Human longevity is always a biological hotspot and so much effort has been devoted to identifying genes and genetic variations associated with longer lives. Most of the demographic studies have highlighted that females have a longer life span than males. The reasons for this are not entirely clear. In this study, we carried out a pool-based, epigenome-wide investigation of DNA methylation profiles in male and female nonagenarians/centenarians using the Illumina 450 K Methylation Beadchip assays. Although no significant difference was detected for the average methylation levels of examined CpGs (or probes) between male and female samples, a significant number of differentially methylated probes (DMPs) were identified, which appeared to be enriched in certain chromosome regions and certain parts of genes. Further analysis of DMP-containing genes (named DMGs) revealed that almost all of them are solely hypermethylated or hypomethylated. Functional enrichment analysis of these DMGs indicated that DNA hypermethylation and hypomethylation may regulate genes involved in different biological processes, such as hormone regulation, neuron projection, and disease-related pathways. This is the first effort to explore the gender-based methylome difference in nonagenarians/centenarians, which may provide new insights into the complex mechanism of longevity gender gap of human beings.

Adiponectin receptor 1 (encoded by ADIPOR1) is one of the major adiponectin receptors, and plays an important role in glucose and lipid metabolism. However, few studies have reported simultaneous associations between ADIPOR1 variants and type 2 diabetes (T2D), coronary artery disease (CAD) and T2D with CAD. Based on the "common soil" hypothesis, we investigated whether ADIPOR1 polymorphisms contributed to the etiology of T2D, CAD, or T2D with CAD in a Northern Han Chinese population.

In this work, we investigated the toxic effects of tritiated water (HTO) on the cardiovascular system. We examined the role of microRNA-34a (miR-34a) in DNA damage and repair in human umbilical vein endothelial cells (HUVECs) exposed to HTO. Cell proliferation capacity was evaluated by cell counting, and miR-34a expression was detected using quantitative PCR (QT-PCR). The Comet assay and γ-H2AX immunostaining were used to measure DNA double-strand breaks (DSBs). Reverse transcription polymerase chain reaction was used to measure the expression level of c-myc messenger RNA (mRNA). The cells exposed to HTO showed significantly lower proliferation than the control cells over 3 days. The DNA damage in the HTO group was more severe than that in the control group, at each time point examined. The expression of miR-34a mimics caused increased DNA DSBs whereas that of the miR-34a inhibitor caused decreased DNA DSBs. The proliferation viability was the opposite for the miR-34a mimics and inhibitor groups. The expression levels of c-myc mRNA in cells transfected with miR-34a mimics were lower than that in cells transfected with the miR-34a-5p inhibitor, at 0.5 hours and 2 hours after transfection. In summary, miR-34a mediates HTO toxicity in HUVECs by downregulating the expression of c-myc.

Transendothelial migration is a pivotal step before the dissemination of tumor cells into the blood circulation. Related researches about the crosstalk between tumor cells and endothelial cells could contribute to understanding the mechanism of transendothelial migration. Cumulative studies showed that CD133 was an important marker for cancer stem cells. In our research, a co-culture system was developed to study the interaction between CD133+ liver cancer cells and human umbilical vein endothelial cells. The results showed that the direct co-cultured supernatants promoted the migration and invasion of CD133+ liver cancer cells. It was further investigated that the expression level of chemokine CXCL9 was significantly elevated in the culture supernatants of direct co-culture system by activating the NF-kB, rather than in the indirect co-culture system or mono-culture system. High expression of CXCL9 in the direct co-cultured supernatants played a significant role in enhancing the migration and invasion of CD133+ liver cancer cells. Collectively, these findings suggest that chemokine CXCL9 may function as a potential target during the process of transendothelial migration.

Many previous studies have provided evidence that the ADIPOQ +45T>G polymorphism (rs2241766) might cause metabolic syndrome (MS). As a cardiovascular manifestation of MS, the incidence of stroke is associated with adiponectin; however, the results remain controversial and inconsistent. Systematic searches of relevant studies published up to Dec 2014 and Jan 2016 on the ADIPOQ +45T>G polymorphism and the risk of MS and adiponectin levels and the risk of stroke, respectively, were conducted in MEDLINE and EMBASE. The odds ratio (OR) or risk ratio (RR) and their 95% confidence interval (95% CI) were extracted. Sixteen studies containing 4,113 MS cases and 3,637 healthy controls indicated a weak positive association between ADIPOQ +45 T>G and MS in the dominant genetic model (OR = 1.30, 95% CI = 1.03-1.65), which was also validated by stratified subgroup analyses. Twelve studies including 26,213 participants and 4,246 stroke cases indicated that 5 μg/ml increments in adiponectin level were not relevant to stroke risk (RR = 1.05, 95% CI = 1.00-1.10, P = 0.069). This study suggested a weak positive association of ADIPOQ +45T>G with MS and a strong association with metabolic-related disease. Additionally, adiponectin level was not a causal factor of increasing stroke risk.

Single-cell analysis has revealed that transcription is dynamic and stochastic, but tools are lacking that can determine the mechanism operating at a single gene. Here we utilize single-molecule observations of RNA in fixed and living cells to develop a single-cell model of steroid-receptor mediated gene activation. We determine that steroids drive mRNA synthesis by frequency modulation of transcription. This digital behavior in single cells gives rise to the well-known analog dose response across the population. To test this model, we developed a light-activation technology to turn on a single steroid-responsive gene and follow dynamic synthesis of RNA from the activated locus. DOI:http://dx.doi.org/10.7554/eLife.00750.001.

Increased aerobic glycolysis is considered as a hallmark of cancer and targeting key glycolytic enzymes will be a promising therapeutic approach in cancer treatment. Alpha-enolase (ENO1), as a prominent glycolytic enzyme, is upregulated in multiple cancers and its overexpression is involved in tumor cell proliferation and metastasis. In the present study, we aimed to investigate the potential role of ENO1 in the development and progression of gastric cancer (GC). Here, we found that ENO1 expression was upregulated in human GC and was associated with Lauren type, lymph node metastasis (LNM) and TNM stage. Knockdown of ENO1 attenuated GC cell proliferation and metastasis and reversed epithelial-mesenchymal transition (EMT) progress in vitro while ENO1 overexpression did the opposite. ENO1 could modulate AKT signaling pathway in GC cells and the enhanced proliferation and migration ability induced by ENO1 overexpression was impaired after incubation with PI3K inhibitor Ly294002 in SGC7901 cells. Our data demonstrated that ENO1 enhances GC cell proliferation and metastasis through the protein kinase B (AKT) signaling pathway, indicating that ENO1/AKT signaling axis may serve as a potential target for treatment of GC.

RNA editing is a post-transcriptional event that leads to transcriptome diversity and has been shown to play important roles in tumorigenesis. However, dynamical changes and the functional significance of editing events during different cancer stages have not yet been characterized systematically. In this paper, we describe a comprehensive study of the RNA editome of four samples from different cancer stages for the same patient based on analysis of both whole-genome and transcriptome sequencing data. We identified 35,225 and 33,784 RNA editing events for poly(A)+ and poly(A)- RNA sequencing data respectively in all four samples and show that 93 and 90% correspond to cancer stage-specific editing events. We also found that half of editing sites in 3' UTR of coding genes were microRNA targets and most of the sites in the coding regions could lead to non-synonymous amino acid changes. Functional analysis of genes which suffered damaging non-synonymous editing events in each cancer stage show the gradual expansion of cancer related pathways accompanied by an increasing malignant grade of the samples. Our study, for the first time to our knowledge, comprehensively profiled and compared the editomes across the different cancer stages and revealed the functional impacts of RNA editing events during cancer development and progression.

Glycated hemoglobin (HbA1c) is used to diagnose type 2 diabetes (T2D) and assess glycemic control in patients with diabetes. Previous genome-wide association studies (GWAS) have identified 18 HbA1c-associated genetic variants. These variants proved to be classifiable by their likely biological action as erythrocytic (also associated with erythrocyte traits) or glycemic (associated with other glucose-related traits). In this study, we tested the hypotheses that, in a very large scale GWAS, we would identify more genetic variants associated with HbA1c and that HbA1c variants implicated in erythrocytic biology would affect the diagnostic accuracy of HbA1c. We therefore expanded the number of HbA1c-associated loci and tested the effect of genetic risk-scores comprised of erythrocytic or glycemic variants on incident diabetes prediction and on prevalent diabetes screening performance. Throughout this multiancestry study, we kept a focus on interancestry differences in HbA1c genetics performance that might influence race-ancestry differences in health outcomes.

Microglia and its polarization play critical roles in intracerebral hemorrhage-induced secondary brain injury. Programmed death protein 1/programmed death-ligand 1 has been reported to regulate neuroimmune cell functions. Signal transducers and activators of transcription 1 participate in microglia polarization, and programmed death protein 1/programmed death-ligand 1 could regulate the activation of signal transducers and activators of transcription 1. We herein show the critical role of programmed death protein 1/programmed death-ligand 1 in the polarization of microglia during intracerebral hemorrhage-induced secondary brain injury in rat models.

High-mobility group box1 (HMGB1) is a nuclear protein widely expressed in the central nervous system. Extracellular HMGB1 serves as a proinflammatory cytokine and contributes to brain injury during the acute stage post-stroke. Recently, increasing evidence has demonstrated beneficial effects of HMGB1 in some types of brain injury, but little is known about its effects during the late phase of subarachnoid hemorrhage (SAH). This study was designed to explore the potential roles and mechanisms of HMGB1 and its receptor, receptor for advanced glycation end-products (Rage), on brain recovery in the late stage of experimental SAH. Two inhibitors of HMGB1, ethyl pyruvate and glycyrrhizin (EP and GA), and Rage antagonist FPS-ZM1 were used to determine whether HMGB1 promotes brain recovery after SAH. The administration of EP, GA, and FPS-ZM1 effectively reduced HMGB1 and Rage expression. Correspondingly, protein levels of beneficial growth factors (NGF, BDNF, and VEGF) and numbers of BrdU and DCX positive neurons in the cortex were also decreased. The biphasic roles of HMGB1 may be based on the different redox modifications of cysteine residues. In this research, rats injected with two different redox status HMGB1 showed different prognosises at 7-14day after SAH. Recombinant HMGB1 can promote cytokine stimulating activity and aggravate brain injury. However, oxidized HMGB1 was unable to stimulate TNF production but can promote brain recovery by promoting neurotrophin expression. In conclusion, our investigation identified that HMGB1 promotes neurovascular recovery via Rage and may act in the oxidized state in the late stage of SAH.

Downregulation of genes involved in lignin biosynthesis and related biochemical pathways has been used as a strategy to improve biofuel production. Plant C1 metabolism provides the methyl units used for the methylation reactions carried out by two methyltransferases in the lignin biosynthetic pathway: caffeic acid 3-O-methyltransferase (COMT) and caffeoyl-CoA 3-O-methyltransferase (CCoAOMT). Mutations in these genes resulted in lower lignin levels and altered lignin compositions. Reduced lignin levels can also be achieved by mutations in the C1 pathway gene, folylpolyglutamate synthetase1 (FPGS1), in both monocotyledons and dicotyledons, indicating a link between the C1 and lignin biosynthetic pathways. To test if lignin content can be further reduced by combining genetic mutations in C1 metabolism and the lignin biosynthetic pathway, fpgs1ccoaomt1 double mutants were generated and functionally characterized.

Objective: In the present study, we aimed to investigate the potential role of fatty acid synthase (FASN) in the development and progression of colorectal cancer (CRC). Materials and methods: FASN levels were analyzed in human CRC tissues and adjacent normal tissues by Western blots and immunohistochemistry. Potential roles of FASN in regulating CRC cell proliferation and migration were examined by genetic manipulation in vitro. The molecular signaling was determined to understand the mechanisms of observed FASN effects. Results: FASN level was upregulated in CRC tissues and high expression of FASN was significantly associated with lymph node metastasis, TNM (Tumor, Node, Metastases) stage and poor prognosis in patients with CRC. Knockdown of FASN attenuated CRC cell proliferation and migration in vitro while FASN overexpression possessed the opposite effects. FASN regulated AMP-activated protein kinase (AMPK)/mechanistic target of rapamycin (mTOR) pathway in CRC cells. Conclusion: FASN enhanced CRC cell proliferation and metastasis potentially through AMPK/mTOR pathway, indicating that FASN/AMPK/mTOR signaling axis may serve as a potential target for the treatment of CRC.

Aging is a major risk factor for many diseases, especially in highly prevalent cardiopulmonary comorbidities and infectious diseases including Coronavirus Disease 2019 (COVID-19). Resolving cellular and molecular mechanisms associated with aging in higher mammals is therefore urgently needed. Here, we created young and old non-human primate single-nucleus/cell transcriptomic atlases of lung, heart and artery, the top tissues targeted by SARS-CoV-2. Analysis of cell type-specific aging-associated transcriptional changes revealed increased systemic inflammation and compromised virus defense as a hallmark of cardiopulmonary aging. With age, expression of the SARS-CoV-2 receptor angiotensin-converting enzyme 2 (ACE2) was increased in the pulmonary alveolar epithelial barrier, cardiomyocytes, and vascular endothelial cells. We found that interleukin 7 (IL7) accumulated in aged cardiopulmonary tissues and induced ACE2 expression in human vascular endothelial cells in an NF-κB-dependent manner. Furthermore, treatment with vitamin C blocked IL7-induced ACE2 expression. Altogether, our findings depict the first transcriptomic atlas of the aged primate cardiopulmonary system and provide vital insights into age-linked susceptibility to SARS-CoV-2, suggesting that geroprotective strategies may reduce COVID-19 severity in the elderly.

In this study, we intended to genotype 2 single nucleotide polymorphisms (SNPs) of tumor necrosis factor α-induced protein 3 (TNFAIP3) genes and explore an association of TNFAIP3 genetic polymorphism with the patients of myasthenia gravis (MG) at clinical level. In brief, 215 of adult MG patients were divided into subgroups according to their clinical features, age of onset, thymic pathology, and autoantibodies. Two hundred thirty-five of healthy controls were also divided into subgroups with gender- and age-matched. The allele and genotype frequencies of subgrouped patients were found to be higher than those of healthy controls. The distribution of TNFAIP3 gene rs7749323*A allele of late onset MG (LOMG, with positive acetylcholine receptor antibody and without thymoma) subgrouped patients was also significantly higher than that of gender- and age-matched healthy controls (7.4% vs 2.4%, odds ratio [OR] = 3.27, 95% confidence interval [CI] 1.01-10.6, P = .04). Furthermore, analysis to the genotype frequencies indicates that the carriers of rs7749323*A allele of LOMG group became more frequent than that of age-matched healthy controls (14.9% vs 4.8%, OR = 3.47, 95% CI 1.04-11.6, dominant model: P = .03). It is interesting to notice that there is no significant association between the rs7749323 and susceptibility of other MG subgroups. Therefore, it is suggested that the SNPs in the 3' flanking region (rs7749323) of TNFAIP3 gene and the genetic variations of TNFAIP3 gene may take an important role in the susceptibility of LOMG.

Human immunodeficiency virus‑1 (HIV‑1) infection severely damages the gut‑associated lymphoid tissue (GALT), the immune system and the gut barrier, which leads to accelerating the disease progression for patients with acquired immune deficiency syndrome (AIDS). Dysregulation of microRNAs (miRNAs) may contribute to this process. However, few studies have investigated the importance of miRNAs in AIDS pathogenesis and progression. The whole miRNA profile of patients with HIV infection from southwest P.R. China and the mode of interaction between HIV‑1 and miRNAs remains to be elucidated. Colon mucosal samples were collected from HIV+ patients and HIV‑ healthy individuals, miRNAs were isolated and subjected to array hybridization in the present study. A total of 476 human and virus‑derived microRNAs were significantly altered in the HIV+ group when compared with the control group (P<0.05), which may be involved in the progression to AIDS. Target genes of the significantly altered miRNAs were predicted using the TargetScan, miRbase and miRanda databases and the 10 shared target genes of upregulated miRNAs and the 391 target genes of downregulated miRNAs were selected. As only 10 target genes were predicted for upregulated miRNAs, subsequent GO and KEGG pathway analyses were focused on the 391 target genes of the downregulated miRNAs. The findings of the present study identified a series of crucial pathways, including cell‑extracellular matrix interaction and chemokine regulation, which indicated close affinity with CD4+ T cell activation. These pathways, involving genes such as integrin α5, led to a gut barrier dysfunction of patients with HIV. Important miRNAs include hsa‑miRNA‑32‑5p, hsa‑miRNA‑195‑5p, hsa‑miRNA‑20b‑5p, hsa‑miRNA‑590‑5p. The expression levels of the miRNAs and their target genes were confirmed using RT‑qPCR. Taking into previous observations, the findings of the present study identified the importance of miRNAs for regulating gut barrier dysfunction via multiple regulatory molecules and signaling pathways, which elucidated the underlying molecular mechanism of gut barrier dysfunction in patients with HIV.

NONCODE (http://www.bioinfo.org/noncode/) is a systematic database that is dedicated to presenting the most complete collection and annotation of non-coding RNAs (ncRNAs), especially long non-coding RNAs (lncRNAs). Since NONCODE 2016 was released two years ago, the amount of novel identified ncRNAs has been enlarged by the reduced cost of next-generation sequencing, which has produced an explosion of newly identified data. The third-generation sequencing revolution has also offered longer and more accurate annotations. Moreover, accumulating evidence confirmed by biological experiments has provided more comprehensive knowledge of lncRNA functions. The ncRNA data set was expanded by collecting newly identified ncRNAs from literature published over the past two years and integration of the latest versions of RefSeq and Ensembl. Additionally, pig was included in the database for the first time, bringing the total number of species to 17. The number of lncRNAs in NONCODEv5 increased from 527 336 to 548 640. NONCODEv5 also introduced three important new features: (i) human lncRNA-disease relationships and single nucleotide polymorphism-lncRNA-disease relationships were constructed; (ii) human exosome lncRNA expression profiles were displayed; (iii) the RNA secondary structures of NONCODE human transcripts were predicted. NONCODEv5 is also accessible through http://www.noncode.org/.

Aims. Fucosyltransferase 2 (FUT2) gene potentially affects the constituent of intestinal microbiota, which play a crucial role in the pathogenesis of inflammatory bowel disease (IBD). This study investigated the association of FUT2 gene polymorphisms with IBD in southeast China. Methods. We collected 671 IBD patients and 502 healthy controls. FUT2 gene polymorphisms (C357T, A385T, and G428A) were determined by SNaPshot. Frequencies of the FUT2 genotypes, alleles, and haplotype between groups were compared by χ2 test. Results. The allele and genotype frequencies of FUT2 did not differ between ulcerative colitis patients and controls (all P > 0.05). However, mutant allele and genotype of FUT2 (A385T) were significantly increased in Crohn's disease (CD) patients (P = 0.024, OR = 1.271, and 95% CI = 1.031-1.565; P < 0.001, OR = 1.927, and 95% CI = 1.353-2.747, resp.). The same conclusion was drawn from FUT2 (G428A) (P = 0.023, OR = 3.324, and 95% CI = 1.108-9.968; P = 0.044, OR = 1.116-10.137, and 95% CI = 1.116-10.137, resp.). The haplotype TT formed with "C357T and A385T" was more prevalent in CD patients than in controls (P = 0.020, OR = 1.277, and 95% CI = 1.036-1.573). Besides, frequencies of mutant allele and genotype of FUT2 (A385T) were significantly lower in patients with ileocolonic CD than in those with colonic CD (P = 0.001 and 0.002, resp.) and ileal CD (P = 0.007 and 0.004, resp.). Conclusions. FUT2 gene polymorphisms and haplotypes were associated with the susceptibility to CD but not UC.

Amyotrophic lateral sclerosis (ALS) is a complex neurodegenerative disease with cellular and molecular mechanisms yet to be fully described. Mutations in a number of genes including SOD1 and FUS are associated with familial ALS. Here we report the generation of induced pluripotent stem cells (iPSCs) from fibroblasts of familial ALS patients bearing SOD1 +/A272C and FUS +/G1566A mutations, respectively. We further generated gene corrected ALS iPSCs using CRISPR/Cas9 system. Genome-wide RNA sequencing (RNA-seq) analysis of motor neurons derived from SOD1 +/A272C and corrected iPSCs revealed 899 aberrant transcripts. Our work may shed light on discovery of early biomarkers and pathways dysregulated in ALS, as well as provide a basis for novel therapeutic strategies to treat ALS.

Animal studies suggest vital roles of sphingolipids, especially ceramides, in the pathogenesis of type 2 diabetes (T2D) via pathways involved in insulin resistance, β-cell dysfunction, and inflammation, but human studies are limited. We aimed to evaluate the associations of circulating sphingolipids with incident T2D and to explore underlying mechanisms.