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Mutational robustness

James B Hilton, Kai Kysenius, Anthony R White, Peter J Crouch
Mutations to the copper-dependent enzyme Cu/Zn-superoxide dismutase (SOD1) cause amyotrophic lateral sclerosis (ALS) in humans, and transgenic overexpression of mutant SOD1 represents a robust murine model of the disease. We have previously shown that the copper-containing compound CuII (atsm) phenotypically improves mutant SOD1 mice and delivers copper to copper-deficient SOD1 in the CNS to restore its physiological function. CuII (atsm) is now in clinical trials for the treatment of ALS. In this study, we demonstrate that cuproenzyme dysfunction extends beyond SOD1 in SOD1G37R mice to also affect the endogenous copper-dependent ferroxidase ceruloplasmin...
June 12, 2018: Experimental Neurology
Claudio Casola, Tomasz E Koralewski
Gene duplications and gene losses are major determinants of genome evolution and phenotypic diversity. The frequency of gene turnover (gene gains and gene losses combined) is known to vary between organisms. Comparative genomic analyses of gene families can highlight such variation; however, estimates of gene turnover may be biased when using highly fragmented genome assemblies resulting in poor gene annotations. Here, we address potential biases introduced by gene annotation errors in estimates of gene turnover frequencies in a dataset including both well-annotated angiosperm genomes and the incomplete gene sets of four Pinaceae including two pine species, Norway spruce and Douglas-fir...
June 14, 2018: Plant Journal: for Cell and Molecular Biology
Ophélie Alyssa Martin, Armand Garot, Sandrine Le Noir, Jean-Claude Aldigier, Michel Cogné, Eric Pinaud, François Boyer
In B-lineage cells, the cytidine deaminase AID not only generates somatic mutations to variable regions of Ig genes but also inflicts, at a lower frequency, mutations to several non-Ig genes named AID off-targets, which include proto-oncogenes. High-throughput sequencing should be in principle the method of choice to detect and document these rare nucleotide substitutions. So far, high-throughput sequencing-based methods are impaired by a global sequencing error rate that usually covers the real mutation rate of AID off-target genes in activated B cells...
June 13, 2018: Journal of Immunology: Official Journal of the American Association of Immunologists
Sören Müller, Ara Cho, Siyuan J Liu, Daniel A Lim, Aaron Diaz
Motivation: Single-cell RNA-sequencing (scRNA-seq) has enabled studies of tissue composition at unprecedented resolution. However, the application of scRNA-seq to clinical cancer samples has been limited, partly due to a lack of scRNA-seq algorithms that integrate genomic mutation data. Results: To address this, we present. CONICS: COpy-Number analysis In single-Cell RNA-Sequencing. CONICS is a software tool for mapping gene expression from scRNA-seq to tumor clones and phylogenies, with routines enabling: the quantitation of copy-number alterations in scRNA-seq, robust separation of neoplastic cells from tumor-infiltrating stroma, inter-clone differential-expression analysis, and intra-clone co-expression analysis...
April 20, 2018: Bioinformatics
Jonathan M Locke, Cécile Saint-Martin, Thomas W Laver, Kashyap A Patel, Andrew R Wood, Seth A Sharp, Sian Ellard, Christine Bellanné-Chantelot, Andrew T Hattersley, Lorna W Harries, Michael N Weedon
There is wide variation in the age at diagnosis of diabetes in individuals with Maturity-Onset Diabetes of the Young (MODY) due to a mutation in the HNF1A gene. We hypothesised that common variants at the HNF1A locus (rs1169288, I27L; rs1800574, A98V), which are associated with type 2 diabetes susceptibility, may modify age at diabetes diagnosis in HNF1A-MODY individuals. Meta-analysis of two independent cohorts, comprising 781 HNF1A-MODY individuals, found no significant associations between genotype and age at diagnosis...
June 12, 2018: Diabetes
Erin T Williams, Liliane Glauser, Elpida Tsika, Haisong Jiang, Shariful Islam, Darren J Moore
Mutations in a number of genes cause familial forms of Parkinson's disease (PD), including mutations in the vacuolar protein sorting 35 ortholog (VPS35) and parkin genes. In this study, we identify a novel functional interaction between parkin and VPS35. We demonstrate that parkin interacts with and robustly ubiquitinates VPS35 in human neural cells. Familial parkin mutations are impaired in their ability to ubiquitinate VPS35. Parkin mediates the attachment of an atypical poly-ubiquitin chain to VPS35 with three lysine residues identified within the C-terminal region of VPS35 that are covalently modified by ubiquitin...
June 11, 2018: Human Molecular Genetics
Ruzanna Mnatsakanyan, Gerta Shema, Mark Basik, Gerald Batist, Christoph H Borchers, Albert Sickmann, René P Zahedi
Numerous diseases are caused by changes in post-translational modifications (PTMs). Therefore, the number of clinical proteomics studies that include the analysis of PTMs is increasing. Combining complementary information - e.g., changes in protein abundance, PTM levels, with the genome and transcriptome (proteogenomics) - holds great promise for discovering important drivers and markers of disease, as variations in copy number, expression levels, or mutations without spatial/functional/isoform information is often insufficient or even misleading...
June 12, 2018: Expert Review of Proteomics
Christian Njatcha, Mariya Farooqui, Adam Kornberg, Daniel E Johnson, Jennifer R Grandis, Jill M Siegfried
Constitutively activated STAT3 plays a critical role in non-small cell lung carcinoma (NSCLC) progression by mediating proliferation and survival. STAT 3 activation in normal cells is transient, making it an attractive target for NSCLC therapy. The therapeutic potential of blocking STAT3 in NSCLC was assessed utilizing a decoy approach by ligating a double-stranded 15-mer oligonucleotide that corresponds to the STAT3 response element of STAT3-target genes, to produce a cyclic STAT3 decoy (CS3D). The decoy was evaluated using NSCLC cells containing either wild-type (WT) EGFR (201T) or mutant EGFR with an additional EGFRi resistance mutation (H1975)...
June 11, 2018: Molecular Cancer Therapeutics
Chen-Wei Tsai, Ming-Feng Tsai
The mitochondrial calcium uniporter is a multisubunit Ca2+ channel that mediates mitochondrial Ca2+ uptake, a cellular process crucial for the regulation of oxidative phosphorylation, intracellular Ca2+ signaling, and apoptosis. In the last few years, genes encoding uniporter proteins have been identified, but a lack of efficient tools for electrophysiological recordings has hindered quantitative analysis required to determine functional mechanisms of this channel complex. Here, we redirected Ca2+ -conducting subunits (MCU and EMRE) of the human uniporter to the plasma membrane of Xenopus oocytes...
June 11, 2018: Journal of General Physiology
Arsen S Hunanyan, Ashley R Helseth, Elie Abdelnour, Bassil Kherallah, Monisha Sachdev, Leeyup Chung, Melanie Masoud, Jordan Richardson, Qiang Li, J Victor Nadler, Scott D Moore, Mohamad A Mikati
OBJECTIVE: Na+ /K+ -ATPase dysfunction, primary (mutation) or secondary (energy crisis, neurodegenerative disease) increases neuronal excitability in the brain. To evaluate the mechanisms underlying such increased excitability we studied mice carrying the D801N mutation, the most common mutation causing human disease, specifically alternating hemiplegia of childhood (AHC) including epilepsy. Because the gene is expressed in all neurons, particularly γ-aminobutyric acid (GABA)ergic interneurons, we hypothesized that the pathophysiology would involve both pyramidal cells and interneurons and that fast-spiking interneurons, which have increased firing rates, would be most vulnerable...
June 11, 2018: Epilepsia
Sara Lomonaco, Matthew A Crawford, Christine Lascols, Ruth E Timme, Kevin Anderson, David R Hodge, Debra J Fisher, Segaran P Pillai, Stephen A Morse, Erum Khan, Molly A Hughes, Marc W Allard, Shashi K Sharma
The emergence and dissemination of carbapenemases, bacterial enzymes able to inactivate most β-lactam antibiotics, in Enterobacteriaceae is of increasing concern. The concurrent spread of resistance against colistin, an antibiotic of last resort, further compounds this challenge further. Whole-genome sequencing (WGS) can play a significant role in the rapid and accurate detection/characterization of existing and emergent resistance determinants, an essential aspect of public health surveillance and response activities to combat the spread of antimicrobial resistant bacteria...
2018: PloS One
Timothy F Miles, Katja Spiess, Kevin M Jude, Naotaka Tsutsumi, John S Burg, Jessica R Ingram, Deepa Waghray, Gertrud M Hjorto, Olav Larsen, Hidde L Ploegh, Mette M Rosenkilde, K Christopher Garcia
Human cytomegalovirus has hijacked and evolved a human G-protein-coupled receptor into US28, which functions as a promiscuous chemokine 'sink' to facilitate evasion of host immune responses. To probe the molecular basis of US28's unique ligand cross-reactivity, we deep-sequenced CX3CL1 chemokine libraries selected on 'molecular casts' of the US28 active-state and find that US28 can engage thousands of distinct chemokine sequences, many of which elicit diverse signaling outcomes. The structure of a G-protein-biased CX3CL1-variant in complex with US28 revealed an entirely unique chemokine amino terminal peptide conformation and remodeled constellation of receptor-ligand interactions...
June 8, 2018: ELife
Made Airanthi K Widjaja-Adhi, Srinivasagan Ramkumar, Johannes von Lintig
Exposure to light and accumulation of aberrant visual cycle by-products causes stress in the retina. The physical and chemical properties of carotenoids may provide protection against such scenario. These pigments exist in retinas of many vertebrates, including humans. However, the absence of carotenoids in mice, the preferred ophthalmologic animal model, hindered molecular and biochemical examination of the pigments' role in vision. We established a mouse model that accumulates significant amounts of carotenoids in the retina due to inactivating mutations in the Isx and Bco2 genes...
June 8, 2018: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
Wafik Zaky, Shekhar S Patil, Minjeong Park, Diane Liu, Wei-Lien Wang, Khalida M Wani, Susana Calle, Leena Ketonen, Soumen Khatua
BACKGROUND: Ganglioglioma (GG) is a rare mixed glial-neuronal neoplasm accounting for 0.5-5% of all pediatric central nervous system (CNS) tumors. Rarity of this tumor has precluded defining robust treatment guidelines. This retrospective study evaluates the prognostic factors and outcomes of this rare neoplasm. PATIENTS AND METHODS: Retrospective analysis of 55 patients with GG was conducted to describe clinical findings, and outcomes. Kaplan-Meier survival and Cox-regression analyses were performed to assess the overall survival (OS) and progression-free survival (PFS)...
June 7, 2018: Journal of Neuro-oncology
Phillip C Witcher, Sara E Miner, Daniel J Horan, Whitney A Bullock, Kyung-Eun Lim, Kyung Shin Kang, Alison L Adaniya, Ryan D Ross, Gabriela G Loots, Alexander G Robling
The WNT pathway has become an attractive target for skeletal therapies. High-bone-mass phenotypes in patients with loss-of-function mutations in the LRP5/6 inhibitor Sost (sclerosteosis), or in its downstream enhancer region (van Buchem disease), highlight the utility of targeting Sost/sclerostin to improve bone properties. Sclerostin-neutralizing antibody is highly osteoanabolic in animal models and in human clinical trials, but antibody-based inhibition of another potent LRP5/6 antagonist, Dkk1, is largely inefficacious for building bone in the unperturbed adult skeleton...
June 7, 2018: JCI Insight
Maria Nevot, Ana Jordan-Paiz, Glòria Martrus, Cristina Andrés, Damir García-Cehic, Josep Gregori, Sandra Franco, Josep Quer, Miguel Angel Martinez
One unexplored aspect of HIV-1 genetic architecture is how codon choice influences population diversity and evolvability. Here we compared the development of HIV-1 resistance to protease inhibitors (PIs) between wild-type (WT) virus and a synthetic virus (MAX) carrying a codon-pair re-engineered protease sequence including 38 (13%) synonymous mutations. WT and MAX viruses showed indistinguishable replication in MT-4 cells or PBMCs. Both viruses were subjected to serial passages in MT-4 cells with selective pressure from the PIs atazanavir (ATV) and darunavir (DRV)...
June 6, 2018: Journal of Virology
Young-Shin Chung, Bumsoo Pak, Sehee Han, Jiyeon Lee, Jiyoung Kim, Seng-Min Back, Cho-Rong Park, Su-Hwan Kim, Jong-Kwon Lee
The mutagenic potencies of 1,3-propane sultone (PS), N-propyl-N-nitrosourea (PNU), and mitomycin C (MMC) were investigated in three independent laboratories in Korea using the Pig-a assay in vivo. Sprague-Dawley rats were treated with vehicle or test substance on three consecutive days. Blood samples were collected for measuring Pig-a mutant phenotypes (CD59-deficient erythrocytes, RBCCD59- ; CD59-deficient reticulocytes, RETCD59- ) on days -1, 15, and 29 after the first treatment. In some studies, blood was collected for determining DNA damage (comet assay) on day 3 and measuring micronucleated reticulocytes (MN-RET) on day 4...
July 2018: Mutation Research
Jianing Xi, Minghui Wang, Ao Li
BACKGROUND: Discovery of mutated driver genes is one of the primary objective for studying tumorigenesis. To discover some relatively low frequently mutated driver genes from somatic mutation data, many existing methods incorporate interaction network as prior information. However, the prior information of mRNA expression patterns are not exploited by these existing network-based methods, which is also proven to be highly informative of cancer progressions. RESULTS: To incorporate prior information from both interaction network and mRNA expressions, we propose a robust and sparse co-regularized nonnegative matrix factorization to discover driver genes from mutation data...
June 5, 2018: BMC Bioinformatics
Samira Locher, Marc Schweneker, Jürgen Hausmann, Gert Zimmer
Vesicular stomatitis virus (VSV) expressing the Ebola virus (EBOV) glycoprotein (GP) in place of the VSV glycoprotein G (VSV/EBOV-GP) is a promising EBOV vaccine candidate which has already entered clinical phase 3 studies. Although this chimeric virus was tolerated overall by volunteers, it still caused viremia and adverse effects such as fever and arthritis, suggesting that it might not be sufficiently attenuated. In this study, the VSV/EBOV-GP vector was further modified in order to achieve attenuation while maintaining immunogenicity...
June 5, 2018: Journal of General Virology
Young-Seok Kim, Ahyun Son, Jihoon Kim, Soon Bin Kwon, Myung Hee Kim, Paul Kim, Jieun Kim, Young Ho Byun, Jemin Sung, Jinhee Lee, Ji Eun Yu, Chan Park, Yeon-Sook Kim, Nam-Hyuk Cho, Jun Chang, Baik L Seong
The folding of monomeric antigens and their subsequent assembly into higher ordered structures are crucial for robust and effective production of nanoparticle (NP) vaccines in a timely and reproducible manner. Despite significant advances in in silico design and structure-based assembly, most engineered NPs are refractory to soluble expression and fail to assemble as designed, presenting major challenges in the manufacturing process. The failure is due to a lack of understanding of the kinetic pathways and enabling technical platforms to ensure successful folding of the monomer antigens into regular assemblages...
2018: Frontiers in Immunology
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