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Andrew J Fisher, Peter A Beal
All messenger RNAs in eukaryotes are modified co-transcriptionally and post-transcriptionally. They are all capped at the 5'-end and polyadenylated at the 3'-end. However, many mRNAs are also found to be chemically modified internally for regulation of mRNA processing, translation, stability, and to recode the message. This review will briefly summarize the structural basis for formation of the two most common modifications found at internal sites in mRNAs; methylation and deamination. The structures of the enzymes that catalyze these modifications show structural similarity to other family members within each modifying enzyme class...
June 15, 2018: Current Opinion in Structural Biology
Kunzhao Du, Longbin Zhang, Trevor Lee, Tao Sun
RNA modifications are involved in many aspects of biological functions. N6-methyladenosine (m6 A) is one of the most important forms of RNA methylation and plays a vital role in regulating gene expression, protein translation, cell behaviors, and physiological conditions in many species, including humans. The dynamic and reversible modification of m6 A is conducted by three elements: methyltransferases ("writers"), such as methyltransferase-like protein 3 (METTL3) and METTL14; m6 A-binding proteins ("readers"), such as the YTH domain family proteins (YTHDFs) and YTH domain-containing protein 1 (YTHDC1); and demethylases ("erasers"), such as fat mass and obesity-associated protein (FTO) and AlkB homolog 5 (ALKBH5)...
June 16, 2018: Molecular Neurobiology
Chi Zhang, Guifang Jia
More than 100 modifications have been found in RNA. Analogous to epigenetic DNA methylation, epitranscriptomic modifications can be written, read, and erased by a complex network of proteins. Apart from N6 -methyladenosine (m6 A), N1 -methyladenosine (m1 A) has been found as a reversible modification in tRNA and mRNA. m1 A occurs at positions 9, 14, and 58 of tRNA, with m1 A58 being critical for tRNA stability. Other than the hundreds of m1 A sites in mRNA and long non-coding RNA transcripts, transcriptome-wide mapping of m1 A also identifies > 20 m1 A sites in mitochondrial genes...
June 13, 2018: Genomics, Proteomics & Bioinformatics
Jiwei Guo, Yan Wu, Jing Du, Lijuan Yang, Weiwei Chen, Kaikai Gong, Juanjuan Dai, Shuang Miao, Dan Jin, Sichuan Xi
The roles of aberrantly regulated autophagy in human malignancy and the mechanisms that initiate and sustain the repression of autophagy in carcinogenesis are less well defined. Activation of the oncogene UBE2C and repression of autophagy are concurrently underlying the initiation, progression, and metastasis of lung cancer and exploration of essential association of UBE2C with autophagy will confer more options in searching novel molecular therapeutic targets in lung cancer. Here we report that aberrant activation of UBE2C in lung tumors from patients associates with adverse prognosis and enhances cell proliferation, clonogenicity, and invasive growth of NSCLC...
June 13, 2018: Oncogenesis
My Pham, Kevin Phan, Ian Teng, Ralph J Mobbs
OBJECTIVE: Cervical spondylosis affects a huge proportion of the middle-aged population. Degenerative changes can occur in multiple regions of the cervical spine typically affecting the joints, intervertebral discs and endplates. These changes lead to compression of adjacent nervous structures, which results in radiculopathic and myelopathic pain. Various treatment modalities are currently available with non-surgical approaches the initial go to if there is no symptomatic cord compression...
May 2018: Orthopaedic Surgery
He Li, Yongdong Song, Zuhong He, Xiaoyun Chen, Xianmin Wu, Xiaofei Li, Xiaohui Bai, Wenwen Liu, Boqin Li, Shanshan Wang, Yuechen Han, Lei Xu, Daogong Zhang, Jianfeng Li, Renjie Chai, Haibo Wang, Zhaomin Fan
Hearing loss is the most common sensory disorder in humans, and a significant number of cases is due to the ototoxicity of drugs such as cisplatin that cause hair cell (HC) damage. Thus, there is great interest in finding agents and mechanisms that protect HCs from ototoxic drug damage. It has been proposed that epigenetic modifications are related to inner ear development and play a significant role in HC protection and HC regeneration; however, whether the m6 A modification and the ethyl ester form of meclofenamic acid (MA2), which is a highly selective inhibitor of FTO (fatmass and obesity-associated enzyme, one of the primary human demethylases), can affect the process of HC apoptosis induced by ototoxic drugs remains largely unexplored...
2018: Frontiers in Cellular Neuroscience
Amelia T Soderholm, Timothy C Barnett, Othmar Korn, Tania Rivera-Hernandez, Lisa M Seymour, Benjamin L Schulz, Victor Nizet, Christine A Wells, Matthew J Sweet, Mark J Walker
Streptococcus pyogenes (Group A Streptococcus ; GAS) commonly causes pharyngitis in children and adults, with severe invasive disease and immune sequelae being an infrequent consequence. The ability of GAS to invade the host and establish infection likely involves subversion of host immune defenses. However, the signaling pathways and innate immune responses of epithelial cells to GAS are not well-understood. In this study, we utilized RNAseq to characterize the inflammatory responses of primary human tonsil epithelial (TEpi) cells to infection with the laboratory-adapted M6 strain JRS4 and the M1T1 clinical isolate 5448...
2018: Frontiers in Cellular and Infection Microbiology
Emerith M Hungria, Samira Bührer-Sékula, Regiane M Oliveira, Lúcio C Aderaldo, Maria Araci A Pontes, Rossilene Cruz, Heitor S de Gonçalves, Maria L F Penna, Gerson O Penna, Mariane M A Stefani
Leprosy serology reflects the bacillary load of patients and multidrug therapy (MDT) reduces Mycobacterium leprae -specific antibody titers of multibacillary (MB) patients. The Clinical Trial for Uniform Multidrug Therapy Regimen for Leprosy Patients in Brazil ( U-MDT/CT-BR ) compared outcomes of regular 12 doses MDT/R-MDT and the uniform 6 doses MDT/U-MDT for MB leprosy, both of regimens including rifampicin, clofazimine, and dapsone. This study investigated the impact of R-MDT and U-MDT and the kinetic of antibody responses to M...
2018: Frontiers in Immunology
Jidong Zhang, Pengmian Feng, Hao Lin, Wei Chen
N6 -methyladenosine (m6 A) plays important roles in a branch of biological and physiological processes. Accurate identification of m6 A sites is especially helpful for understanding their biological functions. Since the wet-lab techniques are still expensive and time-consuming, it's urgent to develop computational methods to identify m6 A sites from primary RNA sequences. Although there are some computational methods for identifying m6 A sites, no methods whatsoever are available for detecting m6 A sites in microbial genomes...
2018: Frontiers in Microbiology
Masatoshi Kobayashi, Mitsuru Ohsugi, Takayoshi Sasako, Motoharu Awazawa, Toshihiro Umehara, Aya Iwane, Naoki Kobayashi, Yukiko Okazaki, Naoto Kubota, Ryo Suzuki, Hironori Waki, Keiko Horiuchi, Takao Hamakubo, Tatsuhiko Kodama, Seiichiro Aoe, Kazuyuki Tobe, Takashi Kadowaki, Kohjiro Ueki
Adipocyte differentiation is regulated by various mechanisms, of which the mitotic clonal expansion (MCE) is a key step. Although this process is known to be regulated by the cell cycle modulators, the precise mechanism remains unclear. N 6 -methyladenosine (m6 A) post-transcriptional RNA modification, whose methylation and demethylation is performed by respective enzymal molecules, has recently been suggested to be involved in the regulation of adipogenesis. Here, we show that an RNA N 6 -adenosine methyltransferase complex consisting of Wilms' tumor 1-associating protein (WTAP), methyltransferase like (METTL) 3 and METTL14 positively control adipogenesis, by promoting cell cycle transition in MCE during adipogenesis...
June 4, 2018: Molecular and Cellular Biology
Océane Landon-Cardinal, Diane Friedman, Marguerite Guiguet, Pascal Laforêt, Nicholas Heming, Emmanuelle Salort-Campana, Fabienne Jouen, Yves Allenbach, Olivier Boyer, Lucienne Chatenoud, Bruno Eymard, Tarek Sharshar, Olivier Benveniste
BACKGROUND: Several retrospective case series have suggested rituximab (RTX) might improve patients with refractory Myasthenia Gravis (MG). OBJECTIVE: In this study, we aimed to evaluate prospectively the efficacy of RTX on muscle function in refractory generalized anti-acetylcholine receptor (AChR) MG patients. METHODS: Enrolled patients received 1 g of RTX at day 0, day 14, and 6-month follow-up (M6). The primary endpoint was improvement of muscle function at 12-month (M12) based on myasthenic muscle score (MMS)...
2018: Journal of Neuromuscular Diseases
Jeffrey A Purslow, Vincenzo Venditti
N6 -methyladenosine (m6 A) is the most abundant and reversible post-transcriptional modification in eukaryotic mRNA and long non-coding RNA (lncRNA). The central role of m6 A in various physiological processes has generated considerable biological and pharmacological interest. Alkbh5 (AlkB homologue 5) belongs to the AlkB family and is a non-heme Fe(II)/α-ketoglutarate-dependent dioxygenase that selectively catalyzes the oxidative demethylation of m6 A. Herein, we report the backbone 1 H, 15 N, 13 C chemical shift assignment of a fully active, 26 kDa construct of human Alkbh5...
June 1, 2018: Biomolecular NMR Assignments
Wei Chen, Pengmian Feng, Hui Yang, Hui Ding, Hao Lin, Kuo-Chen Chou
RNA modifications are additions of chemical groups to nucleotides or their local structural changes. Knowledge about the occurrence sites of these modifications is essential for in-depth understanding of the biological functions and mechanisms and for treating some genomic diseases as well. With the avalanche of RNA sequences generated in the post-genomic age, many computational methods have been proposed for identifying various types of RNA modifications one by one. However, so far no method whatsoever has been developed for simultaneously identifying several different types of RNA modifications...
June 1, 2018: Molecular Therapy. Nucleic Acids
Yujie Deng, Yudong Fu, Shumin Xu, Ping Wang, Nailong Yang, Chengqian Li, Qing Yu
Limonin (LIM), a furan-containing limonoid, is one of the most abundant components of Dictamnus dasycarpus Turcz. Recent studies demonstrated that LIM has great potential for inhibiting the activity of drug-metabolizing enzymes. However, the mechanisms of LIM-induced enzyme inactivation processes remain unexplored. The main objective of this study was to identify the reactive metabolites of LIM using liquid chromatography-mass spectrometry. Three nucleophiles, glutathione (GSH), N -acetyl cysteine (NAC), and N -acetyl lysine (NAL), were used to trap the reactive metabolites of LIM in in vitro and in vivo models...
2018: Journal of Analytical Methods in Chemistry
Jiqin Liu, Dangli Ren, Zhenhua Du, Hekong Wang, Hua Zhang, Ying Jin
N6 -Methyladenosine (m6 A) represents the most prevalent internal modification in mammalian mRNAs. Emerging evidences suggest that m6 A modification is profoundly implicated in many biological processes, including cancer development. However, limited knowledge is available about the functional importance of m6 A in lung cancer. In this study, by data mining The Cancer Genome Atlas (TCGA) database, we first identified fat mass- and obesity-associated protein (FTO) as a prognostic factor for lung squamous cell carcinoma (LUSC)...
May 26, 2018: Biochemical and Biophysical Research Communications
S Sood, C Haifer, L Yu, J Pavlovic, P J Gow, R M Jones, K Visvanathan, P W Angus, A G Testro
INTRODUCTION: Although antiviral prophylaxis is effective in preventing early cytomegalovirus (CMV) reactivation following liver transplantation (OLT), it predisposes patients to late CMV after prophylaxis has ceased. QuantiFERON-CMV (QFN-CMV, Qiagen, The Netherlands) measures an individual's viral-specific immune response. METHODS: Fifty-nine OLT recipients were prospectively monitored post-OLT in an observational cohort study. QFN-CMV was performed at regular time-points...
May 29, 2018: Transplant Infectious Disease: An Official Journal of the Transplantation Society
Seyed Ahmad Sangsefedi, Soheil Sharifi, Hadi Rastegar Moghaddam Rezaion, Afshin Azarpour
The enhancement of the nonlinear properties of materials is an interesting topic since it has many applications in optical devices and medicines. The Z-scan technique was used to study the values of the two-photon absorption (β), second-order molecular hyperpolarizability (γR ), third-order susceptibility (χR ), and nonlinear refractive index (n2 ) of Alizarin Red S in different media using a continuous-wave diode-pump laser radiation at 532 nm. For Alizarin Red S in a droplet, the β, n2 , χR, and γR were estimated at the order of 10-7  cm2 /W and 10-12  cm/W, 10-3  m3  W-1  s-1 and 10-24  m6  W-1  s-1 , respectively...
May 28, 2018: Journal of Fluorescence
Jerlisa Ann Arizala, Mayumi Takahashi, John C Burnett, Dominique L Ouellet, John J Rossi
Combination antiretroviral therapy (cART) fails in complete suppression of HIV-1 due to drug resistance and persistent latency. Novel therapeutic intervention requires knowledge of intracellular pathways responsible for viral replication, specifically those untargeted by antiretroviral drugs. An understudied phenomenon is the nucleolar localization of Rev phosphoprotein, which completes nucleocytoplasmic transport of unspliced/partially spliced HIV mRNA through multimerization with intronic cis-acting targets - the Rev-response element (RRE)...
May 26, 2018: AIDS Research and Human Retroviruses
Yang Liu, Xueting Yao, Ling Song, Hongzhong Liu, Qian Zhao, Ji Jiang, Gang Ni, Chongtie Shi, Xifeng Ma, Huimin Zhou, Dongyang Liu, Pei Hu
Imigliptin has been reported as a novel dipeptidyl-peptidase-IV (DPP-4) inhibitor to treat type 2 Diabetes Mellitus (T2DM), and is currently being tested in clinical trials. In the first human clinical study, imigliptin was well tolerated and proved to be a potent DPP-4 inhibitor. Considering its potential therapeutic benefits and promising future, it is of great importance to study the metabolite profiles in the early stage of drug development. In the present study, a robust and reliable analytical method based on the ultra-high performance liquid chromatography/quadrupole time-of-flight mass spectrometry (UHPLC/Q-TOF MS) method combined with MassLynx software was established to investigate the characterization of metabolites of imigliptin in human and rat plasma, urine and feces after oral administration...
May 23, 2018: Journal of Pharmaceutical and Biomedical Analysis
María Victoria Humbert, Myron Christodoulides
Neisseria meningitidis (Nm) and N. gonorrhoeae (Ng) express a Macrophage Infectivity Potentiator (MIP, NMB1567/NEIS1487) protein in their outer membrane (OM). In this study, we prepared independent batches of liposomes (n = 3) and liposomes + MonoPhosphoryl Lipid A (MPLA) (n = 3) containing recombinant truncated Nm-MIP protein encoded by Allele 2 (rT-Nm-MIP, amino acids 22-142), and used these to immunize mice. We tested the hypothesis that independent vaccine batches showed similar antigenicity, and that antisera could recognise both meningococcal and gonococcal MIP and induce cross-species bactericidal activity...
May 23, 2018: Vaccine
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