👤 Deyou Zheng

Glucose-dependent insulinotropic polypeptide receptor (GIPR) has been identified as a contributor to obesity, and GIPR knockout mice are protected against diet-induced obesity (DIO). Therefore, we developed the anti-GIPR antagonistic monoclonal antibody (mAb) alone and in combination with DPP-4 inhibitor as potential therapeutic strategy for treating obesity and dyslipidemia based on this genetic evidence. Fully neutralized GIPR activity of GIPR-monoclonal antibody (mAb) was assessed by regulating the in vitro production of cAMP in the mouse GIPR stably expressing cells. Chronic efficacies of GIPR-mAb alone and in combination with DPP-4 inhibitor Sitagliptin in diabetic or DIO mice were both investigated. Multiple metabolic parameters including body weight, glucose level, fat mass, lipid metabolism-related indicators as well as H&E staining and immunohistochemical analysis were performed. Role of GIPR in pancreatic cells on regulating fat metabolism was explored in GIPR β-cell knockout mouse model. Chronic treatment of GIPR-mAb improved body weight control, glucose metabolism, and was associated with reduced fat mass, enhanced pancreatic function and exchange ratio of the resting respiratory in diabetic mice. In addition, further study of anti-GIPR mAb combined with Sitagliptin in DIO mice demonstrated significantly improved weight loss compare to the both monomer treatment. Furthermore, we demonstrated important role of GIPR in β-cell in regulating the fat mass and response to antagonistic GIPR-mAb in a conditional GIPR-knockout mouse. Chronic treatment with anti-GIPR mAb alone and combined with DPP-4 inhibitor provide preclinical therapeutic approaches to treat obesity. Show less

Substantial evidence indicated that maternal malnutrition could increase the susceptibility to obesity, insulin resistance, and type 2 diabetes in adulthood. It is increasingly apparent that the brain, especially the hypothalamus, plays a critical role in glucose homeostasis. However, little information is known about the mechanisms linking maternal protein restriction combined with post-weaning high-fat (HF) feeding with altered expression of brain neurotransmitters, and investigations into the epigenetic modifications of hypothalamus in offspring have not been fully elucidated. Our objective was to explore the effects of maternal protein restriction combined with post-weaning HF feeding on glucose metabolism and hypothalamic POMC methylation in male offspring mice. C57/BL6 mice were fed on either low-protein (LP) or normal chow (NC) diet throughout gestation and lactation. Then, the male offspring were randomly weaned to either NC or high-fat (HF) diet until 32 weeks of age. Gene expressions and DNA methylation of hypothalamic proopiomelanocortin (POMC) and melanocortin receptor 4 (MC4R) were determined in male offspring. The results showed that birth weights and body weights at weaning were both significantly lower in male offspring mice of the dams fed with a LP diet. Maternal protein restriction combined with post-weaning high-fat feeding, predisposes higher body weight, persistent glucose intolerance (from weaning to 32 weeks of age), hyperinsulinemia, and hyperleptinemia in male offspring mice. POMC and MC4R expressions were significantly increased in offspring mice fed with maternal LP and postnatal high-fat diet ( Show less

Breeding for good meat quality performance while maintaining large body size and desirable carcass traits has been the major challenge for modern swine selective breeding. To address this goal, in the present work we studied five related populations produced by two commercial breeds (Berkshire and Duroc) and two Chinese breeds (Licha black pig and Lulai black pig). A single-trait GWAS performed on 20 body size and carcass traits using a self-developed China Chip-1 porcine SNP50K BeadChip identified 11 genome-wide significant QTL on nine chromosomes and 22 suggestive QTL on 15 chromosomes. For the 11 genome-wide significant QTL, eight were detected in at least two populations, and the rest were population-specific and only mapped in Shanxia black pig. Most of the genome-wide significant QTL were pleiotropic; for example, the QTL around 75.65 Mb on SSC4 was associated with four traits at genome-wide significance level. After screening the genes within 50 kb of the top SNP for each genome-wide significant QTL, NR6A1 and VRTN were chosen as candidate genes for vertebrae number; PLAG1 and BMP2 were identified as candidate genes for body size; and MC4R was the strong candidate gene for body weight. The four genes have been reported as candidates for thoracic vertebrae number, lumbar vertebrae number, carcass length and body weight respectively in previous studies. The effects of VRTN on thoracic vertebrae number, carcass length and body length have been verified in Shanxia black pig. Therefore, the VRTN genotype could be used in gene-assisted selection, and this could accelerate genetic improvement of body size and carcass traits in Shanxia black pig. Show less

Physiological modulation of melanocortin-4 receptor (MC4R) signaling by MRAP2 proteins plays an indispensable role in appetite control and energy homeostasis in the central nervous system. Great interspecies differences of the interaction and regulation of melanocortin receptors by MRAP protein family have been reported in several diploid vertebrates but never been investigated in the tetrapod amphibian Xenopus laevis. Here, we performed phylogenetic and synteny-based analyses to explore the evolutionary aspects of dual copies of X. laevis MC4R (xlMC4R) and MRAP2 (xlMRAP2) proteins. Our data showed that xlMRAPs directly interacted with xlMC4Rs on the cell surface as a functional antiparallel dimeric topology and pharmacological studies suggested a homology specific regulatory pattern of the melanocortin system in X. laevis. Show less

Asthma is a heterogeneous disease that can be divided into four inflammatory phenotypes: eosinophilic asthma (EA), neutrophilic asthma (NA), mixed granulocytic asthma (MGA), and paucigranulocytic asthma (PGA). While research has mainly focused on EA and NA, the understanding of PGA is limited. In this study, we aimed to identify underlying mechanisms and hub genes of PGA. Based on the dataset from Gene Expression Omnibus(GEO), weighted gene coexpression network analysis (WGCNA), differentially expressed genes (DEGs) analysis and protein-protein interaction (PPI) network analysis were conducted to construct a gene network and to identify key gene modules and hub genes. Functional enrichment analyses were performed to investigate the biological process, pathways and immune status of PGA. The hub genes were validated in a separate dataset. Compared to non-PGA, PGA had a different gene expression pattern, in which 449 genes were differentially expressed. One gene module significantly associated with PGA was identified. Intersection between the differentially expressed genes (DEGs) and the genes from the module that were most relevant to PGA were mainly enriched in inflammation and immune response regulation. The single sample Gene Set Enrichment Analysis (ssGSEA) suggested a decreased immune infiltration and function in PGA. Finally six hub genes of PGA were identified, including ADCY2, CXCL1, FPRL1, GPR109B, GPR109A and ADCY3, which were validated in a separate dataset of GSE137268. Our study characterized distinct gene expression patterns, biological processes and immune status of PGA and identified hub genes, which may improve the understanding of underlying mechanism and provide potential therapeutic targets for PGA. Show less

This study aims to characterize the expression of ANGPTL4 in ovarian granulosa cells (GCs) and its association with polycystic ovary syndrome (PCOS). This study included 104 PCOS patients and 112 women in control group undergoing The RT-qPCR results showed that ANGPTL4 expression in the control group was significantly lower than that in the PCOS group ( Our study revealed higher ANGPTL4 expression in ovarian GCs with PCOS. Its association with glucose and lipid metabolism showed that ANGPTL4 might play an important role in PCOS metabolism and pathogenesis. Show less

Ovarian cancer (OV) is deemed the most lethal gynecological cancer in women. The aim of this study was to construct an effective gene prognostic model for predicting overall survival (OS) in patients with OV. The expression profiles of glycolysis-related genes (GRGs) and clinical data of patients with OV were extracted from The Cancer Genome Atlas (TCGA) database. Univariate, multivariate, and least absolute shrinkage and selection operator Cox regression analyses were conducted, and a prognostic signature based on GRGs was constructed. The predictive ability of the signature was analyzed using training and test sets. A gene risk signature based on nine GRGs (ISG20, CITED2, PYGB, IRS2, ANGPTL4, TGFBI, LHX9, PC, and DDIT4) was identified to predict the survival outcome of patients with OV. The signature showed a good prognostic ability for OV, particularly high-grade OV, in the TCGA dataset, with areas under the curve (AUC) of 0.709 and 0.762 for 3- and 5-year survival, respectively. Similar results were found in the test sets, and the AUCs of 3-, 5-year OS were 0.714 and 0.772 in the combined test set. And our signature was an independent prognostic factor. Moreover, a nomogram combining the prediction model and clinical factors was developed. Our study established a nine-GRG risk model and nomogram to better predict OS in patients with OV. The risk model represents a promising and independent prognostic predictor for patients with OV. Moreover, our study on GRGs could offer guidance for the elucidation of underlying mechanisms in future studies. Show less

There are few studies on the role of iron metabolism genes in predicting the prognosis of lung adenocarcinoma (LUAD). Therefore, our research aims to screen key genes and to establish a prognostic signature that can predict the overall survival rate of lung adenocarcinoma patients. RNA-Seq data and corresponding clinical materials of 594 adenocarcinoma patients from The Cancer Genome Atlas(TCGA) were downloaded. GSE42127 of Gene Expression Omnibus (GEO) database was further verified. The multi-gene prognostic signature was constructed by the Cox regression model of the Least Absolute Shrinkage and Selection Operator (LASSO). We constructed a prediction signature with 12 genes (HAVCR1, SPN, GAPDH, ANGPTL4, PRSS3, KRT8, LDHA, HMMR, SLC2A1, CYP24A1, LOXL2, TIMP1), and patients were split into high and low-risk groups. The survival graph results revealed that the survival prognosis between the high and low-risk groups was significantly different (TCGA: P < 0.001, GEO: P = 0.001). Univariate and multivariate Cox regression analysis confirmed that the risk value is a predictor of patient OS (P < 0.001). The area under the time-dependent ROC curve (AUC) indicated that our signature had a relatively high true positive rate when predicting the 1-year, 3-year, and 5-year OS of the TCGA cohort, which was 0.735, 0.711, and 0.601, respectively. In addition, immune-related pathways were highlighted in the functional enrichment analysis. In conclusion, we developed and verified a 12-gene prognostic signature, which may be help predict the prognosis of lung adenocarcinoma and offer a variety of targeted options for the precise treatment of lung cancer. Show less

Increasing studies have shown that obesity is the primary cause of cardiovascular diseases, non-alcoholic fatty liver diseases, type 2 diabetes, and a variety of cancers. The dysfunction of gut microbiota was proved to result in obesity. Recent research indicated ANGPTL4 was a key regulator in lipid metabolism and a circulating medium for gut microbiota and fat deposition. The present study was conducted to investigate the alteration of gut microbiota and ANGPTL4 expression in the gastrointestinal tract of mice treated by the high-fat diet. Ten C57BL/6J mice were randomly allocated to two groups and fed with a high-fat diet (HFD) containing 60% fat or a normal-fat diet (Control) containing 10% fat. The segments of ileum and colon were collected for the determination of ANGPTL4 expression by RT-qPCR and immunohistochemical analysis while the ileal and colonic contents were collected for 16S rRNA gene sequencing. The results showed HFD significantly increased mice body weight, epididymal fat weight, perirenal fat weight, liver weight, and the lipid content in the liver ( Show less

The purpose of this study was to investigate the impact of single nucleotide polymorphisms (SNPs) in the ANGPTL4 gene and the SNP-SNP interactions on atherosclerotic ischemic stroke (IS) risk. A case-control study was conducted. A total of 360 patients with atherosclerotic IS and 342 controls between December 2018 and December 2019 from Longyan First Hospital affiliated to Fujian Medical University were included. A logistic regression model was used to examine the association between SNPs and atherosclerotic IS risk. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated. Generalized multifactor dimensionality reduction was employed to analyze the SNP-SNP interaction. Logistic regression analysis showed that atherosclerotic IS risk was significantly lower in carriers with the rs11672433-T allele than those with the CC genotype (CT+ TT vs. CC); adjusted OR, 0.005; 95% CI, 0.02-0.11. We found a significant 2-locus model (P = 0.0010) involving rs11672433 and rs4076317; the cross-validation consistency of this model was 10 of 10, and the testing accuracy was 57.96%. Participants with the CT or TT of rs11672433 and CC of rs4076317 genotype have the lowest atherosclerotic IS risk, compared to subjects with CC of rs11672433 and the CC of rs4076317 genotype, OR (95%CI) was 0.06(0.02-0.22), after covariates adjustment for gender, age, smoking and alcohol status, hypertension, Diabetes mellitus, TG, TC, HDL-C, LDL-C, Uric acid. We found that rs11672433 was associated with decreased atherosclerotic IS risk; we also found that gene-gene interaction between rs11672433 and rs4076317 was associated with decreased atherosclerotic IS risk. Show less

Angiopoietin-like protein 4 (ANGPTL-4) had been reported to be associated with the risk of ischemic stroke, but its prognostic value remained unclear. The aim of this study was to investigate the association between plasma ANGPTL-4 concentrations and prognosis of ischemic stroke. Baseline plasma ANGPTL-4 concentrations were measured in 3379 acute ischemic stroke patients. The primary outcome was a combination of death or major disability (modified Rankin Scale score, ≥3) at 3 months after ischemic stroke. At 3 months after ischemic stroke, 850 (26.16%) participants experienced major disability or died (750 major disabilities and 100 deaths). After adjusting for important covariates, odds ratios for the highest tertile of plasma ANGPTL-4 concentrations were 1.59 (1.22-2.06) for primary outcome, 1.53 (1.18-1.97) for major disability, and 2.03 (1.03-4.00) for death when compared with the lowest tertile of plasma ANGPTL-4 concentrations. For 1-SD increase in log-ANGPTL-4 concentrations (0.44 ng/mL), the adjusted odds ratios were 1.24 (1.11-1.38), 1.14 (1.03-1.27), and 1.72 (1.32-2.23), respectively. Adding ANGPTL-4 to a model containing conventional risk factors improved risk prediction for composite outcome of death and major disability. Higher plasma ANGPTL-4 concentration was associated with poor prognosis in acute ischemic stroke patients, suggesting that ANGPTL-4 might be a prognostic marker for ischemic stroke. Show less

Metabolic reprogramming plays an important role in tumorigenesis. However, the metabolic types of different tumors are diverse and lack in-depth study. Here, through analysis of big databases and clinical samples, we identified a carbamoyl phosphate synthetase 1 (CPS1)-deficient hepatocellular carcinoma (HCC) subtype, explored tumorigenesis mechanism of this HCC subtype, and aimed to investigate metabolic reprogramming as a target for HCC prevention. A pan-cancer study involving differentially expressed metabolic genes of 7,764 tumor samples in 16 cancer types provided by The Cancer Genome Atlas (TCGA) demonstrated that urea cycle (UC) was liver-specific and was down-regulated in HCC. A large-scale gene expression data analysis including 2,596 HCC cases in 7 HCC cohorts from Database of HCC Expression Atlas and 17,444 HCC cases from in-house hepatectomy cohort identified a specific CPS1-deficent HCC subtype with poor clinical prognosis. In vitro and in vivo validation confirmed the crucial role of CPS1 in HCC. Liquid chromatography-mass spectrometry assay and Seahorse analysis revealed that UC disorder (UCD) led to the deceleration of the tricarboxylic acid cycle, whereas excess ammonia caused by CPS1 deficiency activated fatty acid oxidation (FAO) through phosphorylated adenosine monophosphate-activated protein kinase. Mechanistically, FAO provided sufficient ATP for cell proliferation and enhanced chemoresistance of HCC cells by activating forkhead box protein M1. Subcutaneous xenograft tumor models and patient-derived organoids were employed to identify that blocking FAO by etomoxir may provide therapeutic benefit to HCC patients with CPS1 deficiency. In conclusion, our results prove a direct link between UCD and cancer stemness in HCC, define a CPS1-deficient HCC subtype through big-data mining, and provide insights for therapeutics for this type of HCC through targeting FAO. Show less

Phenotypes of some rare genetic diseases are atypical and it is a challenge for pediatric intensive care units (PICUs) to diagnose and manage such patients in an emergency. In this study, we investigated 58 PICU patients (39 deceased and 19 surviving) in critical ill status or died shortly without a clear etiology. Whole exome sequencing was performed of 103 DNA samples from their families. Disease-causing single-nucleotide variants (SNVs) and copy number variants (CNVs) were identified to do genotype-phenotypes analysis. In total, 27 (46.6%) patients received a genetic diagnosis. We identified 34 pathogenic or likely pathogenic SNVs from 26 genes, which are related to at least 19 rare diseases. Each rare disease involved an isolated patient except two patients caused by the same gene ACAT1. The genotypic spectrum was expanded by 23 novel SNVs from gene MARS1, PRRT2, TBCK, TOR1A, ECE1, ARX, ZEB2, ACAT1, CPS1, VWF, NBAS, COG4, and INVS. We also identified two novel pathogenic CNVs. Phenotypes associated with respiratory, multiple congenital anomalies, neuromuscular, or metabolic disorders were the most common. Twenty patients (74.1%) accompanied severe infection, 19 patients (70.1%) died. In summary, our findings expanded the genotypes and phenotypes of 19 rare diseases from PICU with complex characteristics. Show less

Here, we investigate the role of SmERF73, a group VII ETHYLENE RESPONSE FACTOR stress response transcription factor, in the regulation of post-modification of the skeleton precursors of diterpene tanshinones in Salvia miltiorrhiza. Most genes found to be involved in tanshinone biosynthesis are located on chromosome 6, and five of these genes comprise a large gene cluster in S. miltiorrhiza. We found that SmERF73 overexpression in S. miltiorrhiza coordinately up-regulated the transcription of seven tanshinone biosynthetic genes, four of which were located in the tanshinone gene cluster, consequently increasing tanshinone accumulation, while SmERF73 silencing reduced corresponding gene transcription and tanshinone accumulation. SmERF73 recognizes GCC-box promoter elements of four tanshinone-associated genes (DXR1, CPS1, KSL1 and CYP76AH3) and activates their expression. Moreover, SmERF73 and its targets were up-regulated by stress elicitors; SmERF73 appears to be at least partly mediated by the jasmonic acid (JA) signaling pathway via interaction with SmJAZ3. SmERF73 coordinately regulates tanshinone biosynthetic gene expression, suggesting a potential link between tanshinone production and plant stress responses. Show less

FGF8-FGFR1 signalling is involved in multiple biological processes, while impairment of this signalling is one of the main reasons for isolated hypogonadotropic hypogonadism (IHH). Recently, several negative modulators of FGF8-FGFR1 signalling were also found to be involved in IHH, including A total of 196 patients with IHH were enrolled in this study. Whole-exome sequencing was performed to identify variants, which was verified by PCR and Sanger sequencing. Four heterozygous Our study greatly enriched the genotypic and phenotypic spectra of Show less

To explore the genetic basis for a pedigree affected with hereditary multiple osteochondroma (HMO). Peripheral blood samples were collected from the proband and members of his pedigree with informed consent. Following extraction of genomic DNA, all coding exons and flanking intronic sequences (-10 bp) of the EXT1 and EXT2 genes were subjected to targeted capture and next generation sequencing (NGS). Suspected variant was verified by Sanger sequencing. A heterozygous nonsense variant (c.1911C>A) was found in exon 10 of the EXT1 gene in the proband and his affected father but not in a healthy sister and normal controls. The variant was classified as a pathogenic based on the guidelines of the American College of Medical Genetics and Genomics (PVS1+PM2+PP1). Bioinformatic analysis predicted that the c.1911C>A variant may be disease-causing via nonsense-mediated mRNA decay and anomalous splicing. The c.1911C>A variant probably underlay the disease in this pedigree. Discovery of this variant enriched the variant spectrum of HMO. Show less

Numerous studies have reported an association between genetic variants in fatty acid desaturases (FADS1 and FADS2) and plasma or erythrocyte long chain polyunsaturated fatty acid (PUFA) levels. Increased levels of n-6 PUFAs have been associated with inflammation and several chronic diseases, including diabetes and cancer. We hypothesized that genetic variants of FADS that more efficiently convert precursor n-6 PUFA to arachidonic acid (AA) may explain the higher burden of chronic diseases observed in African Americans. To test this hypothesis, we measured the level of n-6 and n-3 PUFAs in erythrocyte membrane phospholipids and genotyped the rs174537 FADS variants associated with higher AA conversion among African American and European American populations. We included data from 1,733 individuals who participated in the Tennessee Colorectal Polyp Study, a large colonoscopy-based case-control study. Erythrocyte membrane PUFA percentages were measured using gas chromatography. Generalized linear models were used to estimate association of race and genotype on erythrocyte phospholipid membrane PUFA levels while controlling for self-reported dietary intake. We found that African Americans have higher levels of AA and a higher prevalence of GG allele compared to whites, 81% vs 43%, respectively. Homozygous GG genotype was negatively associated with precursor PUFAs (linoleic [LA], di-homo-γ-linolenic [DGLA]), positively associated with both product PUFA (AA, docosahexaenoic acid [DHA]), product to precursor ratio (AA to DGLA), an indirect measure of FADs efficiency and increased urinary isoprostane F2 (F2-IsoP) and isoprostane F3 (F3-IsoP), markers of oxidative stress. Increased consumption of n-6 PUFA and LA resulting in increased AA and subsequent inflammation may be fueling increased prevalence of chronic diseases especially in African descent. Show less

Higher plasma vitamin C levels are associated with lower type 2 diabetes risk, but whether this association is causal is uncertain. To investigate this, we studied the association of genetically predicted plasma vitamin C with type 2 diabetes. We conducted genome-wide association studies of plasma vitamin C among 52,018 individuals of European ancestry to discover novel genetic variants. We performed Mendelian randomization analyses to estimate the association of genetically predicted differences in plasma vitamin C with type 2 diabetes in up to 80,983 case participants and 842,909 noncase participants. We compared this estimate with the observational association between plasma vitamin C and incident type 2 diabetes, including 8,133 case participants and 11,073 noncase participants. We identified 11 genomic regions associated with plasma vitamin C ( These findings indicate discordance between biochemically measured and genetically predicted plasma vitamin C levels in the association with type 2 diabetes among European populations. The null Mendelian randomization findings provide no strong evidence to suggest the use of vitamin C supplementation for type 2 diabetes prevention. Show less

To explore the genetic basis for a sib pair featuring 17beta-hydroxysteroid dehydrogenase type 3 deficiency. Genomic DNA was extracted from the proband, her sister, and their parents, and was subjected to sequencing analysis with a gene panel for sexual development. Suspected variant was verified by Sanger sequencing and bioinformatic analysis. Both the proband and her sister were found to harbor novel compound heterozygous missense variants of the HSD17B3 gene, namely c.839T>C (p.Leu280Pro) and c.239G>T (p.Arg80Leu), which were derived respectively from their mother and father. The variants were unreported previously and predicted to be deleterious by PolyPhen2, MutationTaster and other online software. Based on the American College of Medical Genetics and Genomics standards and guidelines, both c.839T>C(p.Leu280Pro) and c.239G>T (p.Arg80Leu) were predicted to be likely pathogenic (PM2+PP1+PP2+PP3+PP4, PM2+PM5+PP1+PP2+PP3+PP4). The compound heterogeneous variants of the HSD17B3 gene probably underlay the disease in this sib pair. 17beta-hydroxysteroid dehydrogenase type 3 deficiency may lack specific clinical features and laboratory index, genetic testing can facilitate a definitive diagnosis. Show less

To evaluate the value of interleukin (IL)-27 measured in serum and bronchoalveolar lavage fluid (BALF) for the diagnosis of smear-negative pulmonary tuberculosis (TB). This was a prospective study of patients planned to undergo bronchoscopy at Wuxi No.5 People's Hospital between January 2017 and September 2018. The patients were grouped as the TB and control groups. BALF and serum IL-27 were measured by ELISA. Receiver operating characteristic (ROC) curves were used to assess the diagnostic value and calculate the optimal cutoff values. There were 40 patients in the control group and 87 in the TB group. In the TB group, 20 had positive sputum smear results and 67 were negative. The area under the ROC curve (AUC) of BALF IL-27 for pulmonary TB was 0.897 (95% CI: 0.830-0.944) (P < .001). The AUC of serum IL-27 for pulmonary TB was 0.703 (95% CI: 0.616-0.781) (P < .001). In patients with negative sputum smear results, the AUCs of BALF IL-27 and serum IL-27 for pulmonary TB was 0.882 (95% confidence interval [CI]: 0.805-0.936) (P < .001) and 0.679 (95% CI: 0.601-0.782) (P < .001), respectively. BALF IL-27 can be used for the diagnosis of pulmonary TB, particularly in those with a negative sputum smear result. Serum IL-27 could be an auxiliary method for TB screening. Show less

IL-27, a heterodimeric cytokine of the IL-12 family, has diverse influences on the development of multiple inflammatory diseases. In this study, we identified the protective role of IL-27/IL-27R in host defense against Show less

Vaccines stimulate various immune factors critical to protective immune responses. However, a comprehensive picture of vaccine-induced immune factors and pathways have not been systematically collected and analyzed. To address this issue, we developed VaximmutorDB, a web-based database system of vaccine immune factors (abbreviated as "vaximmutors") manually curated from peer-reviewed articles. VaximmutorDB currently stores 1,740 vaccine immune factors from 13 host species (e.g., human, mouse, and pig). These vaximmutors were induced by 154 vaccines for 46 pathogens. Top 10 vaximmutors include three antibodies (IgG, IgG2a and IgG1), Th1 immune factors (IFN-γ and IL-2), Th2 immune factors (IL-4 and IL-6), TNF-α, CASP-1, and TLR8. Many enriched host processes (e.g., stimulatory C-type lectin receptor signaling pathway, SRP-dependent cotranslational protein targeting to membrane) and cellular components (e.g., extracellular exosome, nucleoplasm) by all the vaximmutors were identified. Using influenza as a model, live attenuated and killed inactivated influenza vaccines stimulate many shared pathways such as signaling of many interleukins (including IL-1, IL-4, IL-6, IL-13, IL-20, and IL-27), interferon signaling, MARK1 activation, and neutrophil degranulation. However, they also present their unique response patterns. While live attenuated influenza vaccine FluMist induced significant signal transduction responses, killed inactivated influenza vaccine Fluarix induced significant metabolism of protein responses. Two different Yellow Fever vaccine (YF-Vax) studies resulted in overlapping gene lists; however, they shared more portions of pathways than gene lists. Interestingly, live attenuated YF-Vax simulates significant metabolism of protein responses, which was similar to the pattern induced by killed inactivated Fluarix. A user-friendly web interface was generated to access, browse and search the VaximmutorDB database information. As the first web-based database of vaccine immune factors, VaximmutorDB provides systematical collection, standardization, storage, and analysis of experimentally verified vaccine immune factors, supporting better understanding of protective vaccine immunity. Show less

Previous genotyping-based assays have identified non-coding variants of several interleukins (ILs) being associated with genetic susceptibility to leprosy. However, understanding of the involvement of coding variants within all IL family genes in leprosy was still limited. To obtain the full mutation spectrum of all ILs in leprosy, we performed a targeted deep sequencing of coding regions of 58 ILs genes in 798 leprosy patients (age 56.2 ± 14.4; female 31.5%) and 990 healthy controls (age 38.1 ± 14.0; female 44.3%) from Yunnan, Southwest China. mRNA expression alterations of ILs in leprosy skin lesions or in response to M. leprae treatment were estimated by using publicly available expression datasets. Two coding variants in IL27 (rs17855750, p.S59A, p = 4.02 × 10 Show less

The present study aimed to provide evidence for the genetic heterogeneity of familial autism spectrum disorder (ASD), which might help to improve our understanding of the complex polygenic basis of this disease. Whole‑exome sequencing (WES) was performed on two autistic children in a family pedigree, and reasonable conditions were set for preliminarily screening variant annotations. Sanger sequencing was used to verify the preliminarily screened variants and to determine the possible sources. In addition, autism‑related genes were screened according to autism databases, and their variants were compared between two autistic children. The results showed that there were 21 genes respectively for autistic children Ⅳ2 and Ⅳ4, preliminarily screened from all variants based on the harmfulness (high) and quality (high or medium) of the variants, as well as the association between mutant genes and autism in human gene mutation database. Furthermore, candidate autism‑related genes were screened according to the evidence score of >4 in the Autism KnowledgeBase (AutismKB) database or ≥3 in the AutDB database. A total of 11 and 10 candidate autism‑related genes were identified in the autistic children Ⅳ2 and Ⅳ4, respectively. Candidate genes with an evidence score of >16 in AutismKB were credible autism‑related genes, which included LAMC3, JMJD1C and CACNA1H in child Ⅳ2, as well as SCN1A, SETD5, CHD7 and KCNMA1 in child Ⅳ4. Other than the c.G1499A mutation of SCN1A, which is known to be associated with Dravet syndrome, the specific missense variant loci of other six highly credible putative autism‑related genes were reported for the first time, to the best of the authors' knowledge, in the present study. These credible autism‑related variants were inherited not only from immediate family members but also from extended family members. In summary, the present study established a reasonable and feasible method for screening credible autism‑related genes from WES results, which by be worth extending into clinical practice. The different credible autism‑related genes between the two autistic children indicated a complex polygenic architecture of ASD, which may assist in the early diagnosis of this disease. Show less

Despite strong evidence of heritability, few studies have attempted to unveil the genetic underpinnings of testosterone levels. To identify testosterone-associated loci in a large study and assess their biological and clinical implications. The participants were men from the UK Biobank. A two-stage genome-wide association study (GWAS) was first used to identify/validate loci for low testosterone (LowT, <8 nmol/l) in 80% of men ( Associations of single nucleotide polymorphisms (SNPs) with LowT were tested using an additive model. Analyses of the expression quantitative trait loci (eQTLs) were performed to assess the associations between significant SNPs and expression of nearby genes (within 1 Mbp). A genetic risk score (GRS) was used to assess the cumulative effect of multiple independent SNPs on LowT risk. The two-stage GWAS found SNPs in 141 loci of 41 cytobands that were significantly associated with LowT ( Identification of the genetic variants associated with LowT may improve our understanding of its etiology and identify high-risk men for LowT screening. We identified 141 new genetic loci that can be incorporated into a genetic risk score that can potentially identify men with low testosterone. Show less

Traumatic brain injury (TBI) is a highly lethal event with a poor prognosis. Recovering residual neuronal function in the intermediate stage of TBI is important for treatment; however, neuroinflammation and neuronal apoptosis impede residual neuronal repair processes. Considering that hyperglycemia influences inflammatory processes and neuronal survival, we examined the effects of high glucose on neuroinflammation and neuronal death during the intermediate phase of TBI. Rat models of type 2 diabetes mellitus and/or TBI were developed and behaviorally assessed. Neurological function and cognitive abilities were impaired in TBI rats and worsened by type 2 diabetes mellitus. Histopathological staining and analyses of serum and hippocampal mRNA and protein levels indicated that neuroinflammation and apoptosis were induced in TBI rats and exacerbated by hyperglycemia. Hyperglycemia inhibited hippocampal mitogen-activated protein kinase kinase 5 (MEK5) phosphorylation in TBI rats. Show less

Insulin-independent glucose metabolism, including anaerobic glycolysis that is promoted in resistance training, plays critical roles in glucose disposal and systemic metabolic regulation. However, the underlying mechanisms are not completely understood. In this study, through genetically manipulating the glycolytic process by overexpressing human glucose transporter 1 (GLUT1), hexokinase 2 (HK2) and 6-phosphofructo-2-kinase-fructose-2,6-biphosphatase 3 (PFKFB3) in mouse skeletal muscle, we examined the impact of enhanced glycolysis in metabolic homeostasis. Enhanced glycolysis in skeletal muscle promoted accelerated glucose disposal, a lean phenotype and a high metabolic rate in mice despite attenuated lipid metabolism in muscle, even under High-Fat diet (HFD). Further study revealed that the glucose metabolite sensor carbohydrate-response element-binding protein (ChREBP) was activated in the highly glycolytic muscle and stimulated the elevation of plasma fibroblast growth factor 21 (FGF21), possibly mediating enhanced lipid oxidation in adipose tissue and contributing to a systemic effect. PFKFB3 was critically involved in promoting the glucose-sensing mechanism in myocytes. Thus, a high level of glycolysis in skeletal muscle may be intrinsically coupled to distal lipid metabolism through intracellular glucose sensing. This study provides novel insights for the benefit of resistance training and for manipulating insulin-independent glucose metabolism. Show less