👤 Wenbo Xia

This study aimed to investigate the significant single nucleotide polymorphisms (SNPs) and genes associated with nine reproduction and morphological traits in three breed populations of Chinese goats. The genome-wide association of nine reproduction and morphological traits (litter size, nipple number, wattle, skin color, coat color, black dorsal line, beard, beard length, and hind leg hair) were analyzed in three Chinese native goat breeds (n = 336) using an Illumina Goat SNP50 Beadchip. A total of 17 genome-wide or chromosome-wide significant SNPs associated with one reproduction trait (litter size) and six morphological traits (wattle, coat color, black dorsal line, beard, beard length, and hind leg hair) were identified in three Chinese native goat breeds, and the candidate genes were annotated. The significant SNPs and corresponding putative candidate genes for each trait are as follows: two SNPs located on chromosomes 6 (CSN3) and 24 (TCF4) for litter size trait; two SNPs located on chromosome 9 (KATNA1) and 1 (UBASH3A) for wattle trait; three SNPs located on chromosome 26 (SORCS3), 24 (DYM), and 20 (PDE4D) for coat color trait; two SNPs located on chromosome 18 (TCF25) and 15 (CLMP) for black dorsal line trait; four SNPs located on chromosome 8, 2 (PAX3), 5 (PIK3C2G), and 28 (PLA2G12B and OIT3) for beard trait; one SNP located on chromosome 18 (KCNG4) for beard length trait; three SNPs located on chromosome 17 (GLRB and GRIA2), 28 (PGBD5), and 4 for hind leg hair trait. In contrast, there were no SNPs identified for nipple number and skin color. The significant SNPs or genes identified in this study provided novel insights into the genetic mechanism underlying important reproduction and morphological traits of three local goat breeds in Southern China as well as further potential applications for breeding goats. Show less

Goat milk is increasingly recognized by consumers due to its high nutritional value, richness in short- and medium-chain fatty acids, and richness in polyunsaturated fatty acids (PUFA). Exogenous supplementation of docosahexaenoic acid (DHA) is an important approach to increasing the content of PUFA in goat milk. Several studies have reported benefits of dietary DHA in terms of human health, including potential against chronic diseases and tumors. However, the mechanisms whereby an increased supply of DHA regulates mammary cell function is unknown. In this study, we investigated the effect of DHA on lipid metabolism processes in goat mammary epithelial cells (GMEC) and the function of H3K9ac epigenetic modifications in this process. Supplementation of DHA promoted lipid droplet accumulation increased the DHA content and altered fatty acid composition in GMEC. Lipid metabolism processes were altered by DHA supplementation through transcriptional programs in GMEC. ChIP-seq analysis revealed that DHA induced genome-wide H3K9ac epigenetic changes in GMEC. Multiomics analyses (H3K9ac genome-wide screening and RNA-seq) revealed that DHA-induced expression of lipid metabolism genes ( Show less

Male idiopathic hypogonadotropic hypogonadism (IHH) is a heterogeneous clinical rare genetic disorder that can be divided into two forms: Kallmann syndrome (KS) and olfactory normal IHH (nIHH). Nearly half of unknown pathogenic genes and related pathogenic mechanisms have yet to be explored. Clinical data of 40 IHH patients (22 KS and 18 nIHH) were retrospectively recorded. All patients were diagnosed at the Department of Endocrinology of Jinling Hospital, Jiangsu Provincial People's Hospital, and the First Affiliated Hospital of the University of Science and Technology of China from 2014 to 2021. The proband genomic DNA (gDNA) was confirmed by whole exome sequencing (WES) and Sanger sequencing. Ten new genetic mutations related to IHH in four families and eight sporadic unrelated IHH patients were identified. The total positive detection rate of 40 patients was 30% (nIHH 8/18 + KS 4/22), and the FGFR1 mutation rate accounted for 7.5% (3/40). Mutation rates of ANOS1, CHD7, and KISS1R were 5% (2/40), respectively. The mutation rates of SEMA3E, PROKR2, and SOX10 were 2.5% (1/40), respectively. After analysis by SIFT and PolyPhen-2 software, all missense mutation sites, such as The study aims to expand the genotype mutation spectrum of IHH and provide evidence for the follow-up clinical treatment and genetic counseling of the disease. Show less

Psoriasis is a systemic inflammatory disease, and the mechanism that links psoriasis to depression is still elusive. Hence, this study aimed to elucidate the potential pathogenesis of psoriasis and depression comorbidity. The gene expression profiles of psoriasis (GSE34248, GSE78097 and GSE161683) and depression (GSE39653) were downloaded from the Gene Expression Omnibus (GEO) DataSets. Functional annotation, protein-protein interaction (PPI) network and module construction, and hub gene identification and co-expression analysis were performed, following identification of the common differentially expressed genes (DEGs) of psoriasis and depression. A total of 115 common DEGs (55 up-regulated and 60 down-regulated) were identified between psoriasis and depression. Functional analysis indicated that T cell activation and differentiation were predominantly implicated in the potential pathogenesis of these two diseases. In addition, Th17 cell differentiation and cytokines is closely related to both. Finally, 17 hub genes were screened, including CTLA4, LCK, ITK, IL7R, CD3D, SOCS1, IL4R, PRKCQ, SOCS3, IL23A, PDGFB, PAG1, TGFA, FGFR1, RELN, ITGB5 and TNXB, which re-emphasized the importance of the immune system in psoriasis and depression. Our study reveals the common pathogenesis of psoriasis and depression. These common pathways and hub genes may apply to a molecular screening tool for depression in psoriasis patients, which could help dermatologists optimize patient management in routine care. Show less

Excessive NOD-like receptor thermal protein domain associated protein 3 (NLRP3) inflammasome activation has an important function in the pathogenesis of Sjögren's syndrome (SS). Increased and dysfunctional myeloid-derived suppressor cells (MDSCs) promoted SS. However, NLRP3 inflammasome activation of MDSCs in SS and its regulated components are unclear. Splenic MDSCs were purified by immunomagnetic beads and cultured. Western blot was used to assess NLRP3 inflammasomes. Interleukin-1β (IL-1β) and IL-18 were measured using enzyme-linked immunosorbent assay. Here we showed that the NLRP3 inflammasome was activated in non-obese diabetic (NOD) mice with SS-like manifestations. We found that NLRP3 inflammasome activation was augmented in MDSCs of SS mice and NLRP3 inflammasome activation was suppressed in IL-27-deficient NOD mice. Consistent with findings of SS mice in vivo, we observed that NLRP3 inflammasome activation by adenosine triphosphate and lipopolysaccharide was remarkably intensified in MDSCs with IL-27 treatment in vitro. Collectively, our data highlighted that IL-27 regulates NLRP3 inflammasome activation of MDSCs in experimental SS. Show less

Polycystic ovarian syndrome (PCOS) is one of the most common gynecological endocrine disorders. MicroRNAs (miRNAs) play extensive roles in the pathogenesis of PCOS and can serve as potential diagnostic markers. However, most studies focused on the regulatory mechanisms of individual miRNAs, and the combined regulatory effects of multiple miRNAs remain unclear. The aim of this study was to identify the common targets of miR-223-3p, miR-122-5p, and miR-93-5p; and assess the transcript levels of some of these targets in PCOS rat ovaries. Transcriptome profiles of granulosa cells from PCOS patients were obtained from the Gene Expression Omnibus (GEO) database to identify differentially expressed genes (DEGs). A total of 1,144 DEGs were screened, 204 of which were upregulated and 940 were downregulated. According to the miRWalk algorithm, 4,284 genes were targeted by all three miRNAs at the same time, and intersection with DEGs was used to obtain candidate target genes. A total of 265 candidate target genes were screened, and the detected target genes were subjected to Gene ontology (GO) and KEGG pathway enrichment, followed by PPI network analysis. Then, qRT-PCR was used to determine the levels of 12 genes in PCOS rat ovaries. The expressions of 10 of these genes were found to be consistent with our bioinformatics results. In conclusion, JMJD1C, PLCG2, SMAD3, FOSL2, TGFB1, TRIB1, GAS7, TRIM25, NFYA, and CALCRL may participate in the development of PCOS. Our findings contribute to the identification of biomarkers that may promote the effective prevention and treatment of PCOS in the future. Show less

Lipoprotein lipase (LPL) deficiency, the most common familial chylomicronemia syndrome (FCS), is a rare autosomal recessive disease characterized by chylomicronemia and severe hypertriglyceridemia (HTG), with limited clinical and genetic characterization. To describe the manifestations and management of 19 pediatric patients with LPL-FCS. LPL-FCS patients from 2014 to 2022 were divided into low-fat (LF), very-low-fat (VLF) and medium-chain-triglyceride (MCT) groups. Their clinical data were evaluated to investigate the effect of different diets. The genotype-phenotype relationship was assessed. Linear regression comparing long-chain triglyceride (LCT) intake and TG levels was analyzed. Nine novel LPL variants were identified in 19 LPL-FCS pediatric patients. At baseline, eruptive xanthomas occurred in 3/19 patients, acute pancreatitis in 2/19, splenomegaly in 6/19 and hepatomegaly in 3/19. The median triglyceride (TG) level (30.3 mmol/L) was markedly increased. The MCT group and VLF group with LCT intakes <20 en% (energy percentage) had considerably lower TG levels than the LF group (both p<0.05). The LF group presented with severe HTG and significantly decreased TG levels after restricting LCT intakes to <20 en% (p<0.05). Six infants decreased TG levels to <10 mmol/L by keeping LCT intake <10 en%. TG levels and LCT intake were positively correlated in both patients under 2 years (r=0.84) and those aged 2-9 years (r=0.89). No genotype-phenotype relationship was observed. This study broadens the clinical and genetic spectra of LPL-FCS. The primary therapy for LPL-FCS pediatric patients is restricting dietary LCTs to <10 en% or <20 en% depending on different ages. MCTs potentially provide extra energy. Show less

This bioinformatics report attempts to explore the cross-talk genes, transcription factors (TFs), and pathways related to myocardial ischemia-reperfusion injury (MIRI) as well as the gut microbiome. The datasets GSE61592 (three MIRI and three sham samples) and GSE160516 (twelve MIRI and four sham samples) were selected in the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) identification (p < 0.05 and |log FC (fold change)| ≥1) together with functional annotation (p < 0.05) was implemented. The Cytoscape platform established the protein-protein interaction (PPI) network. Genes associated with gut microbiome disorder were extracted based on the DisGeNET database, and those associated with MIRI were overlapped. The Recursive Feature Elimination (RFE) algorithm was adopted for selecting features, and cross-talk genes were predicted by the Support Vector Machine (SVM) models. A network encompassing cross-talk genes along with the TFs was thereby established. The MIRI datasets comprised 138 shared DEGs, with 101 showing up-regulation whereas 37 showing down-regulation. Notably, the PPI interwork for MIRI contained 2517 edges along with 1818 nodes. By using RFE and SVM methods, six feature genes with the highest prediction were identified: B2m, VCAM-1, PDIA4, Ptgds, Mlxipl, and ACADS. Among these genes, B2m and PDIA4 were most highly expressed in MIRI and the gut microbiome disorder. B2m and PDIA4 were identified to be significantly correlated with candidate cross-talk genes of MIRI with gut microbiome disorder, implying a similarity between MIRI and Gut microbiome disorder (GMD). These genes can serve as an experimental research basis for future studies. Show less

Antimicrobial peptides (AMPs) are important mediators of intestinal immune surveillance. However, the regional heterogeneity of AMPs and its regulatory mechanisms remain obscure. Here, we clarified the regional heterogeneity of intestinal AMPs at the single-cell level, and revealed a cross-lineages AMP regulation mechanism that bile acid dependent transcription factors (BATFs), NR1H4, NR1H3 and VDR, regulate AMPs through a ligand-independent manner. Bile acids regulate AMPs by perturbing cell differentiation rather than activating BATFs signaling. Chromatin accessibility determines the potential of BATFs to regulate AMPs at the pre-transcriptional level, thus shaping the regional heterogeneity of AMPs. The BATFs-AMPs axis also participates in the establishment of intestinal antimicrobial barriers of fetuses and the defects of antibacterial ability during Crohn's disease. Overall, BATFs and chromatin accessibility play essential roles in shaping the regional heterogeneity of AMPs at pre- and postnatal stages, as well as in maintenance of antimicrobial immunity during homeostasis and disease. Show less

The grass carp (Ctenopharyngodon idella) is the world's most prolific freshwater fish. Little is known, however, about the functional genes and genetic regulatory networks that govern its growth traits. We created three grass carp families in this study by using two grass carp parents with fast-growing offspring and two grass carp parents with slow-growing offspring, namely the fast-growing × fast-growing family (FF), the slow-growing × slow-growing family (SS), and the fast-growing × slow-growing family (FS). Under the satiation and starvation feeding modes, the average body weight of these families' offspring exhibited a consistent ordering (FF > FS > SS). The transcriptomes of grass carp whole brain and hepatopancreas were then acquired for each family, and it was discovered that the number of differentially expressed genes (DEGs) in the different organs demonstrated family specificity. DEGs were mostly identified in the hepatopancreas of FF and the whole brain of SS, but they were more evenly distributed in FS. There were 14 DEGs that were found in all three families, including three that were negatively correlated in hepatopancreas (ahsg2, lect2) or in brain (drd5), and 11 that were positively connected in hepatopancreas (sycn, pabpc4, zgc:112294, cel, endou, ela2, prss3, zbtb41, ela3) or in brain (fabp7, endod1). The deletion of ahsg2 boosted the growth rate only in certain zebrafish, suggesting that the growth-promoting effects of ahsg2 varies among individuals. Furthermore, we examined the SNP in each family and conducted preliminary research on the probable genetic pathways of family-specific control of growth traits. The family specificity of the growth regulation mechanism of grass carp at the transcriptional level was revealed for the first time in this study, and it was discovered that growth differences among individuals in the FF family were primarily due to differences in nutrient metabolism, whereas growth differences among individuals in the SS family may be primarily due to differences in foraging ability caused by differences in brain development. This research adds to our understanding of the genetic regulatory mechanism of grass carp growth. Show less

Thyroid-like low-grade nasopharyngeal papillary adenocarcinoma (TLLGNPPA) is a rare nasopharyngeal carcinoma. To date, less than 60 cases of TLLGNPPA have been reported, and its clinical features and pathogenesis remain unclear. In this paper, four cases of TLLGNPPA were reported to clarify the clinicopathological and molecular features of this disease. Histopathological examination revealed that all tumors had papillary glandular arrangement, with a fibrovascular axis in the tumor stroma and focal nuclear groove. All tumors expressed pan-CK, CK7, and CK19, while TG and Pax-8 were negative, and the Ki-67 index was approximately 1-3%. The expression of TTF-1 was diffusely positive in two cases and focally positive in two cases. EBER was not expressed in four cases. Molecular testing was possible in three cases. No common driver event was noted, but unique, mutually exclusive molecular variants were found in each of the three tumors (FGFR4, PDK1, AXIN2, FOXL2, and PIK3C3), one also with copy number variants in MCL1 and STMN1. All four patients underwent surgical resection of the tumor and had no metastasis or recurrence from 7 to 60 months post-resection. Given the assertion that these tumors do not recur or metastasize in addition to their heterogeneous gene mutation spectrum, we propose that TLLGNPPA is a neoplasm with low malignant potential and should no longer to be referred to as an adenocarcinoma. Show less

The quadrilateral reassortant IAV A/(H1N1) pdm09 is the pathogen responsible for the first influenza pandemic of the 21st century. The virus spread rapidly among hosts causing high mortality within human population. Efficient accumulation of virions is known to be important for the rapid transmission of virus. However, the mechanism by which A/(H1N1) pdm09 promotes its rapid replication has not been fully studied. Here, we found the NS1 of A/(H1N1) pdm09 mediated complete macroautophagy/autophagy, and then facilitated self-replication, which may be associated with the more rapid spread of this virus compared with H1N1 Show less

Colonic mucosal healing is the terminal goal for the treatment of ulcerative colitis (UC), but there is currently no specific drug available. This study investigates the beneficial effect of diallyl trisulfide (DATS) on the colonic mucosal healing. Dextran sulfate sodium (DSS) is used to induce colitis in female C57BL/6 mice, and DATS is orally administered during the recovery period. DATS hardly impacts the inflammation of the colonic tissues, but significantly promotes the mucosal repair. DATS promotes the migration but not proliferation of colonic epithelial cells in the colitis mice. In addition, DATS accelerates the wound healing, cell migration, focal adhesion assembly, and phosphorylation of focal adhesion kinase (FAK) of colonic epithelial cells in vitro, which are evidently reversed by combined use of FAK inhibitor PF-573228. Similar results are shown in colitis mice. Mechanically, DATS promotes the binding of Rab21 to integrin β1 and accelerates the endocytosis of integrin β1, which is significantly attenuated by the knockdown of Rab21. DATS promotes the binding of Rab21 to integrin β1 and the endocytosis of integrin β1, thereby increases FAK phosphorylation and focal adhesion assembly, finally accelerates the migration of colonic epithelial cells and mucosal healing. Show less

Genome-wide association studies (GWASs) have identified numerous susceptibility loci for Parkinson's disease (PD), but its genetic architecture remains underexplored in populations of non-European ancestry. To identify genetic variants associated with PD in the Chinese population, we performed a GWAS using whole-genome sequencing (WGS) in 1,972 cases and 2,478 controls, and a replication study in a total of 8209 cases and 9454 controls. We identified one new risk variant rs61204179 (P Show less

Glucose homeostasis, regulated by glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1) and glucagon (GCG) is critical to human health. Several multi-targeting agonists at GIPR, GLP-1R or GCGR, developed to maximize metabolic benefits with reduced side-effects, are in clinical trials to treat type 2 diabetes and obesity. To elucidate the molecular mechanisms by which tirzepatide, a GIPR/GLP-1R dual agonist, and peptide 20, a GIPR/GLP-1R/GCGR triagonist, manifest their multiplexed pharmacological actions over monoagonists such as semaglutide, we determine cryo-electron microscopy structures of tirzepatide-bound GIPR and GLP-1R as well as peptide 20-bound GIPR, GLP-1R and GCGR. The structures reveal both common and unique features for the dual and triple agonism by illustrating key interactions of clinical relevance at the near-atomic level. Retention of glucagon function is required to achieve such an advantage over GLP-1 monotherapy. Our findings provide valuable insights into the structural basis of functional versatility of tirzepatide and peptide 20. Show less

Bile acid metabolites have been increasingly recognized as pleiotropic signaling molecules that regulate cardiovascular functions, but their role in mesenchymal stromal cells (MSC)-based therapy has never been investigated. It is found that overexpression of farnesoid X receptor (FXR), a main receptor for bile acids, improves the retention and cardioprotection of adipose tissue-derived MSC (ADSC) administered by intramyocardial injection in mice with myocardial infarction (MI), which shows enhanced antiapoptotic, proangiogenic, and antifibrotic effects. RNA sequencing, LC-MS/MS, and loss-of-function studies reveal that FXR overexpression promotes ADSC paracrine angiogenesis via Angptl4. FXR overexpression improves ADSC survival in vivo but fails in vitro. By performing bile acid-targeted metabolomics using ischemic heart tissue, 19 bile acids are identified. Among them, cholic acid and deoxycholic acid significantly increase Angptl4 secretion from ADSC overexpressing FXR and further improve their proangiogenic capability. Moreover, ADSC overexpressing FXR shows significantly lower apoptosis by upregulating Nqo-1 expression only in the presence of FXR ligands. Retinoid X receptor α is identified as a coactivator of FXR. It is first demonstrated that there is a bile acid pool in the myocardial microenvironment. Targeting the bile acid-FXR axis may be a novel strategy for improving the curative effect of MSC-based therapy for MI. Show less

Few intravenously administered mesenchymal stromal cells (MSCs) engraft to the injured myocardium, thereby limiting their therapeutic efficacy for the treatment of ischemic heart injury. Here, it is found that irisin pretreatment increases the cardiac homing of adipose tissue-derived MSCs (ADSCs) administered by single and multiple intravenous injections to mice with MI/R by more than fivefold, which subsequently increases their antiapoptotic, proangiogenic, and antifibrotic effects in rats and mice that underwent MI/R. RNA sequencing, Kyoto Encyclopedia of Genes and Genomes (KEGG) signaling pathway analysis, and loss-of-function studies identified CSF2RB as a cytokine receptor that facilitates the chemotaxis of irisin-treated ADSCs in the presence of CSF2, a chemokine that is significantly upregulated in the ischemic heart. Cardiac-specific CSF2 knockdown blocked the cardiac homing and cardioprotection abilities of intravenously injected irisin-treated ADSCs in mice subjected to MI/R. Moreover, irisin pretreatment reduced the apoptosis of hydrogen peroxide-induced ADSCs and increased the paracrine proangiogenic effect of ADSCs. ERK1/2-SOD2, and ERK1/2-ANGPTL4 are responsible for the antiapoptotic and paracrine angiogenic effects of irisin-treated ADSCs, respectively. Integrin αV/β5 is identified as the irisin receptor in ADSCs. These results provide compelling evidence that irisin pretreatment can be an effective means to optimize intravenously delivered MSCs as therapy for ischemic heart injury. Show less

Lipid metabolic disorders pose a serious threat to human health, and currently no good treatments exist. In earlier studies by the authors, HepG2 cells with diacylglycerol kinase theta (DGKθ) knockout were found to cause significant lipid accumulation, suggesting that DGKθ may be a potential target for treating lipid metabolic disorders. A high-throughput screening of natural products targeting the potential signaling pathway of lipid metabolism was carried out in the DGKθ-T2A-luciferase knock-in HepG2 cell. RNA-sequencing and bioinformatic approaches were used to analyze the potential pathway by which rutaecarpin decreases lipids. Western blot and quantitative polymerase chain reaction were performed to investigate the mechanisms of rutaecarpin's reduction in lipid levels. Rutaecarpin was found to significantly enhance DGKθ expression, and the potential mechanisms by which rutaecarpin accelerates lipid metabolism by targeting DGKθ was explored in vitro and in vivo. The results indicated that rutaecarpin could markedly reduce lipid accumulation in oleic acid-induced HepG2 cells and in high-fat diet-induced obese C57BL/6J mice by targeting the hepatocyte nuclear factor 1-beta (HNF1B)-DGKθ-peroxisome proliferator-activated receptor alpha (PPARα)-apolipoprotein C3 (APOC3) pathway. Rutaecarpin is effective in reducing lipid accumulation, and the development of a high-throughput screening platform based on a reporter knock-in cell line may facilitate the discovery of effective drugs for lipid metabolic disorders based on the DGKθ target. Show less

To investigate the causal role of lipid or apolipoprotein traits in intracerebral hemorrhage (ICH) and determine the effect of lipid-lowering interventions on the disease. Two-sample Mendelian randomization (MR) analyses were conducted to evaluate the associations of high-density lipoprotein cholesterol, low-density lipoprotein cholesterol (LDL-C), triglycerides (TG), apolipoprotein (Apo)B and ApoA1 levels with risks for ICH, and those of LDL-C- (HMGCR, PCSK9, and NPC1L1) and TG-lowering targets (LPL and APOC3) with ICH. Increased levels of ApoB was associated with a decreased risk of overall ICH (OR 0.623, 95% CI 0.413-0.940; p = 0.024) and lobar ICH (OR 0.579, 95% CI 0.342-0.979; p = 0.042). The inverse relationship remained stable in multivariable MR. In addition, elevated TGs showed a causal effect on lobar ICH in multivariable MR (OR 1.600, 95% CI 1.009-2.537; p = 0.046). The LDL-C-reducing genetic variation alleles at or near the HMGCR gene (mimicking the effect of statins) were predicted to increase the overall and deep ICH risk. Additionally, genetic variation at or near the APOC3 gene suggested that genetically reducing the activity of APOC3 (mimicking antisense anti-apoC3 agents) was predicted to decrease lobar ICH. Genetically predicted elevated ApoB may have a protective effect on overall ICH and lobar ICH, whereas elevated TG was associated with a higher risk of lobar ICH conditional on LDL-C and ApoB. MR analysis supports the conclusion that statins may increase the risk of overall and deep ICH independent of their lipid-lowering effect. More specific lipid-lowering targets may end up being the future. ANN NEUROL 2022;92:390-399. Show less

The role of the dynein light chain Tctex-type 3 (DYNLT3) protein in the biological behavior of cervical cancer and its relative molecular mechanisms were investigated. Immunohistochemical staining was used to detect DYNLT3 protein expression in cervical cancer tissues. Cell proliferation and apoptosis rates and invasiveness and migratory capacities were determined by CCK-8 assays, BrdU staining assays and colony formation assays, fluorescence activated cell sorting (FACS), wound healing assays, and Transwell invasion assays of cervical cancer cells after DYNLT3 modulation. The expression levels of Wnt signaling pathway- and EMT-related proteins were examined by Western blotting. Furthermore, the effects of DYNLT3 on the tumorigenicity and metastasis of cervical cancer in nude mice were analyzed by performing immunohistochemistry, and we found that the expression level of the DYNLT3 protein was higher in human normal cervical tissues than in cervical cancer tissues. Overexpression of DYNLT3 obviously attenuated the proliferation, migration and invasion of CaSki and SiHa cells, and promoted cell apoptosis. Upregulation of DYNLT3 expression markedly decreased the expression of Wnt signaling pathway-related proteins (Dvl2, Dvl3, p-LRP6, Wnt3a, Wnt5a/b, Naked1, Naked2, β-catenin and C-Myc) and EMT-related proteins (N-cadherin, SOX2, OCT4, vimentin and Snail), and increased the expression of E-cadherin and Axin1. However, the opposite results were observed after down-regulation of DYNLT3 expression. Up-regulation of DYNLT3 expression significantly inhibited tumor growth in a nude mouse model, while downregulation of DYNLT3 showed the opposite results. In addition, the major metastatic site of cervical cancer cells in mice was the lung, and downregulation of DYNLT3 expression increased cancer metastasis Show less

Alzheimer's disease (AD), as a progressive and irreversible brain disorder, remains the most universal neurodegenerative disease. No effective therapeutic methods are established yet due to the hindrance of the blood-brain barrier (BBB) and the complex pathological condition of AD.  Therefore, a multifunctional nanocarrier (Rapa@DAK/siRNA) for AD treatment is constructed to achieve small interfering RNA of β-site precursor protein (APP) cleaving enzyme-1 (BACE1 siRNA) and rapamycin co-delivery into the brain, based on Aleuria aurantia lectin (AAL) and β-amyploid (Aβ)-binding peptides (KLVFF) modified PEGylated dendrigraft poly-l-lysines (DGLs) via intranasal administration. Nasal administration provides an effective way to deliver drugs directly into the brain through the nose-to-brain pathway. AAL, specifically binding to L-fucose located in the olfactory epithelium, endows Rapa@DAK/siRNA with high brain entry efficiency through intranasal administration. KLVFF peptide as an Aβ targeting ligand and aggregation inhibitor enables nanoparticles to bind with Aβ, inhibit Aβ aggregation, and reduce toxicity. Meanwhile, the release of BACE1 siRNA and rapamycin is confirmed to reduce BACE1 expression, promote autophagy, and reduce Aβ deposition. Rapa@DAK/siRNA is verified to improve the cognition of transgenic AD mice after intranasal administration. Collectively, the multifunctional nanocarrier provides an effective and potential intranasal avenue for combination therapy of AD. Show less

Triple-negative breast cancer (TNBC) is a highly aggressive type of cancer with few available treatment methods. The aim of the current study was to provide a prognostic autophagy-related gene (ARG) model to predict the outcomes for TNBC patients using bioinformatic analysis. mRNA expression data and its clinical information for TNBC samples obtained from The Cancer Genome Atlas (TCGA) and Metabric databases were extracted for bioinformatic analysis. Differentially expressed autophagy genes were identified using the Wilcoxon rank sum test in R software. ARGs were downloaded from the Human Autophagy Database. The Kaplan-Meier plotter was employed to determine the prognostic significance of the ARGs. The sample splitting method and Cox regression analysis were employed to establish the risk model and to demonstrate the association between the ARGs and the survival duration. The corresponding ARG-transcription factor interaction network was visualized using the Cytoscape software. A signature-based risk score model was established for eight genes ( An eight-gene autophagic signature model was developed in this study to predict the survival risk for TNBC. The genes identified in the study may favor the design of target agents for autophagy control in advanced TNBC. Show less

The endothelial glycocalyx regulates vascular permeability, inflammation, and coagulation, and acts as a mechanosensor. The loss of glycocalyx can cause endothelial injury and contribute to several microvascular complications and, therefore, may promote diabetic retinopathy. Studies have shown a partial loss of retinal glycocalyx in diabetes, but with few molecular details of the changes in glycosaminoglycan (GAG) composition. Therefore, the purpose of our study was to investigate the effect of hyperglycemia on GAGs of the retinal endothelial glycocalyx. GAGs were isolated from rat retinal microvascular endothelial cells (RRMECs), media, and retinas, followed by liquid chromatography-mass spectrometry assays. Quantitative real-time polymerase chain reaction was used to study mRNA transcripts of the enzymes involved in GAG biosynthesis. Hyperglycemia significantly increased the shedding of heparan sulfate (HS), chondroitin sulfate (CS), and hyaluronic acid (HA). There were no changes to the levels of HS in RRMEC monolayers grown in high-glucose media, but the levels of CS and HA decreased dramatically. Similarly, while HA decreased in the retinas of diabetic rats, the total GAG and CS levels increased. Hyperglycemia in RRMECs caused a significant increase in the mRNA levels of the enzymes involved in GAG biosynthesis (including EXTL-1,2,3, EXT-1,2, ChSY-1,3, and HAS-2,3), with these increases potentially being compensatory responses to overall glycocalyx loss. Both RRMECs and retinas of diabetic rats exhibited glucose-induced alterations in the disaccharide compositions and sulfation of HS and CS, with the changes in sulfation including N,6-O-sulfation on HS and 4-O-sulfation on CS. Show less

Acute lung injury (ALI) represents a frequent sepsis-induced inflammatory disorder. Mesenchymal stromal cells (MSCs) elicit anti-inflammatory effects in sepsis. This study investigated the mechanism of exosomes from adipose-derived MSCs (ADMSCs) in sepsis-induced ALI. The IL-27r Show less

Koolen-de Vries syndrome (KdVS) is a rare disorder caused by haploinsufficiency of KAT8 regulatory NSL complex subunit 1 (KANSL1), which is characterized by intellectual disability, heart failure, hypotonia, and congenital malformations. To date, no effective treatment has been found for KdVS, largely due to its unknown pathogenesis. Using siRNA screening, we identified KANSL1 as an essential gene for autophagy. Mechanistic study shows that KANSL1 modulates autophagosome-lysosome fusion for cargo degradation via transcriptional regulation of autophagosomal gene, STX17. Kansl1 Show less

Epithelial-mesenchymal transition (EMT) is involved in the pathophysiology of lung cancer (LC) and COPD, and the latter is an important risk factor for LC. We hypothesised that the EMT gene expression profile and signalling cascade may differ in LC patients with COPD from those with no respiratory diseases. In lung tumour specimens obtained through video-assisted thoracoscopic surgery from LC (n=20, control group) and LC-COPD patients (n=30), gene expression (quantitative real-time PCR amplification) of EMT markers Show less

Anti-inflammatory therapies have the potential to become an effective treatment for obesity-related diseases. However, the huge gap of immune system between human and rodent leads to limitations of drug discovery. This work aims at constructing a transgenic pig model with higher risk of metabolic diseases and outlining the immune responses at the early stage of metaflammation by transcriptomic strategy. We used CRISPR/Cas9 techniques to targeted knock-in three humanized disease risk genes, Show less

Glucose-dependent insulinotropic polypeptide (GIP) is a peptide hormone that exerts crucial metabolic functions by binding and activating its cognate receptor, GIPR. As an important therapeutic target, GIPR has been subjected to intensive structural studies without success. Here, we report the cryo-EM structure of the human GIPR in complex with GIP and a G Show less

Contrasting to the established role of the hypothalamic agouti-related protein (AgRP) neurons in feeding regulation, the neural circuit and signaling mechanisms by which they control energy expenditure remains unclear. Here, we report that energy expenditure is regulated by a subgroup of AgRP neurons that send non-collateral projections to neurons within the dorsal lateral part of dorsal raphe nucleus (dlDRN) expressing the melanocortin 4 receptor (MC4R), which in turn innervate nearby serotonergic (5-HT) neurons. Genetic manipulations reveal a bi-directional control of energy expenditure by this circuit without affecting food intake. Fiber photometry and electrophysiological results indicate that the thermo-sensing MC4R Show less