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Site directed mutations

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https://www.readbyqxmd.com/read/28931559/variation-in-position-effect-variegation-within-a-natural-population
#1
Keegan J P Kelsey, Andrew G Clark
Changes in chromatin state may drive changes in gene expression, and it is of growing interest to understand the population genetic forces that drive differences in chromatin state. Here, we use the phenomenon of position effect variegation (PEV), a well-studied proxy for chromatin state, to survey variation in PEV among a naturally derived population. Further, we explore the genetic architecture of natural variation in factors that modify PEV. While previous mutation screens have identified over 150 suppressors and enhancers of PEV, it remains unknown to what extent allelic variation in these modifiers mediate inter-individual variation in PEV...
September 20, 2017: Genetics
https://www.readbyqxmd.com/read/28931206/metabolic-engineering-a-yeast-to-produce-astaxanthin
#2
Yu-Ju Lin, Jui-Jen Chang, Hao-Yeh Lin, Caroline Thia, Yi-Ying Kao, Chieh-Chen Huang, Wen-Hsiung Li
In this study, an astaxanthin-biosynthesis Kluyveromyces marxianus strain Sm23 was first constructed, which could produce 31µg/g DCW astaxanthin. Then, repeated genome integration of the key astaxanthin biosynthesis genes Hpchyb and bkt was done to increase gene copy number and astaxanthin yield. Four improved strains were obtained and the yield of astaxanthin and the total yield of carotenoids in a strain increased with the copy numbers of Hpchyb and bkt. To improve the yield further, the gene Hpchyb from Haematococcus pluvialis was modified by site-directed mutagenesis to increase the enzyme efficiency or/and to prevent the heterologous protein degradation by ubiquitination...
July 23, 2017: Bioresource Technology
https://www.readbyqxmd.com/read/28928732/facile-affinity-maturation-of-antibody-variable-domains-using-natural-diversity-mutagenesis
#3
Kathryn E Tiller, Ratul Chowdhury, Tong Li, Seth D Ludwig, Sabyasachi Sen, Costas D Maranas, Peter M Tessier
The identification of mutations that enhance antibody affinity while maintaining high antibody specificity and stability is a time-consuming and laborious process. Here, we report an efficient methodology for systematically and rapidly enhancing the affinity of antibody variable domains while maximizing specificity and stability using novel synthetic antibody libraries. Our approach first uses computational and experimental alanine scanning mutagenesis to identify sites in the complementarity-determining regions (CDRs) that are permissive to mutagenesis while maintaining antigen binding...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/28928413/allele-age-under-non-classical-assumptions-is-clarified-by-an-exact-computational-markov-chain-approach
#4
Bianca De Sanctis, Ivan Krukov, A P Jason de Koning
Determination of the age of an allele based on its population frequency is a well-studied problem in population genetics, for which a variety of approximations have been proposed. We present a new result that, surprisingly, allows the expectation and variance of allele age to be computed exactly (within machine precision) for any finite absorbing Markov chain model in a matter of seconds. This approach makes none of the classical assumptions (e.g., weak selection, reversibility, infinite sites), exploits modern sparse linear algebra techniques, integrates over all sample paths, and is rapidly computable for Wright-Fisher populations up to N e  = 100,000...
September 19, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28928406/hemoglobin-enhances-mirna-144-expression-and-autophagic-activation-mediated-inflammation-of-microglia-via-mtor-pathway
#5
Zhenyu Wang, Bangqing Yuan, Fenlan Fu, Shaokuan Huang, Zhao Yang
Intracerebral hemorrhage promotes autophagic activation of microglia and enhances neuroinflammation. MiRNAs are key factors to autophagy, contributed to negatively and posttranscriptionally regulate gene expression and function. However, the specific miRNAs involved in the intracerebral hemorrhage mediated microglia autophagic activation are unidentified. In this experiment, microglia was treated with hemoglobin. And then, miRNA-144 expression, autophagic activation and inflammation of microglia were detected...
September 19, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28927152/expression-levels-of-fgfr3-as-a-prognostic-marker-for-the-progression-of-primary-pt1-bladder-cancer-and-its-association-with-mutation-status
#6
Ho Won Kang, Ye-Hwan Kim, Pildu Jeong, Cheol Park, Won Tae Kim, Dong Hee Ryu, Eun-Jong Cha, Yun-Sok Ha, Tae-Hwan Kim, Tae Gyun Kwon, Sung-Kwon Moon, Yung Hyun Choi, Seok-Joong Yun, Wun-Jae Kim
The present study examined the utility of fibroblast growth factor receptor 3 (FGFR3) mutation status and gene expression as a prognostic marker in primary pT1 bladder cancer (BC). A total of 120 patients with primary pT1 BC were enrolled. FGFR3 mutation status was determined by direct sequencing and FGFR3 mRNA expression level was determined by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) analysis. The results were compared with the clinicopathological parameters, and the prognostic value of FGFR3 was evaluated by Kaplan-Meier analysis and a multivariate Cox regression test...
September 2017: Oncology Letters
https://www.readbyqxmd.com/read/28926242/structure-function-studies-of-artemisia-tridentata-farnesyl-diphosphate-synthase-and-chrysanthemyl-diphosphate-synthase-by-site-directed-mutagenesis-and-morphogenesis
#7
J Scott Lee, Jian-Jung Pan, Gurusankar Ramamoorthy, C Dale Poulter
The amino acid sequences of farnesyl diphosphate synthase (FPPase) and chrysanthemyl diphosphate synthase (CPPase) from Artemisia tridentata ssp. Spiciformis, minus their chloroplast targeting regions, are 71% identical and 90% similar. FPPase efficiently and selectively synthesizes the "regular" sesquiterpenoid farnesyl diphosphate (FPP) by coupling isopentenyl diphosphate (IPP) to dimethylallyl diphosphate (DMAPP) and then to geranyl diphosphate (GPP). In contrast, CPPase is an inefficient promiscuous enzyme, which synthesizes the "irregular" monoterpenes chrysanthemyl diphosphate (CPP), lavandulyl diphosphate (LPP), and trace quantities of maconelliyl diphosphate (MPP) from two molecules of DMAPP, in addition to coupling IPP to DMAPP...
September 19, 2017: Journal of the American Chemical Society
https://www.readbyqxmd.com/read/28924049/specific-electrostatic-interactions-between-charged-amino-acid-residues-regulate-binding-of-von-willebrand-factor-to-blood-platelets
#8
Gianluca Interlandi, Olga Yakovenko, An-Yue Tu, Jeff Harris, Jennie Le, Junmei Chen, José A López, Wendy E Thomas
The plasma protein von Willebrand factor (VWF) is essential for hemostasis initiation at sites of vascular injury. The platelet binding A1 domain of VWF is connected to the VWF's N-terminally located D'D3 domain through a relatively unstructured amino acid sequence, called here the N-terminal linker. This region has previously been shown to inhibit the binding of VWF to the platelet surface receptor glycoprotein Ibα (GpIbα). However, the molecular mechanism underlying the inhibitory function of the N-terminal linker has not been elucidated...
September 18, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28923937/direct-engagement-of-the-pi3k-pathway-by-mutant-kit-dominates-oncogenic-signaling-in-gastrointestinal-stromal-tumor
#9
Benedikt Bosbach, Ferdinand Rossi, Yasemin Yozgat, Jennifer Loo, Jennifer Q Zhang, Georgina Berrozpe, Katherine Warpinski, Imke Ehlers, Darren Veach, Andrew Kwok, Katia Manova, Cristina R Antonescu, Ronald P DeMatteo, Peter Besmer
Gastrointestinal stromal tumors (GISTs) predominantly harbor activating mutations in the receptor tyrosine kinase KIT. To genetically dissect in vivo the requirement of different signal transduction pathways emanating from KIT for tumorigenesis, the oncogenic Kit(V558Δ) mutation was combined with point mutations abrogating specific phosphorylation sites on KIT. Compared with single-mutant Kit(V558Δ/+) mice, double-mutant Kit(V558Δ;Y567F/Y567F) knock-in mice lacking the SRC family kinase-binding site on KIT (pY567) exhibited attenuated MAPK signaling and tumor growth...
September 18, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28923508/generation-of-an-infectious-clone-of-amdv-and-identification-of-capsid-residues-essential-for-infectivity-in-cell-culture
#10
Ji Xi, Yanlong Zhang, Jigui Wang, Yongle Yu, Xiaomei Zhang, Zhaoda Li, Shangjin Cui, Weiquan Liu
Pathogenic strains of Aleutian mink disease virus (AMDV) such as Utah-1 do not replicate in cell culture (e.g., Crandell Rees feline kidney cells) while the in vitro-adapted AMDV strain ADV-Gorham (ADV-G) is not pathogenic. Here, we constructed a full-length infectious clone (pADV-G). Alignment of the VP2 gene of ADV-G with that of other AMDV strains revealed many amino acid (a.a.) residues conserved among pathogenic isolates that differed in ADV-G. Four virulence-associated, conserved residues of pADV-G VP2 were studied by site-directed mutagenesis (H92A, Q94S, Y115F, and I116L)...
September 15, 2017: Virus Research
https://www.readbyqxmd.com/read/28920929/structural-investigation-of-nucleophosmin-interaction-with-the-tumor-suppressor-fbw7%C3%AE
#11
A Di Matteo, M Franceschini, A Paiardini, A Grottesi, S Chiarella, S Rocchio, C Di Natale, D Marasco, L Vitagliano, C Travaglini-Allocatelli, L Federici
Nucleophosmin (NPM1) is a multifunctional nucleolar protein implicated in ribogenesis, centrosome duplication, cell cycle control, regulation of DNA repair and apoptotic response to stress stimuli. The majority of these functions are played through the interactions with a variety of protein partners. NPM1 is frequently overexpressed in solid tumors of different histological origin. Furthermore NPM1 is the most frequently mutated protein in acute myeloid leukemia (AML) patients. Mutations map to the C-terminal domain and lead to the aberrant and stable localization of the protein in the cytoplasm of leukemic blasts...
September 18, 2017: Oncogenesis
https://www.readbyqxmd.com/read/28917639/protein-oxidation-involved-in-cys-tyr-post-translational-modification
#12
Susan E Hromada, Adam M Hilbrands, Elysa M Wolf, Jackson L Ross, Taylor R Hegg, Andrew G Roth, Matthew T Hollowell, Carolyn E Anderson, David E Benson
Some post-translationally modified tyrosines can perform reversible redox chemistry similar to metal cofactors. The most studied of these tyrosine modifications is the intramolecular thioether-crosslinked 3'-(S-cysteinyl)-tyrosine (Cys-Tyr) in galactose oxidase. This Cu-mediated tyrosine modification in galactose oxidase involves direct electron transfer (inner-sphere) to the coordinated tyrosine. Mammalian cysteine dioxygenase enzymes also contain a Cys-Tyr that is formed, presumably, through outer-sphere electron transfer from a non-heme iron center ~6Å away from the parent residues...
September 14, 2017: Journal of Inorganic Biochemistry
https://www.readbyqxmd.com/read/28916964/presence-of-a-3fe-4s-cluster-in-a-psac-variant-as-a-functional-component-of-the-photosystem-i-electron-transfer-chain-in-synechococcus-sp-pcc-7002
#13
Adam A Pérez, Bryan H Ferlez, Amanda M Applegate, Karim Walters, Zhihui He, Gaozhong Shen, John H Golbeck, Donald A Bryant
A site-directed C14G mutation was introduced into the stromal PsaC subunit of Synechococcus sp. strain PCC 7002 in vivo in order to introduce an exchangeable coordination site into the terminal FB [4Fe-4S] cluster of Photosystem I (PSI). Using an engineered PSI-less strain (psaAB deletion), psaC was deleted and replaced with recombinant versions controlled by a strong promoter, and the psaAB deletion was complemented. Modified PSI accumulated at lower levels in this strain and supported slower photoautotrophic growth than wild type...
September 15, 2017: Photosynthesis Research
https://www.readbyqxmd.com/read/28916515/reversing-thyroid-hormone-mediated-repression-of-a-hsv-1-promoter-via-computationally-guided-mutagenesis
#14
Robert W Figliozzi, Feng Chen, Shaochung V Hsia
Thyroid hormones (TH or T3) and their DNA binding nuclear receptors (TRs), direct transcriptional regulation in diverse ways depending on the host cell environment and specific promoter characteristics of TH sensitive genes. This study sought to elucidate the impact on transcriptional repression of nucleotide sequence/orientation within TR binding sites, TR elements, (TREs) of TH sensitive promoters, to better understand ligand dependent transcriptional repression of wild-type promoters. Computational analysis of the HSV-1 thymidine kinase (TK) gene TRE bound by TR and RXR revealed a single TRE point mutation sufficient to reverse the TRE orientation...
September 15, 2017: Journal of Cell Science
https://www.readbyqxmd.com/read/28916391/zika-virus-structural-biology-and-progress-in-vaccine-development
#15
REVIEW
Hsiao-Han Lin, Bak-Sau Yip, Li-Min Huang, Suh-Chin Wu
The growing number of zika virus (ZIKV) infections plus a 20-fold increase in neonatal microcephaly in newborns in Brazil have raised alarms in many countries regarding the threat to pregnant women. Instances of microcephaly and central nervous system malformations continue to increase in ZIKV outbreak regions. ZIKV is a small enveloped positive-strand RNA virus belonging to the Flavivirus genus of the Flaviviridae family. High-resolution ZIKV structures recently identified by cryo-electron microscopy indicate that the overall ZIKV structure is similar to those of other flaviviruses...
September 12, 2017: Biotechnology Advances
https://www.readbyqxmd.com/read/28915933/mir-1290-contributes-to-colorectal-cancer-cell-proliferation-by-targeting-inpp4b
#16
Qingzhu Ma, Yan Wang, Hualing Zhang, Fengqiang Wang
Colorectal cancer (CRC) is one of the most common oncological conditions s worldwide, to date, MicroRNA 1290 (miRNA) has been demonstrated to regulate its progression. We studied the role of miR-1290 in CRC progression. The gene was upregulated in CRC tissues and cells, its overexpression promoted CRC cell proliferation analyzed by MTT assay, colony formation assay and soft agar growth assay. IN addition, miR-1290 knockdown inhibited CRC cell proliferation. We also found that miR-1290 overexpression reduced p27 level and increased Cyclin D1 level both in mRNA and protein levels, while miR-1290 knockdown increased p27 and reduced Cyclin D1 (confirming miR-1290 promoted CRC cell proliferation)...
September 15, 2017: Oncology Research
https://www.readbyqxmd.com/read/28915040/elucidating-the-interdependence-of-drug-resistance-from-combinations-of-mutations
#17
Debra A Ragland, Troy W Whitfield, Sook-Kyung Lee, Ronald Swanstrom, Konstantin B Zeldovich, Nese Kurt Yilmaz, Celia A Schiffer
HIV-1 protease is responsible for the cleavage of 12 non-homologous sites within the Gag and Gag-Pro-Pol polyproteins in the viral genome. Under the selective pressure of protease inhibition, the virus evolves mutations within (primary) and outside of (secondary) the active site allowing the protease to process substrates while simultaneously countering inhibition. The primary protease mutations impede inhibitor binding directly, while the secondary mutations are considered accessory mutations that compensate for a loss in fitness...
September 15, 2017: Journal of Chemical Theory and Computation
https://www.readbyqxmd.com/read/28912582/evolution-of-gag-and-gp41-in-patients-receiving-ritonavir-boosted-protease-inhibitors
#18
Justen Manasa, Vici Varghese, Sergei L Kosakovsky Pond, Soo-Yon Rhee, Philip L Tzou, W Jeffrey Fessel, Karen S Jang, Elizabeth White, Thorsteinn Rögnvaldsson, David A Katzenstein, Robert W Shafer
Several groups have proposed that genotypic determinants in gag and the gp41 cytoplasmic domain (gp41-CD) reduce protease inhibitor (PI) susceptibility without PI-resistance mutations in protease. However, no gag and gp41-CD mutations definitively responsible for reduced PI susceptibility have been identified in individuals with virological failure (VF) while receiving a boosted PI (PI/r)-containing regimen. To identify gag and gp41 mutations under selective PI pressure, we sequenced gag and/or gp41 in 61 individuals with VF on a PI/r (n = 40) or NNRTI (n = 20) containing regimen...
September 14, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28912524/precise-insertion-and-guided-editing-of-higher-plant-genomes-using-cpf1-crispr-nucleases
#19
Matthew B Begemann, Benjamin N Gray, Emma January, Gina C Gordon, Yonghua He, Haijun Liu, Xingrong Wu, Thomas P Brutnell, Todd C Mockler, Mohammed Oufattole
Precise genome editing of plants has the potential to reshape global agriculture through the targeted engineering of endogenous pathways or the introduction of new traits. To develop a CRISPR nuclease-based platform that would enable higher efficiencies of precise gene insertion or replacement, we screened the Cpf1 nucleases from Francisella novicida and Lachnospiraceae bacterium ND2006 for their capability to induce targeted gene insertion via homology directed repair. Both nucleases, in the presence of a guide RNA and repairing DNA template flanked by homology DNA fragments to the target site, were demonstrated to generate precise gene insertions as well as indel mutations at the target site in the rice genome...
September 14, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28910194/chikungunya-virus-induced-arthritis-role-of-host-and-viral-factors-in-the-pathogenesis
#20
Sarika Amdekar, Deepti Parashar, Kalichamy Alagarasu
Chikungunya virus (CHIKV), a member of Alphavirus genus, is responsible for chikungunya fever (CHIKF), which is characterized by the presence of fever, rash, myalgia, and arthralgia. Reemergence of CHIKV has become a significant public health concern in Asian and African countries and is newly emerging in the Middle East, Pacific, American, and European countries. Cytokines, innate (monocytes, natural killer cells) and adaptive immune response (role of B cells and T cells i.e. CD4(+) and CD8(+)), and/or viral factors contribute to CHIKV-induced arthritis...
September 14, 2017: Viral Immunology
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