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https://www.readbyqxmd.com/read/28655184/characterization-of-a-coupled-dna-replication-and-translesion-synthesis-polymerase-supraholoenzyme-from-archaea
#1
Matthew T Cranford, Aurea M Chu, Joshua K Baguley, Robert J Bauer, Michael A Trakselis
The ability of the replisome to seamlessly coordinate both high fidelity and translesion DNA synthesis requires a means to regulate recruitment and binding of enzymes from solution. Co-occupancy of multiple DNA polymerases within the replisome has been observed primarily in bacteria and is regulated by posttranslational modifications in eukaryotes, and both cases are coordinated by the processivity clamp. Because of the heterotrimeric nature of the PCNA clamp in some archaea, there is potential to occupy and regulate specific polymerases at defined subunits...
June 26, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/28654954/bioequivalence-between-generic-and-branded-lamotrigine-in-people-with-epilepsy-the-equigen-randomized-clinical-trial
#2
Michel Berg, Timothy E Welty, Barry E Gidal, Francisco J Diaz, Ron Krebill, Jerzy P Szaflarski, Barbara A Dworetzky, John R Pollard, Edmund J Elder, Wenlei Jiang, Xiaohui Jiang, Regina D Switzer, Michael D Privitera
Importance: Switching between generic antiepileptic drugs is a highly debated issue that affects both clinical care and overall health care costs. Objective: To evaluate the single-dose pharmacokinetic bioequivalence of 3 (1 branded and 2 generic drugs) on-market, immediate-release lamotrigine drug products. Design, Setting, and Participants: The Equivalence Among Antiepileptic Drug Generic and Brand Products in People With Epilepsy (EQUIGEN) single-dose study is a crossover, prospective, sequence-randomized, replicate pharmacokinetic study conducted at 5 US academic epilepsy centers...
June 26, 2017: JAMA Neurology
https://www.readbyqxmd.com/read/28654860/transcriptome-wide-pirna-profiling-in-human-brains-of-alzheimer-s-disease
#3
Wenying Qiu, Xiaoyun Guo, Xiandong Lin, Qian Yang, Wanying Zhang, Yong Zhang, Lingjun Zuo, Yong Zhu, Chiang-Shan R Li, Chao Ma, Xingguang Luo
Discovered in the brains of multiple animal species, piRNAs may contribute to the pathogenesis of neuropsychiatric illnesses. The present study aimed to identify brain piRNAs across transcriptome that are associated with Alzheimer's disease (AD). Prefrontal cortical tissues of 6 AD cases and 6 controls were examined for piRNA expression levels using an Arraystar HG19 piRNA array (containing 23,677 piRNAs) and genotyped for 17 genome-wide significant and replicated risk SNPs. We examined whether piRNAs are expressed differently between AD cases and controls and explored the potential regulatory effects of risk SNPs on piRNA expression levels...
June 3, 2017: Neurobiology of Aging
https://www.readbyqxmd.com/read/28654813/conformational-flexibility-and-base-pairing-tendency-of-the-tobacco-carcinogen-o6-4-oxo-4-3-pyridyl-butyl-guanine
#4
Katie A Wilson, Kariann G Szemethy, Stacey D Wetmore
The present work uses DFT calculations to characterize the conformational and hydrogen-bonding properties of O6-[4-oxo-4-(3-pyridyl)butyl]guanine (POB-G), a DNA adduct caused by tobacco. POB-G is found to adopt many isoenergetic conformations that allow for discrete interactions between the bulky moiety and the adducted G and/or pairing base. The calculated structure and stability of the hydrogen-bonded pairs between the Watson-Crick or Hoogsteen face of POB-G and the canonical DNA nucleobases fully rationalize the previously reported mutational spectra...
June 10, 2017: Biophysical Chemistry
https://www.readbyqxmd.com/read/28654687/combined-single-cell-quantitation-of-host-and-siv-genes-and-proteins-ex-vivo-reveals-host-pathogen-interactions-in-individual-cells
#5
Diane L Bolton, Kathleen McGinnis, Greg Finak, Pratip Chattopadhyay, Raphael Gottardo, Mario Roederer
CD4 T cells harboring HIV-1/SIV represent a formidable hurdle to eradicating infection, and yet their detailed phenotype remains unknown. Here we integrate two single-cell technologies, flow cytometry and highly multiplexed quantitative RT-PCR, to characterize SIV-infected CD4 T cells directly ex vivo. Within individual cells, we correlate the cellular phenotype, in terms of host protein and RNA expression, with stages of the viral life cycle defined by combinatorial expression of viral RNAs. Spliced RNA+ infected cells display multiple memory and activation phenotypes, indicating virus production by diverse CD4 T cell subsets...
June 27, 2017: PLoS Pathogens
https://www.readbyqxmd.com/read/28654678/genetic-factors-affecting-ebv-copy-number-in-lymphoblastoid-cell-lines-derived-from-the-1000-genome-project-samples
#6
Rajendra Mandage, Marco Telford, Juan Antonio Rodríguez, Xavier Farré, Hafid Layouni, Urko M Marigorta, Caitlin Cundiff, Jose Maria Heredia-Genestar, Arcadi Navarro, Gabriel Santpere
Epstein-Barr virus (EBV), human herpes virus 4, has been classically associated with infectious mononucleosis, multiple sclerosis and several types of cancers. Many of these diseases show marked geographical differences in prevalence, which points to underlying genetic and/or environmental factors. Those factors may include a different susceptibility to EBV infection and viral copy number among human populations. Since EBV is commonly used to transform B-cells into lymphoblastoid cell lines (LCLs) we hypothesize that differences in EBV copy number among individual LCLs may reflect differential susceptibility to EBV infection...
2017: PloS One
https://www.readbyqxmd.com/read/28654659/environmental-change-drives-accelerated-adaptation-through-stimulated-copy-number-variation
#7
Ryan M Hull, Cristina Cruz, Carmen V Jack, Jonathan Houseley
Copy number variation (CNV) is rife in eukaryotic genomes and has been implicated in many human disorders, particularly cancer, in which CNV promotes both tumorigenesis and chemotherapy resistance. CNVs are considered random mutations but often arise through replication defects; transcription can interfere with replication fork progression and stability, leading to increased mutation rates at highly transcribed loci. Here we investigate whether inducible promoters can stimulate CNV to yield reproducible, environment-specific genetic changes...
June 2017: PLoS Biology
https://www.readbyqxmd.com/read/28654654/identification-and-characterization-of-acka-dependent-protein-acetylation-in-neisseria-gonorrhoeae
#8
Deborah M B Post, Birgit Schilling, Lorri M Reinders, Alexandria K D'Souza, Margaret R Ketterer, Steven J Kiel, Aroon T Chande, Michael A Apicella, Bradford W Gibson
Neisseria gonorrhoeae, the causative agent of gonorrhea, has a number of factors known to contribute to pathogenesis; however, a full understanding of these processes and their regulation has proven to be elusive. Post-translational modifications (PTMs) of bacterial proteins are now recognized as one mechanism of protein regulation. In the present study, Western blot analyses, with an anti-acetyl-lysine antibody, indicated that a large number of gonococcal proteins are post-translationally modified. Previous work has shown that Nε-lysine acetylation can occur non-enzymatically with acetyl-phosphate (AcP) as the acetyl donor...
2017: PloS One
https://www.readbyqxmd.com/read/28654291/photocatalytic-e%C3%A2-z-isomerization-of-polarized-alkenes-inspired-by-the-visual-cycle-mechanistic-dichotomy-and-origin-of-selectivity
#9
Jan B Metternich, Denis Gennadievich Artiukhin, Mareike C Holland, Maximilian von Bremen-Kühne, Johannes Neugebauer, Ryan Gilmour
Iteratively executed with exquisite spatial and temporal control, the selective isomerization of polarized alkenes underpins a plethora of complex biological processes ranging from natural product biosynthesis through to the mammalian visual cycle. However, Nature's proficiency conceals the inherent difficulties in replicating this contra-thermodynamic transformation in the laboratory. Recently, we disclosed the first highly Z-selective isomerization of polarized alkenes, employing the cinnamoyl chromophore as a retinal surrogate under UV-irradiation (402 nm) with (-)-riboflavin (vitamin B2) as an inexpensive, organic photocatalyst (J...
June 27, 2017: Journal of Organic Chemistry
https://www.readbyqxmd.com/read/28654224/comparing-inference-approaches-for-rd-designs-a-reexamination-of-the-effect-of-head-start-on-child-mortality
#10
Matias D Cattaneo, Rocio Titiunik, Gonzalo Vasquez-Bare
The regression discontinuity (RD) design is a popular quasi-experimental design for causal inference and policy evaluation. The most common inference approaches in RD designs employ “flexible” parametric and nonparametric local polynomial methods, which rely on extrapolation and large-sample approximations of conditional expectations using observations somewhat near the cutoff that determines treatment assignment. An alternative inference approach employs the idea of local randomization, where the very few units closest to the cutoff are regarded as randomly assigned to treatment and finite-sample exact inference methods are used...
2017: Journal of Policy Analysis and Management
https://www.readbyqxmd.com/read/28654200/preparation-and-evaluation-of-potent-pentafluorosulfanyl-substituted-anti-tuberculosis-compounds
#11
Garrett C Moraski, Ryan Bristol, Natalie Seeger, Helena I Boshoff, Patricia Siu-Yee Tsang, Marvin J Miller
The global fight to stop tuberculosis (TB) remains a great challenge, particularly with the increase in drug-resistant strains and a lack of funding to support the development of new treatments. To bolster a precarious drug pipeline, we prepared a focused panel of eight pentafluorosulfanyl (SF5 ) compounds which were screened for their activity against Mycobacterium tuberculosis (Mtb) H37Rv in three different assay conditions and media. All eight compounds had sub-micromolar potency, and four displayed MICs <100 nm...
June 27, 2017: ChemMedChem
https://www.readbyqxmd.com/read/28654076/a-method-to-test-the-efficacy-of-handwashing-for-the-removal-of-emerging-infectious-pathogens
#12
Marlene K Wolfe, Daniele S Lantagne
Handwashing is widely recommended to prevent infectious disease transmission. However, little comparable evidence exists on the efficacy of handwashing methods in general. Additionally, little evidence exists comparing handwashing methods to determine which are most efficacious at removing infectious pathogens. Research is needed to provide evidence for the different approaches to handwashing that may be employed during infectious disease outbreaks. Here, a laboratory method to assess the efficacy of handwashing methods at removing microorganisms from hands and their persistence in rinse water is described...
June 7, 2017: Journal of Visualized Experiments: JoVE
https://www.readbyqxmd.com/read/28654051/experimental-protocol-of-a-three-minute-all-out-arm-crank-exercise-test-in-spinal-cord-injured-and-able-bodied-individuals
#13
Joelle L Flueck
Reliable exercise protocols are required to test changes in exercise performance in elite athletes. Performance improvements in these athletes may be small; therefore, sensitive tools are fundamental to exercise physiology. There are currently many exercise tests that allow for the examination of exercise capacity in able-bodied athletes, with protocols mainly for lower-body or whole-body exercise. There is a trend to test athletes in a sport-specific setting that closely resembles the actions that the participants are used to performing...
June 8, 2017: Journal of Visualized Experiments: JoVE
https://www.readbyqxmd.com/read/28654045/rescue-and-characterization-of-recombinant-virus-from-a-new-world-zika-virus-infectious-clone
#14
James Weger-Lucarelli, Nisha K Duggal, Aaron C Brault, Brian J Geiss, Gregory D Ebel
Infectious cDNA clones allow for genetic manipulation of a virus, thus facilitating work on vaccines, pathogenesis, replication, transmission and viral evolution. Here we describe the construction of an infectious clone for Zika virus (ZIKV), which is currently causing an explosive outbreak in the Americas. To prevent toxicity to bacteria that is commonly observed with flavivirus-derived plasmids, we generated a two-plasmid system which separates the genome at the NS1 gene and is more stable than full-length constructs that could not be successfully recovered without mutations...
June 7, 2017: Journal of Visualized Experiments: JoVE
https://www.readbyqxmd.com/read/28653981/the-role-of-replication-associated-repair-factors-on-r-loops
#15
REVIEW
Vaibhav Bhatia, Emilia Herrera-Moyano, Andrés Aguilera, Belén Gómez-González
The nascent RNA can reinvade the DNA double helix to form a structure termed the R-loop, where a single-stranded DNA (ssDNA) is accompanied by a DNA-RNA hybrid. Unresolved R-loops can impede transcription and replication processes and lead to genomic instability by a mechanism still not fully understood. In this sense, a connection between R-loops and certain chromatin markers has been reported that might play a key role in R-loop homeostasis and genome instability. To counteract the potential harmful effect of R-loops, different conserved messenger ribonucleoprotein (mRNP) biogenesis and nuclear export factors prevent R-loop formation, while ubiquitously-expressed specific ribonucleases and DNA-RNA helicases resolve DNA-RNA hybrids...
June 27, 2017: Genes
https://www.readbyqxmd.com/read/28653972/active-hcv-replication-but-not-hcv-or-cmv-seropositive-status-is-associated-with-incident-and-prevalent-type-2-diabetes-in-persons-living-with-hiv
#16
Andrea De Luca, Patrizia Lorenzini, Antonella Castagna, Massimo Puoti, Nicola Gianotti, Francesco Castelli, Claudio Mastroianni, Franco Maggiolo, Andrea Antinori, Giovanni Guaraldi, Miriam Lichtner, Antonella dʼArminio Monforte
OBJECTIVE: To analyze the association between chronic hepatitis C virus (HCV) and cytomegalovirus (CMV) infections with type 2 diabetes in HIV-infected patients. METHODS: HIV-1-infected patients enrolled in ICONA, a prospective cohort study involving 42 tertiary care centers in Italy, were selected with the following characteristics: for the diabetes incidence analysis, all patients with available CMV IgG results (first available test = baseline) and without type 2 diabetes were followed until onset of type 2 diabetes, last available clinical follow-up, death or September 30, 2014, whichever occurred first; for the prevalence analysis, all ICONA patients were analyzed at their last follow-up visit...
August 1, 2017: Journal of Acquired Immune Deficiency Syndromes: JAIDS
https://www.readbyqxmd.com/read/28653741/gas-exchanges-and-water-use-efficiency-in-the-selection-of-tomato-genotypes-tolerant-to-water-stress
#17
M E A Borba, G M Maciel, E F Fraga Júnior, C S Machado Júnior, G R Marquez, I G Silva, R S Almeida
Water stress can affect the yield in tomato crops and, despite this, there are few types of research aiming to select tomato genotypes resistant to the water stress using physiological parameters. This experiment aimed to study the variables that are related to the gas exchanges and the efficiency in water use, in the selection of tomato genotypes tolerant to water stress. It was done in a greenhouse, measuring 7 x 21 m, in a randomized complete block design, with four replications (blocks), being five genotypes in the F2BC1 generation, which were previously obtained from an interspecific cross between Solanum pennellii versus S...
June 20, 2017: Genetics and Molecular Research: GMR
https://www.readbyqxmd.com/read/28653737/a-validated-algorithm-for-selecting-non-toxic-chemical-concentrations
#18
Julita Stadnicka-Michalak, Melanie Knöbel, Anže Županič, Kristin Schirmer
The maximal chemical concentration that causes an acceptably small or no effect in an organism or isolated cells is an often-sought-after value in toxicology. Existing approaches to derive this value have raised several concerns; thus, it is often chosen case-by-case based on personal experience. To overcome this ambiguity, we propose an approach for choosing the non-toxic concentration (NtC) of a chemical in a rational, tractable way. We developed an algorithm that identifies the highest chemical concentration which causes no more than 10% effect (=EC10) including the modeled 95% confidence intervals and considering each of the measured biological replicates; and whose toxicity is not significantly different from no effect...
June 26, 2017: ALTEX
https://www.readbyqxmd.com/read/28653661/the-structural-and-functional-characterization-of-human-recq4-reveals-insights-into-its-helicase-mechanism
#19
Sebastian Kaiser, Florian Sauer, Caroline Kisker
RecQ4 is a member of the RecQ helicase family, an evolutionarily conserved class of enzymes, dedicated to preserving genomic integrity by operating in telomere maintenance, DNA repair and replication. While reduced RecQ4 activity is associated with cancer predisposition and premature aging, RecQ4 upregulation is related to carcinogenesis and metastasis. Within the RecQ family, RecQ4 assumes an exceptional position, lacking several characteristic RecQ domains. Here we present the crystal structure of human RecQ4, encompassing the conserved ATPase core and a novel C-terminal domain that lacks resemblance to the RQC domain observed in other RecQ helicases...
June 27, 2017: Nature Communications
https://www.readbyqxmd.com/read/28653660/phosphate-steering-by-flap-endonuclease-1-promotes-5-flap-specificity-and-incision-to-prevent-genome-instability
#20
Susan E Tsutakawa, Mark J Thompson, Andrew S Arvai, Alexander J Neil, Steven J Shaw, Sana I Algasaier, Jane C Kim, L David Finger, Emma Jardine, Victoria J B Gotham, Altaf H Sarker, Mai Z Her, Fahad Rashid, Samir M Hamdan, Sergei M Mirkin, Jane A Grasby, John A Tainer
DNA replication and repair enzyme Flap Endonuclease 1 (FEN1) is vital for genome integrity, and FEN1 mutations arise in multiple cancers. FEN1 precisely cleaves single-stranded (ss) 5'-flaps one nucleotide into duplex (ds) DNA. Yet, how FEN1 selects for but does not incise the ss 5'-flap was enigmatic. Here we combine crystallographic, biochemical and genetic analyses to show that two dsDNA binding sites set the 5'polarity and to reveal unexpected control of the DNA phosphodiester backbone by electrostatic interactions...
June 27, 2017: Nature Communications
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