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https://www.readbyqxmd.com/read/27906059/a-mitochondrial-hsp70-hspa9b-is-linked-to-miltefosine-resistance-and-stress-response-in-leishmania-donovani
#1
P Vacchina, B Norris-Mullins, E S Carlson, M A Morales
BACKGROUND: Protozoan parasites of the genus Leishmania are responsible for leishmaniasis, a neglected tropical disease affecting millions worldwide. Visceral leishmaniasis (VL), caused by Leishmania donovani, is the most severe form of leishmaniasis with high rates of mortality if left untreated. Current treatments include pentavalent antimonials and amphotericin B. However, high toxicity and emergence of resistance hinder the success of these options. Miltefosine (HePC) is the first oral treatment available for leishmaniasis...
December 1, 2016: Parasites & Vectors
https://www.readbyqxmd.com/read/27905914/development-of-a-gene-synthesis-platform-for-the-efficient-large-scale-production-of-small-genes-encoding-animal-toxins
#2
Ana Filipa Sequeira, Joana L A Brás, Catarina I P D Guerreiro, Renaud Vincentelli, Carlos M G A Fontes
BACKGROUND: Gene synthesis is becoming an important tool in many fields of recombinant DNA technology, including recombinant protein production. De novo gene synthesis is quickly replacing the classical cloning and mutagenesis procedures and allows generating nucleic acids for which no template is available. In addition, when coupled with efficient gene design algorithms that optimize codon usage, it leads to high levels of recombinant protein expression. RESULTS: Here, we describe the development of an optimized gene synthesis platform that was applied to the large scale production of small genes encoding venom peptides...
December 1, 2016: BMC Biotechnology
https://www.readbyqxmd.com/read/27905529/efficient-targeted-mutagenesis-of-rice-and-tobacco-genomes-using-cpf1-from-francisella-novicida
#3
Akira Endo, Mikami Masafumi, Hidetaka Kaya, Seiichi Toki
CRISPR/Cas9 systems are nowadays applied extensively to effect genome editing in various organisms including plants. CRISPR from Prevotella and Francisella 1 (Cpf1) is a newly characterized RNA-guided endonuclease that has two distinct features as compared to Cas9. First, Cpf1 utilizes a thymidine-rich protospacer adjacent motif (PAM) while Cas9 prefers a guanidine-rich PAM. Cpf1 could be used as a sequence-specific nuclease to target AT-rich regions of a genome that Cas9 had difficulty accessing. Second, Cpf1 generates DNA ends with a 5' overhang, whereas Cas9 creates blunt DNA ends after cleavage...
December 1, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27905490/inter-laboratory-evolution-of-a-model-organism-and-its-epistatic-effects-on-mutagenesis-screens
#4
Michael D Bradley, Devin Neu, Fatmagul Bahar, Roy D Welch
In theory, a few naturally occurring evolutionary changes in the genome of a model organism may have little or no observable impact on its wild type phenotype, and yet still substantially impact the phenotypes of mutant strains through epistasis. To see if this is happening in a model organism, we obtained nine different laboratories' wild type Myxococcus xanthus DK1622 "sublines" and sequenced each to determine if they had evolved after their physical separation. Under a common garden experiment, each subline satisfied the phenotypic prerequisites for wild type, but many differed to a significant degree in each of the four quantitative phenotypic traits we measured, with some sublines differing by several-fold...
December 1, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27904889/reactive-oxygen-species-in-bcr-abl1-expressing-cells-relevance-to-chronic-myeloid-leukemia
#5
Joanna Antoszewska-Smith, Elzbieta Pawlowska, Janusz Blasiak
Chronic myeloid leukemia (CML) results from the t(9;22) reciprocal chromosomal translocation producing the BCR-ABL1 gene, conferring growth and proliferation advantages in the CML cells. CML progresses from chronic, often syndrome-free, to blast phase, fatal if not treated. Although the involvement of BCR-ABL1 in some signaling pathways is considered as the cause of CML, the mechanisms resulting in its progression are not completely known. However, BCR-ABL1 stimulates the production of reactive oxygen species (ROS), which levels increase with CML progression and induce BCR-ABL1 self-mutagenesis...
December 1, 2016: Acta Biochimica Polonica
https://www.readbyqxmd.com/read/27904033/impact-of-slc6a-transporters-in-physiological-taurine-transport-at-the-blood-retinal-barrier-and-in-the-liver
#6
Yoshiyuki Kubo, Shin-Ichi Akanuma, Ken-Ichi Hosoya
Cumulative studies showed that taurine (2-aminoethanesulfonic acid) contributes to a variety of physiological events. Transport study suggested the cellular taurine transport in an Na(+)- and Cl(-)-dependent manner, and the several members of SLC6A family have been shown as taurine transporter. At the inner blood-retinal barrier (BRB), taurine transporter (TauT/SLC6A) is involved in the transport of taurine to the retina from the circulating blood. The involvement of TauT is also suggested in γ-aminobutyric acid (GABA) transport at the inner BRB, and its role is assumed in the elimination of GABA from the retinal interstitial fluid...
2016: Biological & Pharmaceutical Bulletin
https://www.readbyqxmd.com/read/27903904/yeast-dna-polymerase-%C3%AE-maintains-consistent-activity-and-mutagenicity-across-a-wide-range-of-physiological-dntp-concentrations
#7
Olga V Kochenova, Rachel Bezalel-Buch, Phong Tran, Alena V Makarova, Andrei Chabes, Peter M J Burgers, Polina V Shcherbakova
In yeast, dNTP pools expand drastically during DNA damage response. We show that similar dNTP elevation occurs in strains, in which intrinsic replisome defects promote the participation of error-prone DNA polymerase ζ (Polζ) in replication of undamaged DNA. To understand the significance of dNTP pools increase for Polζ function, we studied the activity and fidelity of four-subunit Polζ (Polζ4) and Polζ4-Rev1 (Polζ5) complexes in vitro at 'normal S-phase' and 'damage-response' dNTP concentrations. The presence of Rev1 inhibited the activity of Polζ and greatly increased the rate of all three 'X-dCTP' mispairs, which Polζ4 alone made extremely inefficiently...
November 29, 2016: Nucleic Acids Research
https://www.readbyqxmd.com/read/27903453/repair-of-8-oxo-7-8-dihydroguanine-in-prokaryotic-and-eukaryotic-cells-properties-and-biological-roles-of-the-fpg-and-ogg1-dna-n-glycosylases
#8
Serge Boiteux, Franck Coste, Bertrand Castaing
Oxidatively damaged DNA results from the attack of sugar and base moieties by reactive oxygen species (ROS), which are formed as byproducts of normal cell metabolism and during exposure to endogenous or exogenous chemical or physical agents. Guanine, having the lowest redox potential, is the DNA base the most susceptible to oxidation, yielding products such as 8-oxo-7,8-dihydroguanine (8-oxoG) and 2-6-diamino-4-hydroxy-5-formamidopyrimidine (FapyG). In DNA, 8-oxoG was shown to be mutagenic yielding GC to TA transversions upon incorporation of dAMP opposite this lesion by replicative DNA polymerases...
November 26, 2016: Free Radical Biology & Medicine
https://www.readbyqxmd.com/read/27902415/inversion-of-correia-repeat-enclosed-elements-in-neisseria-gonorrhoeae
#9
Firat Elbeyioglu, Sabrina B Roberts, Russell Spencer-Smith, Madhuri Pulijala, Marta A Zelewska, Jean-Christophe Nebel, Lori As Snyder
Neisseria gonorrhoeae is capable of causing gonorrhoea and more complex diseases in the human host. Within the gonococcal genome are over 100 copies of the IS-like Correia Repeat Enclosed Element, which has been predicted to be mobile within the neisserial genomes. Although there is evidence of ancestral movement of these elements, no previous study has provided evidence for current mobilisation. The Correia Repeat Enclosed Element has the ability to alter gene expression and regulation in many ways: by insertional mutagenesis; by introducing promoter elements; by generating mRNA processing sites, and by association with ncRNAs...
November 16, 2016: Microbiology
https://www.readbyqxmd.com/read/27901124/analysis-of-chikungunya-virus-proteins-reveals-that-non-structural-proteins-nsp2-and-nsp3-exhibit-rna-interference-rnai-suppressor-activity
#10
Kalika Mathur, Abhishek Anand, Sunil Kumar Dubey, Neeti Sanan-Mishra, Raj K Bhatnagar, Sujatha Sunil
RNAi pathway is an antiviral defence mechanism employed by insects that result in degradation of viral RNA thereby curbing infection. Several viruses including flaviviruses encode viral suppressors of RNAi (VSRs) to counteract the antiviral RNAi pathway. Till date, no VSR has been reported in alphaviruses. The present study was undertaken to evaluate chikungunya virus (CHIKV) proteins for RNAi suppressor activity. We systematically analyzed all nine CHIKV proteins for RNAi suppressor activity using Sf21 RNAi sensor cell line based assay...
November 30, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27900567/clinical-potential-of-human-induced-pluripotent-stem-cells-perspectives-of-induced-pluripotent-stem-cells
#11
REVIEW
Dharmendra Kumar, Taruna Anand, Wilfried A Kues
The recent establishment of induced pluripotent stem (iPS) cells promises the development of autologous cell therapies for degenerative diseases, without the ethical concerns associated with human embryonic stem (ES) cells. Initially, iPS cells were generated by retroviral transduction of somatic cells with core reprogramming genes. To avoid potential genotoxic effects associated with retroviral transfection, more recently, alternative non-viral gene transfer approaches were developed. Before a potential clinical application of iPS cell-derived therapies can be planned, it must be ensured that the reprogramming to pluripotency is not associated with genome mutagenesis or epigenetic aberrations...
November 29, 2016: Cell Biology and Toxicology
https://www.readbyqxmd.com/read/27899116/the-correlation-between-antimutagenic-activity-and-total-phenolic-content-of-extracts-of-31-plant-species-with-high-antioxidant-activity
#12
Tshepiso Jan Makhafola, Esameldin Elzein Elgorashi, Lyndy Joy McGaw, Luc Verschaeve, Jacobus Nicolaas Eloff
BACKGROUND: Antimutagenic activity of plant extracts is important in the discovery of new, effective cancer preventing agents. There is increasing evidence that cancer and other mutation-related diseases can be prevented by intake of DNA protective agents. The identification of antimutagenic agents present in plants presents an effective strategy to inhibit pathogenic processes resulting from exposure to mutagenic and/or carcinogenic substances present in the environment. There are no reports on the antimutagenic activities of the plant species investigated in this study...
November 29, 2016: BMC Complementary and Alternative Medicine
https://www.readbyqxmd.com/read/27898710/identification-of-a-novel-inhibitory-allosteric-site-in-p38%C3%AE
#13
Patricia Gomez-Gutierrez, Pedro M Campos, Miguel Vega, Juan J Perez
In the present study, we report the discovery of a novel allosteric inhibitory site for p38α, a subclass of the mitogen-activated protein kinases (MAPK) family. The putative site was discovered after inspection of the crystallographic structure of the p38α-MK2 complex. MK2 (MAPK-activated protein kinase 2) is an interesting protein playing a dual role as modulator and substrate of p38α. This intriguing behavior is due to the ability of the two proteins to form distinctive heterodimers when p38α is phosphorylated or not...
2016: PloS One
https://www.readbyqxmd.com/read/27897366/active-site-crowding-of-p450-3a4-as-a-strategy-to-alter-its-selectivity
#14
Paolo Schiavini, Kin J Cheong, Nicolas Moitessier, Karine Auclair
Substrate promiscuous enzymes are a promising starting point for the development of versatile biocatalysts. In this study, human cytochrome P450 3A4, known for its ability to metabolize hundreds of drugs, was engineered to alter its regio- and stereoselectivity. Rational mutagenesis was used to specifically introduce steric hindrance in the large active site of P450 3A4 and favour oxidation at a more sterically accessible position on the substrate. Hydroxylation of a synthetic precursor of (R)-lisofylline, a compound under investigation for its anti-inflammatory properties, was chosen as a first proof-of-principle application of our protein engineering strategy...
November 29, 2016: Chembiochem: a European Journal of Chemical Biology
https://www.readbyqxmd.com/read/27897348/enzymatic-activity-and-thermodynamic-stability-of-biliverdin-ix%C3%AE-reductase-are-maintained-by-an-active-site-serine
#15
Wen-Ting Chu, Natasha M Nesbitt, Dmitri V Gnatenko, Zongdong Li, Beibei Zhang, Markus A Seeliger, Seamus Browne, Timothy J Mantle, Wadie F Bahou, Jin Wang
Biliverdin reductase IXβ (BLVRB) is a crucial enzyme in heme metabolism. Recent studies in humans have identified a loss-of-function mutation (Ser111Leu) that unmasks a fundamentally important role in hematopoiesis. We have applied experimental and thermodynamic modeling studies to provide further insight into role of the cofactor in substrate accessibility and protein folding properties regulating BLVRB catalytic mechanisms. Site-directed mutagenesis with molecular dynamic (MD) simulations establish the critical role of NAD(P)H-dependent conformational changes on substrate accessibility by forming the "hydrophobic pocket", along with identification of a single key residue (Arg35) modulating NAD(P)H/NADH selectivity...
November 29, 2016: Chemistry: a European Journal
https://www.readbyqxmd.com/read/27896920/fusion-of-ssm6a-with-a-protein-scaffold-retains-selectivity-on-nav-1-7-and-improves-its-therapeutic-potential-against-chronic-pain
#16
Chuan Wang, Bin Shan, Qiong Wang, Qunyuan Xu, Hailin Zhang, Huimeng Lei
Voltage gated sodium channel NaV 1.7 serves an attractive target for chronic pain treatment. Several venom peptides were found to selectively inhibit NaV 1.7 but with intrinsic problems. Among them, Ssm6a, a recently discovered centipede venom peptide, shows the greatest selectivity against NaV 1.7, but dissociates from the target too fast and loses bioactivity in synthetic forms. As a disulfide-rich venom peptide, it is difficult to optimize Ssm6a by artificial mutagenesis and produce the peptide with common industrial manufacturing methods...
November 29, 2016: Chemical Biology & Drug Design
https://www.readbyqxmd.com/read/27896869/identifying-the-location-of-epidermal-growth-factor-responsive-element-involved-in-the-regulation-of-type-iib-sodium-phosphate-cotransporter-expression-in-porcine-intestinal-epithelial-cells
#17
T Xing, X Tan, Q Yu, T Yang, R Fang
Phosphate is an important mineral nutrient for both human and animals in growth and physiological functions; thus, much effort in the past has been made to clarify the mechanisms governing its absorption. Previous studies have found that epidermal growth factor (EGF) inhibits phosphate absorption in human intestinal cells via modulating the interaction of transcriptional factor c-myb with sodium-phosphate cotransporter (NaPi-IIb) gene promoter. This finding provoked our interest in determining the effect of EGF on NaPi-IIb gene expression in intestinal cells of pigs and the location of EGF-responsive element in the gene promoter...
November 29, 2016: Journal of Animal Physiology and Animal Nutrition
https://www.readbyqxmd.com/read/27895632/predicting-resistance-by-mutagenesis-lessons-from-45-years-of-mbc-resistance
#18
Nichola J Hawkins, Bart A Fraaije
When a new fungicide class is introduced, it is useful to anticipate the resistance risk in advance, attempting to predict both risk level and potential mechanisms. One tool for the prediction of resistance risk is laboratory selection for resistance, with the mutational supply increased through UV or chemical mutagenesis. This enables resistance to emerge more rapidly than in the field, but may produce mutations that would not emerge under field conditions. The methyl benzimidazole carbamates (MBCs) were the first systemic single-site agricultural fungicides, and the first fungicides affected by rapid evolution of target-site resistance...
2016: Frontiers in Microbiology
https://www.readbyqxmd.com/read/27895582/introduction-of-an-n-glycosylation-site-into-udp-glucuronosyltransferase-2b3-alters-its-sensitivity-to-cytochrome-p450-3a1-dependent-modulation
#19
Tatsuro Nakamura, Naho Yamaguchi, Yuu Miyauchi, Tomoki Takeda, Yasushi Yamazoe, Kiyoshi Nagata, Peter I Mackenzie, Hideyuki Yamada, Yuji Ishii
Our previous studies have demonstrated functional protein-protein interactions between cytochrome P450 (CYP) 3A and UDP-glucuronosyltransferase (UGT). However, the role of carbohydrate chains of UGTs in the interaction with CYP is not well understood. To address this issue, we examined whether CYP3A1 modulates the function of UGT2B3 which lacks potential glycosylation sites. We also examined whether the introduction of N-glycosylation to UGT2B3 affects CYP3A-dependent modulation of UGT function. To introduce a potential glycosylation site into UGT2B3, Ser 316 of UGT2B3 was substituted with Asn by site-directed mutagenesis...
2016: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/27895128/characterization-of-the-pathogenicity-of-streptococcus-intermedius-tyg1620-isolated-from-a-human-brain-abscess-based-on-the-complete-genome-sequence-with-transcriptome-analysis-and-transposon-mutagenesis-in-a-murine-subcutaneous-abscess-model
#20
Noriko Hasegawa, Tsuyoshi Sekizuka, Yutaka Sugi, Nobuhiro Kawakami, Yumiko Ogasawara, Kengo Kato, Akifumi Yamashita, Fumihiko Takeuchi, Makoto Kuroda
Streptococcus intermedius is known to cause periodontitis and pyogenic infections in the brain and liver. Here we report the complete genome sequence of strain TYG1620 (genome size: 2,006,877 bp; GC content: 37.6%; 2,020 predicted ORFs) isolated from a brain abscess in an infant. Comparative genome analysis of S. intermedius genome sequences suggested that TYG1620 carries a notable type VII secretion system (T7SS), two long-repeat regions and 19 ORFs for cell-wall-anchored proteins (CWAPs). To elucidate genes responsible for the pathogenicity of TYG1620, transcriptome analysis was performed in a murine subcutaneous abscess model...
November 28, 2016: Infection and Immunity
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