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Ross D Blundell, Simon J Williams, Samantha D M Arras, Jessica L Chitty, Kirsten L Blake, Daniel J Ericsson, Nidhi Tibrewal, Jurgen Rohr, Y Q Andre E Koh, Ulrike Kappler, Avril A B Robertson, Mark S Butler, Matthew A Cooper, Bostjan Kobe, James A Fraser
Opportunistic fungal pathogens such as Cryptococcus neoformans are a growing cause of morbidity and mortality among immunocompromised populations worldwide. To address the current paucity of antifungal therapeutic agents, further research into fungal-specific drug targets is required. Adenylosuccinate synthetase (AdSS) is a crucial enzyme in the adeosine triphosphate (ATP) biosynthetic pathway, catalyzing the formation of adenylosuccinate from inosine monophosphate and aspartate. We have investigated the potential of this enzyme as an antifungal drug target, finding that loss of function results in adenine auxotrophy in C...
September 9, 2016: ACS Infectious Diseases
Kayo Sugimoto, Soo Ki Kim, Soo Ryang Kim, Mana Kobayashi, Airi Kato, Eri Morimoto, Susumu Imoto, Chi Wan Kim, Yasuhito Tanaka, Masatoshi Kudo, Yoshihiko Yano, Yoshitake Hayashi
OBJECTIVES: The efficacy of sofosbuvir plus ribavirin (RBV) treatment for hepatitis C virus (HCV) genotype 2 focusing on virological response was compared with that of pegylated interferon (peg-IFN) plus RBV treatment. Safety of the former focusing on the decline in hemoglobin levels was compared with that of the latter and assessed in terms of age and inosine triphosphatase (ITPA). METHODS: Patients (n = 17) receiving sofosbuvir plus RBV and those (n = 24) receiving peg-IFN plus RBV diagnosed with chronic HCV genotype 2 were enrolled in this study, and the efficacy and safety of both treatments were assessed...
2016: Digestive Diseases
Gerson Dierley Keppeke, Monica Simon Prado, Eunice Nunes, Sandro Felix Perazzio, Silvia Helena Rodrigues, Maria Lucia Gomes Ferraz, Edward K L Chan, Luis Eduardo Coelho Andrade
Some HCV patients using ribavirin and interferon alpha (IFN-α) develop anti-rods and rings (RR) autoantibodies, the main target of which is inosine monophosphate dehydrogenase (IMPDH), the rate-determining enzyme in de novo GTP biosynthesis. In vitro inhibition of IMPDH by ribavirin induces RR formation. Here we investigate whether other commonly used drugs that interfere with GTP biosynthesis can induce RR structures in vitro and vivo and elicit generation of autoantibodies. HEp-2 cells treated for 24h with ribavirin, mycophenolic acid (MPA), azathioprine, methotrexate or acyclovir were positive for RR structures...
October 13, 2016: Clinical Immunology: the Official Journal of the Clinical Immunology Society
X Cui, R Liu, H Cui, G Zhao, M Zheng, Q Li, J Liu, Z Liu, J Wen
Capons and ovariectomized chickens are birds that have been gonadectomized to improve the meat quality. This study investigated the effects of caponization and ovariectomy on physical, chemical, and fatty acid and amino acid profiles of meat from Beijing-You chickens (a Chinese local breed) at market age (17 wk). All birds (20 capons, 20 ovariectomized, and 40 controls) were reared under the same conditions. Breast muscle fiber diameter and area were significantly smaller and the fiber density was higher in capons and ovariectomized chickens than in controls (P < 0...
October 12, 2016: Poultry Science
Jin-Jin Lu, Bing-Jie Jia, Lin Yang, Wen Zhang, Xin Dong, Ping Li, Jun Chen
It has been proved that the purine metabolic pathway has been implicated in various biological disorders including gout, diabetes, coronary heart diseases, and neurodegenerative diseases. The analysis of the purine metabolic pathway in organisms reveals important alterations under different physiological and pathological conditions, which contributes to the pathological study, diagnosis, and therapy of related diseases. In the present study, an ultra-high performance liquid chromatography with ultraviolet and tandem mass spectrometry (UHPLC-UV-MS/MS) method was developed for conducting the comprehensive analysis of the metabolite profiles of the purine pathway in rat plasma through a single analysis...
September 28, 2016: Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences
Vinayak Singh, Stefano Donini, Angela Pacitto, Claudia Sala, Ruben C Hartkoorn, Neeraj Dhar, Gyorgy Keri, David B Ascher, Guillaume Mondésert, Anthony Vocat, Andréanne Lupien, Raphael Sommer, Hélène Vermet, Sophie Lagrange, Joe Buechler, Digby F Warner, John D McKinney, Janos Pato, Stewart T Cole, Tom L Blundell, Menico Rizzi, Valerie Mizrahi
VCC234718, a molecule with growth inhibitory activity against Mycobacterium tuberculosis (Mtb), was identified by phenotypic screening of a 15344-compound library. Sequencing of a VCC234718-resistant mutant identified a Y487C substitution in the inosine monophosphate dehydrogenase, GuaB2, which was subsequently validated to be the primary molecular target of VCC234718 in Mtb. VCC234718 inhibits Mtb GuaB2 with a Ki of 100 nM and is uncompetitive with respect to IMP and NAD(+). This compound binds at the NAD(+) site, after IMP has bound, and makes direct interactions with IMP; therefore, the inhibitor is by definition uncompetitive...
September 8, 2016: ACS Infectious Diseases
Wei Chen, Pengmian Feng, Hui Ding, Hao Lin
The adenosine to inosine (A-to-I) editing is the most prevalent kind of RNA editing and involves in many biological processes. Accurate identification of A-to-I editing site is invaluable for better understanding its biological functions. Due to the limitations of experimental methods, in the present study, a support vector machine based-model, called PAI, is proposed to identify A-to-I editing site in D. melanogaster. In this model, RNA sequences are encoded by "pseudo dinucleotide composition" into which six RNA physiochemical properties were incorporated...
October 11, 2016: Scientific Reports
Yumi Park, Angela Pacitto, Tracy Bayliss, Laura A T Cleghorn, Zhe Wang, Travis Hartman, Kriti Arora, Thomas R Ioerger, Jim Sacchettini, Menico Rizzi, Stefano Donini, Tom L Blundell, David B Ascher, Kyu Y Rhee, Ardala Breda, Nian Zhou, Veronique Dartois, Surendranadha Reddy Jonnala, Laura E Via, Valerie Mizrahi, Ola Epemolu, Laste Stojanovski, Frederick Ryan Carne Simeons, Maria Osuna-Cabello, Lucy Ellis, Claire J MacKenzie, Alasdair R C Smith, Susan Helen Davis, Dinakaran Murugesan, Kirsteen I Buchanan, Penelope A Turner, Margaret Huggett, Fabio Zuccotto, Maria Jose Rebollo-Lopez, Maria Jose Lafuente-Monasterio, Olalla Sanz, Gracia Santos Diaz, Joël Lelièvre, Lluis Ballell, Carolyn Selenski, Matthew Axtman, Sonja Ghidelli-Disse, Hannah Pflaumer, Markus Boesche, Gerard Drewes, Gail Freiberg, Matthew D Kurnick, Myron Srikumaran, Dale J Kempf, Simon R Green, Peter Christopher Ray, Kevin D Read, Paul G Wyatt, Clifton E Barry Rd, Helena I M Boshoff
A potent, non-cytotoxic indazole sulfonamide was identified by high-throughput screening of >100,000 synthetic compounds for activity against Mycobacterium tuberculosis (Mtb). This non-cytotoxic compound did not directly inhibit cell wall biogenesis but triggered a slow lysis of Mtb cells as measured by release of intracellular green fluorescent protein (GFP). Isolation of resistant mutants followed by whole-genome sequencing showed an unusual gene amplification of a 40 gene region spanning Rv3371 to Rv3411c and in one case a potential promoter mutation upstream of guaB2 (Rv3411c) encoding inosine monophosphate dehydrogenase (IMPDH)...
October 5, 2016: ACS Infectious Diseases
Li Dai, Xue-Chen Liu, Sen Ye, Hua-Wei Li, Dian-Fu Chen, Xiao-Jian Yu, Xue-Ting Huang, Li Zhang, Fan Yang, Jin-Shu Yang, Wei-Jun Yang
The most widespread type of RNA editing, conversion of adenosine to inosine (A→I), is catalyzed by two members of the adenosine deaminase acting on RNA (ADAR) family, ADAR1 and ADAR2. These enzymes edit transcripts for neurotransmitter receptors and ion channels during adaption to changes in the physical environment. In the primitive crustacean Artemia, when maternal adults are exposed to unfavorable conditions, they release diapause embryos to withstand harsh environments. The aim of the current study was therefore to elucidate the role of ADAR of Artemia diapause embryos in resistance to stress...
October 4, 2016: Stress: the International Journal on the Biology of Stress
Yan Du, Yin-Jie Li, Xun-Xiu Hu, Xu Deng, Zeng-Ting Qian, Zheng Li, Meng-Zhe Guo, Dao-Quan Tang
As essential endogenous compounds, nucleobases and nucleosides fulfill various functions in living organisms. This work presents the development and validation of a new hydrophilic interaction liquid chromatography (HILIC) tandem mass spectrometry method for simultaneous quantification of 19 nucleobases and nucleosides in rat plasma. For the sample preparation, 15 kinds of protein precipitants were evaluated according to the chromatographic profile and ion response of analytes. The optimization of chromatographic separation was respectively performed using reversed-phase liquid chromatography (RPLC) and HILIC mode; each separation mode included two test columns with different stationary phases...
October 3, 2016: Biomedical Chromatography: BMC
Gabe Haller, David Alvarado, Kevin McCall, Robi D Mitra, Matthew B Dobbs, Christina A Gurnett
Large-scale mutagenesis of target DNA sequences allows researchers to comprehensively assess the effects of single-nucleotide changes. Here we demonstrate the construction of a systematic allelic series (SAS) using massively parallel single-nucleotide mutagenesis with reversibly terminated deoxyinosine triphosphates (rtITP). We created a mutational library containing every possible single-nucleotide mutation surrounding the active site of the TEM-1 β-lactamase gene. When combined with high-throughput functional assays, SAS mutational libraries can expedite the functional assessment of genetic variation...
October 3, 2016: Nature Methods
Ling-Ling Jiang, Mei-Hui Liu, Jian-Ying Li, Zhi-Heng He, Huan Li, Ning Shen, Ping Wei, Ming-Fang He
With the increasing use of mycophenolic acid (MPA) in solid organ transplantation, some clinical studies indicate that it is also a human teratogen. However, it is unknown by which mechanism MPA acts as a teratogen. Mycophenolic acid was a selective blocker of de novo purine synthesis, and its immunosuppressive effect is mediated by the inhibition of inosine monophosphate dehydrogenase, which could be a target for MPA-induced toxicity as well. The aim of our study was to examine the direct influence of MPA exposure on zebrafish (Danio rerio) embryos...
September 30, 2016: International Journal of Toxicology
David John, Tyler Weirick, Stefanie Dimmeler, Shizuka Uchida
RNA editing of adenosine residues to inosine ('A-to-I editing') is the most common RNA modification event detectible with RNA sequencing (RNA-seq). While not directly detectable, inosine is read by next-generation sequencers as guanine. Therefore, mapping RNA-seq reads to their corresponding reference genome can detect potential editing events by identifying 'A-to-G' conversions. However, one must exercise caution when searching for editing sites, as A-to-G conversions also arise from sequencing errors as well as mutations...
September 30, 2016: Briefings in Bioinformatics
Woro Sri Suharti, Akihiro Nose, Shao-Hui Zheng
Rhizoctonia solani is a fungal pathogen that causes sheath blight disease in rice plants. In this study, metabolomic analysis using CE/TOF-MS in negative ion mode was used to investigate the resistance response of resistant and susceptible rice lines (32R and 29S, respectively) due to R. solani infection. Two rice lines showed different responses to the infection of R. solani. In 32R, R. solani infection induced significant increases in adenosine diphosphate (ADP), glyceric acid, mucic acid and jasmonic acid...
September 20, 2016: Journal of Plant Physiology
Si Qiu, Wenhui Li, Heng Xiong, Dongbing Liu, Yali Bai, Kui Wu, Xiuqing Zhang, Huanming Yang, Kun Ma, Yong Hou, Bo Li
BACKGROUND: A-to-I RNA-editing mediated by ADAR (adenosine deaminase acting on RNA) enzymes that converts adenosine to inosine in RNA sequence can generate mutations and alter gene regulation in metazoans. Previous studies have shown that A-to-I RNA-editing plays vital roles in mouse embryogenesis. However, the RNA-editing activities in early human embryonic development have not been investigated. RESULTS: Here, we characterized genome-wide A-to-I RNA-editing activities during human early embryogenesis by profiling 68 single cells from 29 human embryos spanning from oocyte to morula stages...
September 29, 2016: BMC Genomics
Yuliia Kaljas, Chengqian Liu, Maksym Skaldin, Chengxiang Wu, Qing Zhou, Yuanan Lu, Ivona Aksentijevich, Andrey V Zavialov
At sites of inflammation and tumor growth, the local concentration of extracellular adenosine rapidly increases and plays a role in controlling the immune responses of nearby cells. Adenosine deaminases ADA1 and ADA2 (ADAs) decrease the level of adenosine by converting it to inosine, which serves as a negative feedback mechanism. Mutations in the genes encoding ADAs lead to impaired immune function, which suggests a crucial role for ADAs in immune system regulation. It is not clear why humans and other mammals possess two enzymes with adenosine deaminase activity...
September 23, 2016: Cellular and Molecular Life Sciences: CMLS
Bee Lynn Chew, Ian D Fisk, Rupert Fray, Gregory A Tucker, Zsuzsanna Bodi, Alison Ferguson, Wei Xia, Graham B Seymour
This study highlights the changes in umami-related nucleotide and glutamate levels when the AMP deaminase gene was elevated in transgenic tomato. Taste is perceived as one of a combination of five sensations, sweet, sour, bitter, salty, and umami. The umami taste is best known as a savoury sensation and plays a central role in food flavour, palatability, and eating satisfaction. Umami flavour can be imparted by the presence of glutamate and is greatly enhanced by the addition of ribonucleotides, such as inosine monophosphate (IMP) and guanosine monophosphate (GMP)...
September 23, 2016: Plant Cell Reports
Elisa Orecchini, Margherita Doria, Ambra Antonioni, Silvia Galardi, Silvia Anna Ciafrè, Loredana Frassinelli, Carmine Mancone, Claudia Montaldo, Marco Tripodi, Alessandro Michienzi
Adenosine deaminases acting on RNA (ADARs) are involved in RNA editing that converts adenosines to inosines in double-stranded RNAs. ADAR1 was demonstrated to be functional on different viruses exerting either antiviral or proviral effects. Concerning HIV-1, several studies showed that ADAR1 favors viral replication. The aim of this study was to investigate the composition of the ADAR1 ribonucleoprotein complex during HIV-1 expression. By using a dual-tag affinity purification procedure in cells expressing HIV-1 followed by mass spectrometry analysis, we identified 14 non-ribosomal ADAR1-interacting proteins, most of which are novel...
September 21, 2016: Nucleic Acids Research
Elizabeth A Jolley, Brent M Znosko
Non-standard nucleotides are ubiquitous in RNA. Thermodynamic studies with RNA duplexes containing non-standard nucleotides, whether incorporated naturally or chemically, can provide insight into the stability of Watson-Crick pairs and the role of specific functional groups in stabilizing a Watson-Crick pair. For example, an A-U, inosine•U and pseudouridine•A pair each form two hydrogen bonds. However, an RNA duplex containing a central I•U pair or central Ψ•A pair is 2.4 kcal/mol less stable or 1...
September 19, 2016: Nucleic Acids Research
A Dasgupta
Mycophenolic acid (MPA) is an immunosuppressant requiring therapeutic drug monitoring. Although immunoassays are commercially available, there is significant positive bias using this approach when compared to high-performance liquid chromatography or LC combined with mass spectrometry (LC/MS) or tandem mass spectrometry (LC/MS/MS). Positive bias is due to variable cross-reactivity of MPA acyl glucuronide with antibodies traditionally used in immunoassay formats. As can be expected, the magnitude of bias varies considerably...
2016: Advances in Clinical Chemistry
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