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https://www.readbyqxmd.com/read/27933712/the-importance-of-mrna-structure-in-determining-the-pathogenicity-of-synonymous-and-non-synonymous-mutations-in-haemophilia
#1
N Hamasaki-Katagiri, B C Lin, J Simon, R C Hunt, T Schiller, E Russek-Cohen, A A Komar, H Bar, C Kimchi-Sarfaty
INTRODUCTION: Mutational analysis is commonly used to support the diagnosis and management of haemophilia. This has allowed for the generation of large mutation databases which provide unparalleled insight into genotype-phenotype relationships. Haemophilia is associated with inversions, deletions, insertions, nonsense and missense mutations. Both synonymous and non-synonymous mutations influence the base pairing of messenger RNA (mRNA), which can alter mRNA structure, cellular half-life and ribosome processivity/elongation...
December 9, 2016: Haemophilia: the Official Journal of the World Federation of Hemophilia
https://www.readbyqxmd.com/read/27932587/a-divalent-cation-dependent-variant-of-the-glms-ribozyme-with-stringent-ca2-selectivity-co-opts-a-pre-existing-non-specific-metal-ion-binding-site
#2
Matthew W L Lau, Robert J Trachman, Adrian R Ferré-D'Amaré
Ribozymes employ divalent cations for structural stabilization, as catalytic cofactors, or both. Because of the prominent role of Ca2+ in intracellular signaling, engineered ribozymes with stringent Ca2+ selectivity would be important in biotechnology. The wild-type glmS ribozyme (glmSWT) requires glucosamine-6-phosphate (GlcN6P) as a catalytic cofactor. Previously, a glmS ribozyme variant with three adenosine mutations (glmSAAA) was identified, which dispenses with GlcN6P and instead uses, with little selectivity, divalent cations as cofactors for site-specific RNA cleavage...
December 8, 2016: RNA
https://www.readbyqxmd.com/read/27932584/the-eif3-complex-of-typanosoma-brucei-composition-conservation-does-not-imply-the-conservation-of-structural-assembly-and-subunits-function
#3
Kunrao Li, Shuru Zhou, Qixuan Guo, Xin Chen, Dehua Lai, Zhaorong Lun, Xuemin Guo
The multisubunit eukaryotic initiation factor 3 (eIF3) plays multiple roles in translation, but poorly understood in trypanosomes. The putative subunits eIF3a and eIF3f of Trypanosoma brucei (TbIF3a and TbIF3f) were overexpressed and purified, and 11 subunits were identified, TbIF3a through l minus j, which form a tight complex. Both TbIF3a and TbIF3f are essential for viability of T. brucei. RNAi knockdown of either of them severely reduced total translation and the ratio of polysome/80S peak area. TbIF3f and TbIF3a RNAi cell lines were modified to express tagged-TbIF3a and -TbIF3f, respectively...
December 8, 2016: RNA
https://www.readbyqxmd.com/read/27932527/mechanisms-of-in-vivo-ribosome-maintenance-change-in-response-to-nutrient-signals
#4
Andrew D Mathis, Bradley C Naylor, Richard H Carson, Eric Evans, Justin Harwell, Jared Knect, Eric Hexem, Fredrick Peelor, Benjamin F Miller, Karyn L Hamilton, Mark K Transtrum, Benjamin T Bikman, John C Price
Control of protein homeostasis is fundamental to the health and longevity of all organisms. Because the rate of protein synthesis by ribosomes is a central control point in this process, regulation and maintenance of ribosome function could have amplified importance in the overall regulatory circuit. Indeed, ribosomal defects are commonly associated with loss of protein homeostasis, aging and disease, whereas improved protein homeostasis, implying optimal ribosomal function, is associated with disease resistance and increased lifespan...
December 8, 2016: Molecular & Cellular Proteomics: MCP
https://www.readbyqxmd.com/read/27932516/global-analysis-of-regulatory-divergence-in-the-evolution-of-mouse-alternative-polyadenylation
#5
Mei-Sheng Xiao, Bin Zhang, Yi-Sheng Li, Qingsong Gao, Wei Sun, Wei Chen
Alternative polyadenylation (APA), which is regulated by both cis-elements and trans-factors, plays an important role in post-transcriptional regulation of eukaryotic gene expression. However, comparing to the extensively studied transcription and alternative splicing, the extent of APA divergence during evolution and the relative cis- and trans-contribution remain largely unexplored. To directly address these questions for the first time in mammals, by using deep sequencing-based methods, we measured APA divergence between C57BL/6J and SPRET/EiJ mouse strains as well as allele-specific APA pattern in their F1 hybrids...
December 8, 2016: Molecular Systems Biology
https://www.readbyqxmd.com/read/27932457/structural-basis-for-the-dimerization-of-nab2-generated-by-rna-binding-provides-insight-into-its-contribution-to-both-poly-a-tail-length-determination-and-transcript-compaction-in-saccharomyces-cerevisiae
#6
Shintaro Aibara, James M B Gordon, Anja S Riesterer, Stephen H McLaughlin, Murray Stewart
In Saccharomyces cerevisiae generation of export-competent mRNPs terminates the nuclear phase of the gene expression pathway and facilitates transport to the cytoplasm for translation. Nab2 functions in this process to control both mRNP compaction that facilitates movement through nuclear pore complexes and the length of transcript poly(A) tails. Nab2 has a modular structure that includes seven CCCH Zn fingers that bind to A-rich RNAs and fingers 5-7 are critical for these functions. Here, we demonstrate, using both biophysical and structural methods, that binding A11G RNA induces dimerization of Zn fingers 5-7 mediated by the novel spatial arrangement of the fingers promoting each RNA chain binding two protein chains...
December 8, 2016: Nucleic Acids Research
https://www.readbyqxmd.com/read/27932311/daclatasvir-prevents-hepatitis-c-virus-by-blocking-transfer-of-viral-genome-to-assembly-sites
#7
Bertrand Boson, Solène Denolly, Fanny Turlure, Christophe Chamot, Marlène Dreux, François-Loïc Cosset
BACKGROUND & AIMS: Daclatasvir is a direct-acting antiviral agent and potent inhibitor of NS5A, which is involved in replication of the hepatitis C virus (HCV) genome, presumably via membranous web shaping, and assembly of new virions, likely via transfer of the HCV RNA genome to viral particle assembly sites. Daclatasvir inhibits the formation of new membranous web structures and, ultimately, of replication complex vesicles, but also inhibits an early assembly step. We investigated the relationship between daclatasvir-induced clustering of HCV proteins, intracellular localization of viral RNAs and inhibition of viral particle assembly...
December 5, 2016: Gastroenterology
https://www.readbyqxmd.com/read/27931227/epigenetics-of-amphetamine-induced-sensitization-hdac5-expression-and-microrna-in-neural-remodeling
#8
Philip K Liu, Christina H Liu
BACKGROUND: Histone deacetylase (HDAC) activities modify chromatin structure and play a role in learning and memory during developmental processes. Studies of adult mice suggest HDACs are involved in neural network remodeling in brain repair, but its function in drug addiction is less understood. We aimed to examine in vivo HDAC5 expression in a preclinical model of amphetamine-induced sensitization (AIS) of behavior. We generated specific contrast agents to measure HDAC5 levels by in vivo molecular contrast-enhanced (MCE) magnetic resonance imaging (MRI) in amphetamine-naïve mice as well as in mice with AIS...
December 8, 2016: Journal of Biomedical Science
https://www.readbyqxmd.com/read/27930677/de-novo-sequencing-and-comparative-analysis-of-schima-superba-seedlings-to-explore-the-response-to-drought-stress
#9
Bao-Cai Han, Wei Wei, Xiang-Cheng Mi, Ke-Ping Ma
Schima superba is an important dominant species in subtropical evergreen broadleaved forests of China, and plays a vital role in community structure and dynamics. However, the survival rate of its seedlings in the field is low, and water shortage could be a factor that limits its regeneration. In order to better understand the response of its seedlings to drought stress on a functional genomics scale, RNA-seq technology was utilized in this study to perform a large-scale transcriptome sequencing of the S. superba seedlings under drought stress...
2016: PloS One
https://www.readbyqxmd.com/read/27930654/whole-organism-developmental-expression-profiling-identifies-rab-28-as-a-novel-ciliary-gtpase-associated-with-the-bbsome-and-intraflagellar-transport
#10
Victor L Jensen, Stephen Carter, Anna A W M Sanders, Chunmei Li, Julie Kennedy, Tiffany A Timbers, Jerry Cai, Noemie Scheidel, Breandán N Kennedy, Ryan D Morin, Michel R Leroux, Oliver E Blacque
Primary cilia are specialised sensory and developmental signalling devices extending from the surface of most eukaryotic cells. Defects in these organelles cause inherited human disorders (ciliopathies) such as retinitis pigmentosa and Bardet-Biedl syndrome (BBS), frequently affecting many physiological and developmental processes across multiple organs. Cilium formation, maintenance and function depend on intracellular transport systems such as intraflagellar transport (IFT), which is driven by kinesin-2 and IFT-dynein motors and regulated by the Bardet-Biedl syndrome (BBS) cargo-adaptor protein complex, or BBSome...
December 2016: PLoS Genetics
https://www.readbyqxmd.com/read/27930330/simultaneous-dimension-reduction-and-adjustment-for-confounding-variation
#11
Zhixiang Lin, Can Yang, Ying Zhu, John Duchi, Yao Fu, Yong Wang, Bai Jiang, Mahdi Zamanighomi, Xuming Xu, Mingfeng Li, Nenad Sestan, Hongyu Zhao, Wing Hung Wong
Dimension reduction methods are commonly applied to high-throughput biological datasets. However, the results can be hindered by confounding factors, either biological or technical in origin. In this study, we extend principal component analysis (PCA) to propose AC-PCA for simultaneous dimension reduction and adjustment for confounding (AC) variation. We show that AC-PCA can adjust for (i) variations across individual donors present in a human brain exon array dataset and (ii) variations of different species in a model organism ENCODE RNA sequencing dataset...
December 7, 2016: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/27930312/metal-dependence-and-branched-rna-cocrystal-structures-of-the-rna-lariat-debranching-enzyme-dbr1
#12
Nathaniel E Clark, Adam Katolik, Kenneth M Roberts, Alexander B Taylor, Stephen P Holloway, Jonathan P Schuermann, Eric J Montemayor, Scott W Stevens, Paul F Fitzpatrick, Masad J Damha, P John Hart
Intron lariats are circular, branched RNAs (bRNAs) produced during pre-mRNA splicing. Their unusual chemical and topological properties arise from branch-point nucleotides harboring vicinal 2',5'- and 3',5'-phosphodiester linkages. The 2',5'-bonds must be hydrolyzed by the RNA debranching enzyme Dbr1 before spliced introns can be degraded or processed into small nucleolar RNA and microRNA derived from intronic RNA. Here, we measure the activity of Dbr1 from Entamoeba histolytica by using a synthetic, dark-quenched bRNA substrate that fluoresces upon hydrolysis...
December 6, 2016: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/27929729/fyco1-and-autophagy-control-the-integrity-of-the-haploid-male-germ-cell-specific-rnp-granules
#13
Matteo Da Ros, Tiina Lehtiniemi, Opeyemi Olotu, Daniel Fischer, Fu-Ping Zhang, Helena Vihinen, Eija Jokitalo, Anu Sironen, Jorma Toppari, Noora Kotaja
Ribonucleoprotein (RNP) granules play a major role in compartmentalizing cytoplasmic RNA regulation. Haploid round spermatids that have exceptionally diverse transcriptomes are characterized by a unique germ cell-specific RNP granule, the chromatoid body (CB). The CB shares many characteristics with somatic RNP granules but also has germline-specific features. The CB appears to be a central structure in PIWI-interacting RNA (piRNA)-targeted RNA regulation. Here, we identified a novel CB component, FYCO1, which is involved in the intracellular transport of autophagic vesicles in somatic cells...
December 8, 2016: Autophagy
https://www.readbyqxmd.com/read/27929395/deficiency-in-the-ubiquitin-conjugating-enzyme-ube2a-in-alzheimer-s-disease-ad-is-linked-to-deficits-in-a-natural-circular-mirna-7-sponge-circrna-cirs-7
#14
Yuhai Zhao, Peter N Alexandrov, Vivian Jaber, Walter J Lukiw
Our understanding of the highly specialized functions for small non-coding single-stranded RNA (ssRNA) in the transcriptome of the human central nervous system (CNS) continues to evolve. Circular RNAs (circRNAs), a recently discovered class of ssRNA enriched in the brain and retina, are extremely stable and intrinsically resilient to degradation by exonuclease. Conventional methods of ssRNA, microRNA (miRNA), or messenger RNA (mRNA) detection and quantitation requiring free ribonucleotide ends may have considerably underestimated the quantity and significance of CNS circRNA in the CNS...
December 5, 2016: Genes
https://www.readbyqxmd.com/read/27929099/stat1-is-essential-for-the-inhibition-of-hepatitis-c-virus-replication-by-interferon-%C3%AE-but-not-by-interferon-%C3%AE
#15
Shota Yamauchi, Kenji Takeuchi, Kazuyasu Chihara, Chisato Honjoh, Yuji Kato, Hatsumi Yoshiki, Hak Hotta, Kiyonao Sada
Interferon-α (IFN-α) and IFN-λ are structurally distinct cytokines that bind to different receptors, but induce expression of similar sets of genes through Janus kinase (JAK)-signal transducers and activators of transcription (STAT) pathways. The difference between IFN-α and IFN-λ signaling remains poorly understood. Here, using the CRISPR/Cas9 system, we examine the role of STAT1 and STAT2 in the inhibition of hepatitis C virus (HCV) replication by IFN-α and IFN-λ. Treatment with IFN-α increases expression of IFN-stimulated genes (ISGs) such as double-stranded RNA-activated protein kinase (PKR) and decreases viral RNA and protein levels in HCV-infected Huh-7...
December 8, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27929094/peptidylarginine-deiminase-1-catalyzed-histone-citrullination-is-essential-for-early-embryo-development
#16
Xiaoqian Zhang, Xiaoqiu Liu, Mei Zhang, Tingting Li, Aaron Muth, Paul R Thompson, Scott A Coonrod, Xuesen Zhang
Peptidylarginine deiminase (PADI) enzymes are increasingly being associated with the regulation of chromatin structure and gene activity via histone citrullination. As one of the PADI family members, PADI1 has been mainly reported to be expressed in the epidermis and uterus, where the protein in keratinocytes is thought to promote differentiation by citrullinating filament proteins. However, the roles of PADI1 in preimplantation development have not been addressed. Using a PADI1-specific inhibitor and Padi1-morpholino knockdown, we found that citrullination of histone tails at H4R3 and H3R2/8/17 were markedly reduced in the 2- and 4-cell embryos...
December 8, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27928057/modulation-of-the-splicing-regulatory-function-of-srsf10-by-a-novel-compound-that-impairs-hiv-1-replication
#17
Lulzim Shkreta, Marco Blanchette, Johanne Toutant, Emmanuelle Wilhelm, Brendan Bell, Benjamin A Story, Ahalya Balachandran, Alan Cochrane, Peter K Cheung, P Richard Harrigan, David S Grierson, Benoit Chabot
We recently identified the 4-pyridinone-benzisothiazole carboxamide compound 1C8 as displaying strong anti-HIV-1 potency against a variety of clinical strains in vitro Here we show that 1C8 decreases the expression of HIV-1 and alters splicing events involved in the production of HIV-1 mRNAs. Although 1C8 was designed to be a structural mimic of the fused tetracyclic indole compound IDC16 that targets SRSF1, it did not affect the splice site shifting activity of SRSF1. Instead, 1C8 altered splicing regulation mediated by SRSF10...
December 7, 2016: Nucleic Acids Research
https://www.readbyqxmd.com/read/27928012/emergence-of-a-viral-rna-polymerase-variant-during-gene-copy-number-amplification-promotes-rapid-evolution-of-vaccinia-virus
#18
Kelsey R Cone, Zev N Kronenberg, Mark Yandell, Nels C Elde
: Viruses are under relentless selective pressure from host immune defenses. To study how poxviruses adapt to innate immune detection pathways, we performed serial infections of vaccinia virus in primary human cells. Independent courses of experimental evolution with a recombinant strain lacking E3L revealed several high frequency point mutations in conserved poxvirus genes, suggesting important roles for essential poxvirus proteins in innate immune subversion. Two distinct mutations were identified in the viral RNA polymerase gene A24R, which seem to act through different mechanisms to increase virus replication...
December 7, 2016: Journal of Virology
https://www.readbyqxmd.com/read/27927278/comparative-genomic-analysis-of-enterovirus-71-revealed-six-new-potential-neurovirulence-associated-sites
#19
Qing Jun Jia, Xin Yu Chen, De Zhou Li, Juan Juan Xu, Zhi Gang Xu, Zhi Liang Duan, Jin Sheng Wen
In the present study, the complete genomes of four common (4/EV71/Wenzhou/CHN/2014, 15/ EV71/Wenzhou/CHN/2014, 116/EV71/Wenzhou/ CHN/2014, and 120/EV71/Wenzhou/CHN/2014) and two virulent (11/EV71/Wenzhou/CHN/2014 and 109/EV71/Wenzhou/CHN/2014) enterovirus 71 (EV71) isolates were sequenced and described. They are 7405 bp in length and belong to EV71 sub-genotype C4 (C4a cluster). Nucleotide sequence alignment revealed six nucleotide variations (GP151→TP151, GP199→AP199, GP261→TP261, AP328→CP328, GP422→AP422, and GP437→TP437) in the two virulent isolates within the 5'UTR of the IRES element...
October 2016: Biomedical and Environmental Sciences: BES
https://www.readbyqxmd.com/read/27927222/tollip-an-early-regulator-of-the-acute-inflammatory-response-in-the-substantia-nigra
#20
Marie Humbert-Claude, D Duc, D Dwir, L Thieren, J Sandström von Tobel, C Begka, F Legueux, D Velin, M H Maillard, K Q Do, F Monnet-Tschudi, L Tenenbaum
BACKGROUND: Tollip is a ubiquitously expressed protein, originally described as a modulator of the IL-1R/TLR-NF-κB signaling pathways. Although this property has been well characterized in peripheral cells, and despite some evidence of its expression in the central nervous system, the role of Tollip in neuroinflammation remains poorly understood. The present study sought to explore the implication of Tollip in inflammation in the substantia nigra pars compacta, the structure affected in Parkinson's disease...
December 7, 2016: Journal of Neuroinflammation
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