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Background Aging and neurodegenerative diseases are typical metabolic-related processes. As a metabolism-related long non-coding RNA, EPB41L4A-AS has been reported to be potentially involved in the development of brain aging and neurodegenerative diseases. In this study, we sought to reveal the mechanisms of EPB41L4A-AS in aging and neurodegenerative diseases. Methods Human hippocampal gene expression profiles downloaded from the Genotype-Tissue Expression database were analyzed to obtain age-stratified differentially expressed genes; a weighted correlation network analysis algorithm was then used to construct a gene co-expression network of these differentially expressed genes to obtain gene clustering modules. Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, protein–protein interaction network, and correlation analysis were used to reveal the role of EPB41L4A-AS1. The mechanism was verified using Gene Expression Omnibus dataset GSE5281 and biological experiments (construction of cell lines, Real-time quantitative PCR, Western blot, measurement of ATP and NAD+ levels, nicotinamide riboside treatment, Chromatin Immunoprecipitation) in neurons and glial-derived cells. Results EPB41L4A-AS1 was downregulated in aging and Alzheimer's disease. EPB41L4A-AS1 related genes were found to be enriched in the electron transport chain and NAD+ synthesis pathway. Furthermore, these genes were highly associated with neurodegenerative diseases and positively correlated with EPB41L4A-AS1. In addition, biological experiments proved that the downregulation of EPB41L4A-AS1 could reduce the expression of these genes via histone H3 lysine 27 acetylation, resulting in decreased NAD+ and ATP levels, while EPB41L4A-AS1 overexpression and nicotinamide riboside treatment could restore the NAD+ and ATP levels. Conclusions Downregulation of EPB41L4A-AS1 not only disturbs NAD+ biosynthesis but also affects ATP synthesis. As a result, the high demand for NAD+ and ATP in the brain cannot be met, promoting the development of brain aging and neurodegenerative diseases. However, overexpression of EPB41L4A-AS1 and nicotinamide riboside, a substrate of NAD+ synthesis, can reduce EPB41L4A-AS1 downregulation-mediated decrease of NAD+ and ATP synthesis. Our results provide new perspectives on the mechanisms underlying brain aging and neurodegenerative diseases.

Single atom catalysts (SACs) stabilized by nitrogen in a carbon support and having maximized atom utilization efficiency and an unsaturated environment exhibit high catalytic activity and selectivity. Incorporating nitrogen into the carbon lattice efficiently and uniformly is a critical step in preparing such catalysts but is challenging. The synthesis of Co and N co-doped porous carbon nanospheres (CoN-PCNS) in which Co is dispersed on the atomic scale is described herein, based on the facile pyrolysis of a mixture of cyclodextrin-based supermolecules with CoCl2. Non-covalent host–guest interactions between cyclodextrin and p-phenylenediamine in the supramolecular complex give optimal nitrogen species mobility and retention. These factors enable a thorough reaction between nitrogen and carbon during crosslinking to give ultrahigh nitrogen doping efficiency, with approximately 57% nitrogen retention upon pyrolysis and consequently a homogeneous dispersion of coordinated CoN4 sites throughout the carbon matrix. The CoN-PCNS exhibits impressive electrocatalytic activity during oxygen reduction, with an onset potential of 0.93 V, limiting current density of 5.74 mA cm−2, good methanol tolerance and negligible activity decay under alkaline conditions after 10 000 voltage cycles. Density functional theory calculations suggest that CoN4 is the most active among the various sites.

GPNCA is a long non-coding RNA with unknown functions. In this study, using data from 9 cancers obtained from The Cancer Genome Atlas (TCGA), GPNCA was identified as overexpressed in cancer vs. normal tissues. The upregulation of GPNCA was associated with poor overall prognosis in colon, liver, renal clear cell and breast cancers. The upregulation of GPNCA was partly due to enhanced H3K27ac occupancy on its promoter region via EP300 and KAT2A/GCN5. The overexpression of GPNCA was positively related to tumor metastasis in colon cancer and poor disease-free and recurrence-free survival in colon and liver cancer. Both gene ontology (GO) enrichment and Kyoto encyclopedia of genes and genomes (KEGG) pathway enrichment analysis indicated that GPNCA was closely linked to regulation of gene transcription and post-transcriptional modifications, which was further supported by in vitro cell cytoplasmic and nuclear RNA purification assessments. Furthermore, GPNCA was associated with cell growth. Our in vitro experiments demonstrated that GPNCA silencing inhibited tumor growth via inhibiting its nearby gene GSK3B. Taken together, these findings highlight GPNCA as a biomarker for cancer diagnosis and a potential target for future cancer drug development.

Chitinases possess an extraordinary ability to directly hydrolyze highly insoluble chitin polymers to low-molecular-weight chito-oligomers, which possess particular biological functions, such as elicitor action and antitumor activity. A novel strain, Paenibacillus xylanilyticus W4, which was isolated from soil, showed strong chitin degradation activity. Here, we first reported the complete genome information of P. xylanilyticus. Paenibacillus xylanilyticus W4 contains a 5,532,141 bp single circular chromosome with 47.33% GC content. The genome contains 5,996 genes, including 39 rRNA- and 109 tRNA-coding genes. Phylogenetic analysis and Genome-to-Genome Distance revealed its taxonomic characterization into a separate family. Six glycoside hydrolase 18 (GH18) and 2 GH23 enzymes involved in chitin degradation. Although many of the chitinases were conserved in Paenibacillus, several GH18 chitinases share high similarity with Bacillus circulans. The genome information provided here could benefit for understanding the chitin-degrading properties of P. xylanilyticus as well as its potential application in biotechnological and pharmaceutical fields.

PPP1R14B-AS1 is an antisense long noncoding RNA with unknown functions. Herein, gene differential analyses were performed using the data of patients with liver cancer and lung adenocarcinoma from The Cancer Genome Atlas database. PPP1R14B-AS1 was found to be upregulated and also overexpressed in 10 other types of cancers. In addition, PPP1R14B-AS1 overexpression was associated with poor overall prognosis in eight cancers. Furthermore, PPPAR14B-AS1 upregulation was positively associated with the worsening development of liver and lung adenocarcinoma cancers and related to poor disease-free survival. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses suggested that PPP1R14B-AS1 strongly participated in regulating cell aerobic respiration processes, such as mitochondrial electron respiration chain and NADH dehydrogenation processes. Cell cytoplasmic and nuclear RNA purification assessment results revealed that PPP1R14B-AS existed in the cell nucleus and cytoplasm. The knockdown of PPP1R14B-AS1 in HepG2 and A549 cells using PPP1R14B-AS1-specific siRNAs decreased mitochondrial respiration as demonstrated by the reduction in basal respiration and ATP production. Moreover, PPP1R14B-AS1 downregulation did not obviously affect cell glycolysis ability. Finally, PPP1R14B-AS1 inhibition inhibited HepG2 and A549 cell migration and proliferation. In summary, our study found for the first time that PPP1R14B-AS1 could be a potential biomarker for cancer diagnosis and that PPP1R14B-AS1 inhibition could be a potentially effective therapy.

Ziqing Wang,1,2 Weijie Liao,2,3 Fuhai Liu,2,4 Tingpeng Yang,2 Weidong Xie,2,3 Meijian Liao,3,4 Dayong Gu,5 Yaou Zhang2,3 1School of Chemistry, Tsinghua University, Beijing 100084, People’s Republic of China; 2State Key Laboratory of Chemical Oncogenomics, Tsinghua Shenzhen International Graduate School, Shenzhen 518055, People’s Republic of China; 3Key Laboratory in Healthy Science and Technology, Division of Life Science, Tsinghua Shenzhen International Graduate School, Shenzhen 518055, People’s Republic of China; 4Department of Pathology, Xuzhou Medical University, Xuzhou 221104, People’s Republic of China; 5Department of Laboratory Medicine, Shenzhen Second People’s Hospital, The First Affiliated Hospital of Shenzhen University, Shenzhen 518035, People’s Republic of ChinaCorrespondence: Yaou ZhangState Key Laboratory of Chemical Oncogenomics, Tsinghua Shenzhen International Graduate School, Shenzhen 518055, People’s Republic of ChinaTel +86-755-2603-6884Email zhangyo@sz.tsinghua.edu.cnDayong GuDepartment of Laboratory Medicine, Shenzhen Second People’s Hospital, The First Affiliated Hospital of Shenzhen University, Shenzhen 518035, People’s Republic of ChinaTel +86-13602601597Email wanhood@163.comPurpose: Long non-coding RNAs (lncRNAs) have been shown to be involved in many human diseases. In this study, we aimed to reveal the role and molecular mechanism of lncRNA EPB41L4A-AS1 in type 2 diabetic mellitus (T2DM)-related inflammation.Methods: To explore the relationships between the expression of EPB41L4A-AS1 and inflammatory factors in the blood of T2DM patients, we analyzed peripheral blood mononuclear cell (PBMC) expression microarrays of T2DM patients and expression microarrays of PBMC treated with lipopolysaccharide (LPS) from the GEO database. The relationship between EPB41L4A-AS1 and phospho-p65 was explored by Western blotting (WB) and immunofluorescence. The interactions between EPB41L4A-AS1 and myeloid differentiation factor 88 (MYD88) were also verified through quantitative real-time PCR, WB, and chromatin immunoprecipitation. Glycolysis and mitochondrial stress were detected by Seahorse.Results: EPB41L4A-AS1 showed very low expression, which was significantly negatively correlated with levels of inflammatory factors in PBMCs of T2DM patients and PBMCs treated with LPS. These results were verified by cell experiments on PBMC and THP-1 cells. Knockdown of EPB41L4A-AS1 led to the phosphorylation and nuclear translocation of p65 and thus activated the NF-κB signaling pathway; it also reduced the enrichment of H3K9me3 in the MYD88 promoter and increased expression of MYD88. Overall, EPB41L4A-AS1 knockdown promoted the level of glycolysis and ultimately enhanced the inflammatory response.Conclusion: EPB41L4A-AS1 knockdown activated the NF-κB signaling pathway through a MYD88-dependent regulatory mechanism, promoted glycolysis, and ultimately enhanced the inflammatory response. These results demonstrate that EPB41L4A-AS1 is closely associated with inflammation in T2DM, and that low expression of EPB41L4A-AS1 may be used as an indicator of chronic inflammation and possible diabetic vascular complications in T2DM patients.Keywords: inflammation, diabetes, EPB41L4A-AS1, NF-κB, MYD88

Apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like 3 (APOBEC3) has been identified as a group of enzymes that catalyze cytosine deamination in single-stranded (ss) DNA to form uracil, causing somatic mutations in some cancers. We analyzed the APOBEC3 family in 33 TCGA cancer types and the results indicated that APOBEC3s are upregulated in multiple cancers and strongly correlate with prognosis, particularly in low grade glioma (LGG). Then we constructed a prognostic model based on family expression in LGG where the APOBEC3 family signature is an accurate predictive model (AUC of 0.85). Gene mutation, copy number variation (CNV), and a differential gene expression (DEG) analysis were performed in different risk groups, and the weighted gene co-expression network analysis (WGCNA) was employed to clarify the role of various members in LGG, CIBERSORT algorithm was deployed to evaluate the landscape of LGG immune infiltration. We found that upregulation of the APOBEC3 family expression can strengthen Ras/MAPK signaling pathway, promote tumor progression, and ultimately reduce the treatment benefits of Raf inhibitors. Moreover, the APOBEC3 family was shown to enhance the immune response mediated by myeloid cells and interferon gamma, as well as PD-L1 and PD-L2 expression, implying that they have immunotherapy potential. Therefore, the APOBEC3 signature enables an efficient assessment of LGG patient survival outcomes and expansion of clinical benefits by selecting appropriate individualized treatment strategies.

To evaluate light extinction contributions of aerosol chemical constituents and their impacts on atmospheric visibility, the PM2.5 and its chemical components, light scattering (bsp) and absorption (bap) were continuously measured in Wuhan from January to February 2018. The average of PM2.5 concentration, bsp and bap were 96.5 ± 13.7 μg m−3, 564 ± 124 Mm−1 and 44 ± 8 Mm−1 during polluted days, respectively, which was about 2.0, 2.1 and 1.6 times higher than those of clean days, respectively. Compared with the clean days, the increase of the mass concentrations of SNA (SO42−, NO3−, NH4+) during polluted days was higher than those of organic (OC) and elemental (EC) carbon, indicated the increase of SNA was the main cause of air pollution. The PM2.5 concentration threshold was 66 μg m−3, corresponding to the visibility lower than 10 km. The revised Interagency Monitoring of Protected Visual Environments (IMPROVE) algorithm was used to reconstruct the light extinction coefficient (bext) in Wuhan. The sum of light extinction coefficients of (NH4)2SO4, NH4NO3 and organic matter (OM) accounted for 70.5% and 83.9% of bext during clean and polluted days, respectively. The backward trajectory and potential source contribution function (PSCF) analysis revealed that regional transport accounted for 55.6% of the total airflow, which originated from south, northwest and west of Wuhan. The increases of (NH4)2SO4 and NH4NO3 concentrations, emitted from local vehicle exhaust and coal combustion, and their hygroscopic growth in ambient were the major causes of pollution in Wuhan.

// Min Cheng 1, 2, * , Lei Liu 1, 2, * , Yuanzhi Lao 3 , Weijie Liao 1, 2 , Meijian Liao 1, 2 , Xuan Luo 2, 4 , Jiangbin Wu 2 , Weidong Xie 2 , Yaou Zhang 2, 5 , Naihan Xu 2, 5 1 School of Life Sciences, Tsinghua University, Beijing 100084, China 2 Key Lab in Healthy Science and Technology, Division of Life Science, Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, China 3 School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China 4 Department of Chemistry, Tsinghua University, Beijing 100084, P.R. China 5 Open FIESTA Center, Tsinghua University, Shenzhen 518055, P.R. China * These authors have contributed equally to this work Correspondence to: Naihan Xu, email: xu.naihan@sz.tsinghua.edu.cn Yaou Zhang, email: zhangyo@sz.tsinghua.edu.cn Keywords: microRNA, mitochondria, mitophagy, parkin, apoptosis Received: January 11, 2016 Accepted: May 20, 2016 Published: June 02, 2016 ABSTRACT Damage to mitochondria often results in the activation of both mitophagy and mitochondrial apoptosis. The elimination of dysfunctional mitochondria is necessary for mitochondrial quality maintenance and efficient energy supply. Here we report that miR-181a is a novel inhibitor of mitophagy. miR-181a is downregulated by mitochondrial uncouplers in human neuroblastoma SH-SY5Y cells. Overexpression of miR-181a inhibits mitochondrial uncoupling agents-induced mitophagy by inhibiting the degradation of mitochondrial proteins without affecting global autophagy. Knock down of endogenous miR-181a accelerates the autophagic degradation of damaged mitochondria. miR-181a directly targets Parkin E3 ubiquitin ligase and partially blocks the colocalization of mitochondria and autophagosomes/lysosomes. Re-expression of exogenous Parkin restores the inhibitory effect of miR-181a on mitophagy. Furthermore, miR-181a increases the sensitivity of neuroblastoma cells to mitochondrial uncoupler-induced apoptosis, whereas miR-181a antagomir prevents cell death. Because mitophagy defects are associated with a variety of human disorders, these findings indicate an important link between microRNA and Parkin-mediated mitophagy and highlights a potential therapeutic strategy for human diseases.

Background LncRNAs have been found to be involved in various aspects of biological processes. In this study, we aimed to uncover the molecular mechanisms of lncRNA EPB41L4A-AS1 in regulating glycolysis and glutaminolysis in cancer cells. Methods The expression of EPB41L4A-AS1 in cancer patients was analyzed in TCGA and GEO datasets. The level of cellular metabolism was determined by extracellular flux analyzer. The relationship between p53 and EPB41L4A-AS1 was explored by qRT-PCR, luciferase assay and ChIP assay. The interactions between EPB41L4A-AS1 and HDAC2 or NPM1 were determined by RNA immunoprecipitation, RNA pull-down assay and RNA-FISH- immunofluorescence. Findings EPB41L4A-AS1 was a p53-regulated gene. Low expression and deletion of lncRNA EPB41L4A-AS1 were found in a variety of human cancers and associated with poor prognosis of cancer patients. Knock down EPB41L4A-AS1 expression triggered Warburg effect, demonstrated as increased aerobic glycolysis and glutaminolysis. EPB41L4A-AS1 interacted and colocalized with HDAC2 and NPM1 in nucleolus. Silencing EPB41L4A-AS1 reduced the interaction between HDAC2 and NPM1, released HDAC2 from nucleolus and increased its distribution in nucleoplasm, enhanced HDAC2 occupation on VHL and VDAC1 promoter regions, and finally accelerated glycolysis and glutaminolysis. Depletion of EPB41L4A-AS1 increased the sensitivity of tumor to glutaminase inhibitor in tumor therapy. Interpretation EPB41L4A-AS1 functions as a repressor of the Warburg effect and plays important roles in metabolic reprogramming of cancer.

Long non-coding RNAs (lncRNAs) have been shown to be crucial regulators in numerous human diseases. However, little is known about their effects on early recurrent miscarriage (RM). Here we aimed to investigate the role of lncRNA EPB41L4A-AS1 on placental trophoblast cell metabolic reprogramming, which might be involved in the pathogenesis of RM. After microarray and GEO database analyses, we found that EPB41L4A-AS1 was significantly increased in early RM placental tissue, and this increase may relate to estradiol-mediated upregulation of PGC-1α. EPB41L4A-AS1 overexpression inhibits glycolysis but increases the dependence on fatty acid oxidation in mitochondrion metabolism and suppresses the Warburg effect, which is necessary for rapid growth of the placental villus, leading to miscarriage. Mechanistic analyses demonstrated that EPB41L4A-AS1 functions as a lncRNA in the regulation of VDAC1 and HIF-1α expression through enhancement of H3K4me3 levels in the promoters of VDAC1 and HIF1A-AS1, a natural antisense transcript (NAT) lncRNA of HIF-1α. Taken together, these findings demonstrate that aberrant expression of EPB41L4A-AS1 is involved in the etiology of early RM, and it may be a candidate diagnostic hallmark and a potential therapeutic target for early RM treatment. Keywords: lncRNA EPB41L4A-AS1, HIF-1α, VDAC1, recurrent miscarriage, metabolic reprogramming

Long noncoding RNAs (lncRNA) are reported to be potential cancer biomarkers. This study aims to find new lncRNA biomarker relevant to lung adenocarcinoma. Gene expression profile and clinical data of lung adenocarcinoma and lung squamous cell carcinoma patients were downloaded from the UCSC Xena database. These data were analyzed to identify potential lncRNA prognostic biomarkers, and the candidate lncRNAs were analyzed and verified with association analysis, meta-analysis, survival analysis, gene ontology analysis, gene set enrichment analysis, and other statistical methods. A group of 5 lncRNAs was identified from the 1965 differentially expressed (fold-change >2) genes. Four of these 5 lncRNAs were expressed at a lower level in lung adenocarcinoma tissues and the other one at a higher level (P < .0001). A risk score model was constructed using a linear combination of the expression levels of these lncRNAs. High-risk patients showed poorer overall survival (hazard ratio [HR] = 2.14; 95% confidence interval [CI], 1.67-3.06, P < .0001), disease-free survival (HR = 1.84; 95% CI, 1.26-2.35, P = .0007), and recurrence-free survival (HR = 1.51; 95% CI, 1.02-2.40, P = .04). The 5-fold cross-validation and subsequent meta-analysis further verified that patients in the low-risk group had better survival (95% CI, 0.74-1.79, Z = 4.72, P < .00001). Furthermore, both univariate and multivariate Cox regression analyses revealed that the prognostic value of these 5 lncRNAs was independent of other clinical prognostic factors. Further analysis indicated that these 5 lncRNAs might be associated with tumor metastasis. Taken together, our study suggests new prognostic lncRNA biomarkers for lung adenocarcinoma.

In order to bring into full play the advantages of motor braking and enhance the handling stability of distributed electric vehicle, a motor braking-based direct yaw moment control (DYC) strategy was proposed. This strategy could identify whether a vehicle has under-steered or overs-steered, to calculate the direct yaw moment required for vehicle steering correction by taking the corrected yaw velocity deviation and slip-angle deviation as control variables, and exert motor braking moment on the target wheels to perform correction in the manner of differential braking. For validation of the results, a combined simulation platform was set up finally to simulate the motor braking control strategy proposed. As shown by the results, the motor braking-based DYC strategy timely adjusted the motor braking moment and hydraulic braking moment on the target wheels, and corrected the steering deviation and sideslip of the vehicle in unstable state, improving the handling stability.

// Meijian Liao 1, 2, * , Bing Li 1, 2, * , Shikuan Zhang 2 , Qing Liu 1, 2 , Weijie Liao 1, 2 , Weidong Xie 2, 3 , Yaou Zhang 2, 3 1 School of Life Sciences, Tsinghua University, Beijing 100084, P.R. China 2 Key Lab in Healthy Science and Technology, Division of Life Science, Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, P.R. China 3 Open FIESTA Center, Tsinghua University, Shenzhen 518055, P.R. China * These authors contributed equally to this work Correspondence to: Weidong Xie, email: xiewd@sz.tsinghua.edu.cn Yaou Zhang, email: zhangyo@sz.tsinghua.edu.cn Keywords: LncRNA, LINC00341, metastasis, meta-analysis, prognostication Received: November 15, 2016 Accepted: January 17, 2017 Published: January 27, 2017 ABSTRACT LINC00341 is a novel long intergenic non-protein coding RNA with unknown functions. In our report, we investigated LINC00341 expression and its prognostic value in cancer patients. DNA over-methylation triggered low expression of LINC00341 and that was associated with poor prognosis in cancers. A meta-analysis further confirmed that high expression of LINC00341 was associated with a better prognosis in cancer patients. Both gene set enrichment analysis and meta-analysis showed that LINC00341 inhibited cancer metastasis. Finally, a large-scale multicentre analysis supported a prognostic value of LINC00341 in cancers.