable to reprogram desirable signaling output via adapting a designated receptor, such as MET and FGFR1. Using a mouse model of drug-induced acute liver injury (DILI), we demonstrate the functionality of a designer miRNA-CDR in rewiring the recognition of the DILI-elevated miR-122 to promote MET signaling of hepatocytes for biomarker-driven in situ repair and liver function restoration. Our synthetic miRNA-CDR platform provides a novel molecular device enabling biomarker-driven therapeutic cellular response, potentially paving the way for improving the precision of cell therapy in regenerative medicine. Show less

Mesenchymal stem cell (MSC) therapy is a promising candidate for inflammatory bowel disease (IBD) treatment, while overcoming the limitations of naive seeding cells function and realizing efficient intestinal targeting remains a challenge. Here, a bioadhesive microparticle carrying interleukin-27 (IL-27) MSC-derived extracellular vesicles (MSC Show less

Improvement of nutrient utilization to promote growth performance is always pursued in poultry. In this study, a total of 360 1-d-old male ducklings was randomly assigned to 3 treatments in terms of diet treatment groups. Three treatments were as follows: basal diet (Con group) or basal diet supplemented with 300 mg/kg multi-enzymes (ENZ group) or 500 mg/kg lysophospholipids (LPL group). On day 42, ducks were slaughtered for samplings. The results revealed that supplementary LPL improved the body weight (BW) at day 14 and average daily gain (ADG) during days 1 to 14 and improved the feed conversion rate (FCR) for the overall period (P < 0.05) by improving nutrient utilization of dry matter and ether extract (P < 0.05) compared with the Con group. Dietary ENZ improved the FCR from days 15-42 and 1-42, and nitrogen utilization (P < 0.05) compared with the Con group. Jejunal villus height and villus height/crypt depth ratio were higher (P < 0.05) in the LPL group and tended to be higher (P < 0.1) in the ENZ group compared to the Con group. Supplementation with either LPL or ENZ reduced interleukin-1β concentration in jejunal mucus (P < 0.05). Both LPL and ENZ enhanced serum total superoxide dismutase activity (P < 0.05), whereas only supplementation with LPL elevated total antioxidant capacity (P < 0.05). In terms of cecal microbiota, microbial richness tended to be reduced by LPL, with low observed-OTUs and Chao1 (0.05 < P < 0.1). Supplementation with ENZ led to higher abundances of cellulolytic bacteria such as Fibrobacterota, [Eubacterium]_xylanophilum_group, and Bifidobacterium. Overall, both LPL and ENZ improved FCR, which may be relevant to ameliorative intestinal health, overall antioxidant ability, and cecal microbiome. Show less

Variants in myosin-binding protein C3 (MYBPC3) gene are a main cause of hypertrophic cardiomyopathy (HCM), accounting for 30% to 40% of the total number of HCM mutations. Gene editing represents a potential permanent cure for HCM. The aim of this study was to investigate whether genome editing of MYBPC3 using the CRISPR/Cas9 system in vivo could rescue the phenotype of rats with HCM. We generated a rat model of HCM ("1098hom") that carried an Mybpc3 premature termination codon mutation (p.W1098x) discovered in a human HCM pedigree. On postnatal day 3, the CRISPR/Cas9 system was introduced into rat pups by a single dose of AAV9 particles to correct the variant using homology-directed repair (HDR). Analysis was performed 6 months after AAV9 injection. The 1098hom rats didn't express MYBPC3 protein and developed an HCM phenotype with increased ventricular wall thickness and diminished cardiac function. Importantly, CRISPR HDR genome editing corrected 3.56% of total mutations, restored MYBPC3 protein expression by 2.12%, and normalized the HCM phenotype of 1098hom rats. Our work demonstrates that the HDR strategy is a promising approach for treating HCM associated with MYBPC3 mutation, and that CRISPR technology has great potential for treating hereditary heart diseases. Show less