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Mutational robustness

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https://www.readbyqxmd.com/read/28092658/mutation-effects-predicted-from-sequence-co-variation
#1
Thomas A Hopf, John B Ingraham, Frank J Poelwijk, Charlotta P I Schärfe, Michael Springer, Chris Sander, Debora S Marks
Many high-throughput experimental technologies have been developed to assess the effects of large numbers of mutations (variation) on phenotypes. However, designing functional assays for these methods is challenging, and systematic testing of all combinations is impossible, so robust methods to predict the effects of genetic variation are needed. Most prediction methods exploit evolutionary sequence conservation but do not consider the interdependencies of residues or bases. We present EVmutation, an unsupervised statistical method for predicting the effects of mutations that explicitly captures residue dependencies between positions...
January 16, 2017: Nature Biotechnology
https://www.readbyqxmd.com/read/28092155/discovery-of-first-in-class-potent-and-orally-bioavailable-eed-inhibitor-with-robust-anti-cancer-efficacy
#2
Ying Huang, Jeff Zhang, Zhengtian Yu, Hailong Zhang, Youzhen Wang, Andreas Lingel, Wei Qi, X Justin Gu, Kehao Zhao, Michael David Shultz, Long Wang, Xingnian Fu, Yongfeng Sun, Qiong Zhang, Xiangqing Jiang, Jiang-Wei Zhang, Chunye Zhang, Ling Li, Jue Zeng, Lijian Feng, Chao Zhang, Yueqin Liu, Man Zhang, Lijun Zhang, Mengxi Zhao, Zhenting Gao, Xianghui Liu, Douglas Fang, Haibing Guo, Yuan Mi, Tobias Gabriel, Michael P Dillon, Peter Atadja, Counde Oyang
Overexpression and somatic heterozygous mutations of EZH2, the catalytic subunit Polycomb repressive complex 2 (PRC2), are associated with several tumor types. EZH2 inhibitor, EPZ-6438 (Tazemetostat), demonstrated clinical efficacy in patients with acceptable safety profile as monotherapy. EED, another subunit of PRC2 complex, is essential for its histone methyltransferase activity through direct binding to trimethylated lysine 27 on histone 3 (H3K27Me3). Herein we disclose the discovery of a first-in-class potent, selective and orally bioavailable EED inhibitor EED226 (compound 43)...
January 16, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28087830/recognition-of-the-magnaporthe-oryzae-effector-avr-pia-by-the-decoy-domain-of-the-rice-nlr-immune-receptor-rga5
#3
Diana Ortiz, Karine De Guillen, Stella Cesari, Véronique Chalvon, Jérome Gracy, André Padilla, Thomas Kroj
Nucleotide-binding domain and leucine-rich repeat proteins (NLRs) are important receptors in plant immunity that allow recognition of pathogen effectors. The rice NLR RGA5 recognizes the Magnaporthe oryzae effector AVR-Pia through direct interaction. Here, we gained detailed insights into the molecular and structural bases of AVR-Pia-RGA5 interaction and the role of the RATX1 decoy domain of RGA5. NMR titration combined with in vitro and in vivo protein-protein interaction analyses identified the AVR-Pia interaction surface that binds to the RATX1 domain...
January 13, 2017: Plant Cell
https://www.readbyqxmd.com/read/28087713/functional-genomics-reveals-that-tumors-with-activating-phosphoinositide-3-kinase-mutations-are-dependent-on-accelerated-protein-turnover
#4
Teresa Davoli, Kristen E Mengwasser, Jingjing Duan, Ting Chen, Camilla Christensen, Eric C Wooten, Anthony N Anselmo, Mamie Z Li, Kwok-Kin Wong, Kristopher T Kahle, Stephen J Elledge
Activating mutations in the phosphoinositide 3-kinase (PI3K) signaling pathway are frequently identified in cancer. To identify pathways that support PI3K oncogenesis, we performed a genome-wide RNAi screen in isogenic cell lines harboring wild-type or mutant PIK3CA to search for PI3K synthetic-lethal (SL) genes. A combined analysis of these results with a meta-analysis of two other large-scale RNAi screening data sets in PI3K mutant cancer cell lines converged on ribosomal protein translation and proteasomal protein degradation as critical nononcogene dependencies for PI3K-driven tumors...
December 15, 2016: Genes & Development
https://www.readbyqxmd.com/read/28087578/distinct-binding-of-pet-ligands-pbb3-and-av-1451-to-tau-fibril-strains-in-neurodegenerative-tauopathies
#5
Maiko Ono, Naruhiko Sahara, Katsushi Kumata, Bin Ji, Ruiqing Ni, Shunsuke Koga, Dennis W Dickson, John Q Trojanowski, Virginia M-Y Lee, Mari Yoshida, Isao Hozumi, Yasumasa Yoshiyama, John C van Swieten, Agneta Nordberg, Tetsuya Suhara, Ming-Rong Zhang, Makoto Higuchi
Diverse neurodegenerative disorders are characterized by deposition of tau fibrils composed of conformers (i.e. strains) unique to each illness. The development of tau imaging agents has enabled visualization of tau lesions in tauopathy patients, but the modes of their binding to different tau strains remain elusive. Here we compared binding of tau positron emission tomography ligands, PBB3 and AV-1451, by fluorescence, autoradiography and homogenate binding assays with homologous and heterologous blockades using tauopathy brain samples...
January 12, 2017: Brain: a Journal of Neurology
https://www.readbyqxmd.com/read/28077418/a-novel-humanized-mouse-model-with-significant-improvement-of-class-switched-antigen-specific-antibody-production
#6
Hua Yu, Chiara Borsotti, Jean-Nicolas Schickel, Shu Zhu, Till Strowig, Elizabeth E Eynon, Davor Frleta, Cagan Gurer, Andrew J Murphy, George D Yancopoulos, Eric Meffre, Markus G Manz, Richard A Flavell
Humanized mice are a powerful tool for the study of human hematopoiesis and immune function in vivo. However, the existing models cannot support robust adaptive immune responses, especially the generation of class-switched, antigen-specific antibody responses. Here we describe a new mouse strain, in which human IL6 gene encoding the cytokine that is important for B and T cell differentiation was knocked into its respective mouse locus. The provision of human IL6 not only enhanced thymopoiesis and periphery T-cell engraftment, but also significantly increased class switched memory B cells and serum IgG...
January 11, 2017: Blood
https://www.readbyqxmd.com/read/28077247/mouse-dna-polymerase-%C3%AE-lacking-the-forty-two-amino-acids-encoded-by-exon-2-is-catalytically-inactive-in-vitro
#7
Ekaterina G Frank, John P McDonald, Wei Yang, Roger Woodgate
In 2003, we reported that 129-derived strains of mice carry a naturally occurring nonsense mutation at codon 27 of the Poli gene that would produce a polι peptide of just 26 amino acids, rather then the full-length 717 amino acid wild-type polymerase. In support of the genomic analysis, no polι protein was detected in testes extracts from 129X1/SvJmice, where wild-type polι is normally highly expressed. The early truncation in polι occurs before any structural domains of the polymerase are synthesized and as a consequence, we reasoned that 129-derived strains of mice should be considered as functionally defective in polι activity...
December 21, 2016: DNA Repair
https://www.readbyqxmd.com/read/28074036/redox-crisis-underlies-conditional-light-dark-lethality-in-cyanobacterial-mutants-that-lack-the-circadian-regulator-rpaa
#8
Spencer Diamond, Benjamin E Rubin, Ryan K Shultzaberger, You Chen, Chase D Barber, Susan S Golden
Cyanobacteria evolved a robust circadian clock, which has a profound influence on fitness and metabolism under daily light-dark (LD) cycles. In the model cyanobacterium Synechococcus elongatus PCC 7942, a functional clock is not required for diurnal growth, but mutants defective for the response regulator that mediates transcriptional rhythms in the wild-type, regulator of phycobilisome association A (RpaA), cannot be cultured under LD conditions. We found that rpaA-null mutants are inviable after several hours in the dark and compared the metabolomes of wild-type and rpaA-null strains to identify the source of lethality...
January 10, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28068993/improvement-of-yeast-tolerance-to-acetic-acid-through-haa1-transcription-factor-engineering-towards-the-underlying-mechanisms
#9
Steve Swinnen, Sílvia F Henriques, Ranjan Shrestha, Ping-Wei Ho, Isabel Sá-Correia, Elke Nevoigt
BACKGROUND: Besides being a major regulator of the response to acetic acid in Saccharomyces cerevisiae, the transcription factor Haa1 is an important determinant of the tolerance to this acid. The engineering of Haa1 either by overexpression or mutagenesis has therefore been considered to be a promising avenue towards the construction of more robust strains with improved acetic acid tolerance. RESULTS: By applying the concept of global transcription machinery engineering to the regulon-specific transcription factor Haa1, a mutant allele containing two point mutations could be selected that resulted in a significantly higher acetic acid tolerance as compared to the wild-type allele...
January 9, 2017: Microbial Cell Factories
https://www.readbyqxmd.com/read/28060411/scarless-cas9-assisted-recombineering-no-scar-in-escherichia-coli-an-easy-to-use-system-for-genome-editing
#10
Christopher R Reisch, Kristala L J Prather
The discovery and development of genome editing systems that leverage the site-specific DNA endonuclease system CRISPR/Cas9 has fundamentally changed the ease and speed of genome editing in many organisms. In eukaryotes, the CRISPR/Cas9 system utilizes a "guide" RNA to enable the Cas9 nuclease to make a double-strand break at a particular genome locus, which is repaired by non-homologous end joining (NHEJ) repair enzymes, often generating random mutations in the process. A specific alteration of the target genome can also be generated by supplying a DNA template in vivo with a desired mutation, which is incorporated by homology-directed repair...
January 5, 2017: Current Protocols in Molecular Biology
https://www.readbyqxmd.com/read/28057708/development-of-an-in-vitro-pig-a-gene-mutation-assay-in-human-cells
#11
Benjamin J Rees, Matthew Tate, Anthony M Lynch, Catherine A Thornton, Gareth J Jenkins, Richard M Walmsley, George E Johnson
Mutagens can be carcinogens, and traditionally, they have been identified in vitro using the Salmonella 'Ames' reverse mutation assay. However, prokaryotic DNA packaging, replication and repair systems are mechanistically very different to those in the humans we inevitably seek to protect. Therefore, for many years, mammalian cell line genotoxicity assays that can detect eukaryotic mutagens as well as clastogens and aneugens have been used. The apparent lack of specificity in these largely rodent systems, due partly to their mutant p53 status, has contributed to the use of animal studies to resolve data conflicts...
January 4, 2017: Mutagenesis
https://www.readbyqxmd.com/read/28054552/c-src-phosphorylation-and-activation-of-hexokinase-promotes-tumorigenesis-and-metastasis
#12
Jia Zhang, Suili Wang, Bin Jiang, Lihong Huang, Zhiliang Ji, Xiaotong Li, Huamin Zhou, Aidong Han, Ai Chen, Yanan Wu, Huanhuan Ma, Wentao Zhao, Qingwen Zhao, Changchuan Xie, Xiaoyan Sun, Yanming Zhou, Huiying Huang, Muhammad Suleman, Furong Lin, Lin Zhou, Fang Tian, Meijun Jin, Yana Cai, Nan Zhang, Qinxi Li
It is well known that c-Src has important roles in tumorigenesis. However, it remains unclear whether c-Src contributes to metabolic reprogramming. Here we find that c-Src can interact with and phosphorylate hexokinases HK1 and HK2, the rate-limiting enzymes in glycolysis. Tyrosine phosphorylation dramatically increases their catalytic activity and thus enhances glycolysis. Mechanistically, c-Src phosphorylation of HK1 at Tyr732 robustly decreases its Km and increases its Vmax by disrupting its dimer formation...
January 5, 2017: Nature Communications
https://www.readbyqxmd.com/read/28053186/intracardiac-injection-of-aav9-npc1-significantly-ameliorates-purkinje-cell-death-and-behavioral-abnormalities-in-mouse-niemann-pick-type-c-disease
#13
Chang Xie, Xue-Min Gong, Jie Luo, Bo-Liang Li, Bao-Liang Song
Niemann-Pick type C (NPC) disease is a fatal, inherited neurodegenerative disorder caused by loss-of-function mutations in the NPC1 or NPC2 gene. There is no effective way to treat NPC disease. In this study, we used adeno-associated virus (AAV) serotype 9 to deliver a functional NPC1 gene systemically into NPC1-/- mice at postnatal day 4 (P4). One single AAV9-NPC1 injection resulted in robust NPC1 expression in various tissues including the brain, heart and lung. Strikingly, AAV9-mediated NPC1 delivery significantly promoted Purkinje cell survival, restored locomotor activity and coordination, as well as increased the lifespan of NPC1-/- mice...
January 4, 2017: Journal of Lipid Research
https://www.readbyqxmd.com/read/28053086/myosin-iia-heavy-chain-phosphorylation-mediates-adhesion-maturation-and-protrusion-in-3d
#14
Vandana Rai, Dustin G Thomas, Jordan R Beach, Thomas T Egelhoff
Nonmuscle myosin II (NMII) is a conserved force-producing cytoskeletal enzyme with important but poorly understood roles in cell migration. To investigate myosin heavy chain (MHC) phosphorylation roles in 3D migration, we expressed GFP-tagged NMIIA wild type or mutant constructs in cells depleted of endogenous NMIIA protein. We find that individual mutation or double mutation of S1916 or S1943 to alanine potently blocks recruitment of GFP-NM-IIA filaments to leading edge protrusions in 2D, and this in turn blocks maturation of anterior focal adhesions...
January 4, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28049852/in-vivo-severity-ranking-of-ras-pathway-mutations-associated-with-developmental-disorders
#15
Granton A Jindal, Yogesh Goyal, Kei Yamaya, Alan S Futran, Iason Kountouridis, Courtney A Balgobin, Trudi Schüpbach, Rebecca D Burdine, Stanislav Y Shvartsman
Germ-line mutations in components of the Ras/MAPK pathway result in developmental disorders called RASopathies, affecting about 1/1,000 human births. Rapid advances in genome sequencing make it possible to identify multiple disease-related mutations, but there is currently no systematic framework for translating this information into patient-specific predictions of disease progression. As a first step toward addressing this issue, we developed a quantitative, inexpensive, and rapid framework that relies on the early zebrafish embryo to assess mutational effects on a common scale...
January 3, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28045264/exploring-the-mutational-robustness-of-nucleic-acids-by-searching-genotype-neighborhoods-in-sequence-space
#16
Qingtong Zhou, Xianbao Sun, Xiaole Xia, Zhou Fan, Zhaofeng Luo, Suwen Zhao, Eugene Shakhnovich, Haojun Liang
To assess the mutational robustness of nucleic acids, many genome- and protein-level studies have been performed, where nucleic acids are treated as genetic information carriers and transferrers. However, the molecular mechanisms through which mutations alter the structural, dynamic, and functional properties of nucleic acids are poorly understood. Here we performed a SELEX in silico study to investigate the fitness distribution of the l-Arm-binding aptamer genotype neighborhoods. Two novel functional genotype neighborhoods were isolated and experimentally verified to have comparable fitness as the wild-type...
January 5, 2017: Journal of Physical Chemistry Letters
https://www.readbyqxmd.com/read/28044225/simple-mssm-a-simple-and-efficient-method-for-simultaneous-multi-site-saturation-mutagenesis
#17
Feng Cheng, Jian-Miao Xu, Chao Xiang, Zhi-Qiang Liu, Li-Qing Zhao, Yu-Guo Zheng
OBJECTIVE: To develop a practically simple and robust multi-site saturation mutagenesis (MSSM) method that enables simultaneously recombination of amino acid positions for focused mutant library generation. RESULTS: A general restriction enzyme-free and ligase-free MSSM method (Simple-MSSM) based on prolonged overlap extension PCR (POE-PCR) and Simple Cloning techniques. As a proof of principle of Simple-MSSM, the gene of eGFP (enhanced green fluorescent protein) was used as a template gene for simultaneous mutagenesis of five codons...
January 2, 2017: Biotechnology Letters
https://www.readbyqxmd.com/read/28043616/whole-genome-sequencing-as-the-ultimate-tool-to-diagnose-tuberculosis
#18
Dick van Soolingen, Rana Jajou, Arnout Mulder, Han de Neeling
In the past two decades, DNA techniques have been increasingly used in the laboratory diagnosis of tuberculosis (TB). The (sub) species of the Mycobacterium tuberculosis complex are usually identified using reverse line blot techniques. The resistance is predicted by the detection of mutations in genes associated with resistance. Nevertheless, all cases are still subjected to cumbersome phenotypic resistance testing. The production of a strain-characteristic DNA fingerprint, to investigate the epidemiology of TB, is done by the 24-locus variable number tandem repeat (VNTR) typing...
December 2016: International Journal of Mycobacteriology
https://www.readbyqxmd.com/read/28038466/drug-dependent-functionalization-of-wild-type-and-mutant-p53-in-cisplatin-resistant-human-ovarian-tumor-cells
#19
Michelle Bhatt, Cristina Ivan, Xiaolei Xie, Zahid H Siddik
Cisplatin (cis-Pt) resistance in tumor cells from p53 dysfunction is a significant clinical problem. Although mutation can inhibit p53 function, >60% of p53 mutants retain normal function according to literature reports. Therefore, we examined the status of p53 in cisplatin-resistant ovarian tumor models and its functional response to cis-Pt and the mechanistically-distinct non-cross-resistant oxaliplatin (oxali-Pt). Relative to sensitive A2780 cells harboring wild-type p53, the 2780CP/Cl-16, OVCAR-10, Hey and OVCA-433 cell lines were 10- to 30-fold resistant to cis-Pt, but was substantially circumvented by oxali-Pt...
December 26, 2016: Oncotarget
https://www.readbyqxmd.com/read/28035989/neuroblastoma-a-paradigm-for-big-data-science-in-pediatric-oncology
#20
REVIEW
Brittany M Salazar, Emily A Balczewski, Choong Yong Ung, Shizhen Zhu
Pediatric cancers rarely exhibit recurrent mutational events when compared to most adult cancers. This poses a challenge in understanding how cancers initiate, progress, and metastasize in early childhood. Also, due to limited detected driver mutations, it is difficult to benchmark key genes for drug development. In this review, we use neuroblastoma, a pediatric solid tumor of neural crest origin, as a paradigm for exploring "big data" applications in pediatric oncology. Computational strategies derived from big data science-network- and machine learning-based modeling and drug repositioning-hold the promise of shedding new light on the molecular mechanisms driving neuroblastoma pathogenesis and identifying potential therapeutics to combat this devastating disease...
December 27, 2016: International Journal of Molecular Sciences
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