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Dna-encoded library

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https://www.readbyqxmd.com/read/28813418/mechanism-of-intracellular-allosteric-%C3%AE-2ar-antagonist-revealed-by-x-ray-crystal-structure
#1
Xiangyu Liu, Seungkirl Ahn, Alem W Kahsai, Kai-Cheng Meng, Naomi R Latorraca, Biswaranjan Pani, A J Venkatakrishnan, Ali Masoudi, William I Weis, Ron O Dror, Xin Chen, Robert J Lefkowitz, Brian K Kobilka
G-protein-coupled receptors (GPCRs) pose challenges for drug discovery efforts because of the high degree of structural homology in the orthosteric pocket, particularly for GPCRs within a single subfamily, such as the nine adrenergic receptors. Allosteric ligands may bind to less-conserved regions of these receptors and therefore are more likely to be selective. Unlike orthosteric ligands, which tonically activate or inhibit signalling, allosteric ligands modulate physiologic responses to hormones and neurotransmitters, and may therefore have fewer adverse effects...
August 16, 2017: Nature
https://www.readbyqxmd.com/read/28810737/identification-of-the-colicin-v-bacteriocin-gene-cluster-by-functional-screening-of-a-human-microbiome-metagenomic-library
#2
Louis Cohen, Sun Han, Yun-Han Huang, Sean F Brady
The forces that shape human microbial ecology are complex. It is likely, that human microbiota, similarly to other microbiomes, use antibiotics as one way to establish an ecological niche. In this study, we use functional metagenomics to identify human microbial gene clusters that encode for antibiotic functions. Screening of a metagenomic library prepared from a healthy patient stool sample led to the identification of a family of clones with inserts that are 99% identical to a region of a virulence plasmid found in avian pathogenic Escherichia coli...
August 15, 2017: ACS Infectious Diseases
https://www.readbyqxmd.com/read/28767678/pharmacoperone-rescue-of-vasopressin-2-receptor-mutants-reveals-unexpected-constitutive-activity-and-coupling-bias
#3
Jo Ann Janovick, Timothy P Spicer, Thomas D Bannister, Louis Scampavia, P Michael Conn
Pharmacoperones are small molecules that diffuse into cells and rescue misfolded, mistrafficked protein mutants, restoring their function. These substances act with high target specificity, serving as templates to fold (or refold) receptors, enzymes, ion channels or other proteins and enable them to pass the scrutiny of the cellular quality control system ("rescue"). In the present study we demonstrate that a rescued mutant (L83Q) of the vasopressin type 2 receptor (V2R), shows a strong bias for Gs coupling unlike the WT V2 receptor, which couples to both Gs and Gq/11...
2017: PloS One
https://www.readbyqxmd.com/read/28757348/draft-genome-sequence-of-an-aminoglycoside-resistant-rmtd-2-producing-enterobacter-cloacae-subsp-cloacae-st-395-in-brazil
#4
Evelin Rodrigues Martins, Maria Fernanda Campagnari Bueno, Gabriela Rodrigues Francisco, Fernanda Modesto Tolentino, Louise Cerdeira, Tiago Casella, Monalisa Nogueira Costa, Carla Cevada, Nilton Lincopan, Doroti de Oliveira Garcia, Mara Corrêa Lelles Nogueira
OBJECTIVES: Enterobacter cloacae has recently emerged as an important agent of nosocomial infections, due to the diffusion of extended spectrum β-lactamases and carbapenemases in this species. In this context, a raise in the use of aminoglycosides for therapy was noticed, being followed by the accelerated development of resistance mechanisms. In this study, we report the draft genome sequence of a multidrug-resistant Enterobacter cloacae subsp. cloacae strain (Ec2), isolated from active surveillance culture of a patient with Chagas disease...
July 27, 2017: Journal of Global Antimicrobial Resistance
https://www.readbyqxmd.com/read/28747151/comparative-analysis-of-targeted-long-read-sequencing-approaches-for-characterization-of-a-plant-s-immune-receptor-repertoire
#5
Michael Giolai, Pirita Paajanen, Walter Verweij, Kamil Witek, Jonathan D G Jones, Matthew D Clark
BACKGROUND: The Oxford Nanopore Technologies MinION™ sequencer is a small, portable, low cost device that is accessible to labs of all sizes and attractive for in-the-field sequencing experiments. Selective breeding of crops has led to a reduction in genetic diversity, and wild relatives are a key source of new genetic resistance to pathogens, usually via NLR immune receptor-encoding genes. Recent studies have demonstrated how crop NLR repertoires can be targeted for sequencing on Illumina or PacBio (RenSeq) and the specific gene conveying pathogen resistance identified...
July 26, 2017: BMC Genomics
https://www.readbyqxmd.com/read/28742329/selecting-a-dna-encoded-chemical-library-against-non-immobilized-proteins-using-a-ligate-cross-link-purify-strategy
#6
Bingbing Shi, Yuqing Deng, Peng Zhao, Xiaoyu Li
DNA-encoded chemical libraries (DELs) have recently emerged and become an important technology platform in biomedical research and drug discovery. DELs containing large numbers of compounds can be prepared and selected against biological targets to discover novel ligands and inhibitors. In practice, DELs are usually selected against purified and immobilized proteins using the typical "bind-wash-elute" protocol; however, selection methods compatible with non-immobilized proteins would be able to greatly expand the target scope of DELs beyond purified proteins to more-complex and biologically relevant targets...
August 10, 2017: Bioconjugate Chemistry
https://www.readbyqxmd.com/read/28732479/an-integrated-computational-experimental-approach-reveals-yersinia-pestis-genes-essential-across-a-narrow-or-a-broad-range-of-environmental-conditions
#7
Nicola J Senior, Kalesh Sasidharan, Richard J Saint, Andrew E Scott, Mitali Sarkar-Tyson, Philip M Ireland, Helen L Bullifent, Z Rong Yang, Karen Moore, Petra C F Oyston, Timothy P Atkins, Helen S Atkins, Orkun S Soyer, Richard W Titball
BACKGROUND: The World Health Organization has categorized plague as a re-emerging disease and the potential for Yersinia pestis to also be used as a bioweapon makes the identification of new drug targets against this pathogen a priority. Environmental temperature is a key signal which regulates virulence of the bacterium. The bacterium normally grows outside the human host at 28 °C. Therefore, understanding the mechanisms that the bacterium used to adapt to a mammalian host at 37 °C is central to the development of vaccines or drugs for the prevention or treatment of human disease...
July 21, 2017: BMC Microbiology
https://www.readbyqxmd.com/read/28729862/rad51-interacts-with-non-structural-3-protein-of-hepatitis-c-virus-and-regulates-viral-production
#8
Kidong Son, Tram T T Nguyen, Jae-Woong Choi, Long V Pham, Trang T D Luong, Yun-Sook Lim, Soon B Hwang
Hepatitis C virus (HCV) is a leading cause of chronic liver disease affecting over 170 million people worldwide. Chronic infection with HCV progresses to liver fibrosis, cirrhosis, and hepatocellular carcinoma. HCV exploits host cellular factors for viral propagation. To investigate the cellular factors required for HCV propagation, we screened a siRNA library targeting human cell cycle genes using cell culture grown HCV-infected cells. In the present study, we selected and characterized a gene encoding Rad51...
2017: Frontiers in Microbiology
https://www.readbyqxmd.com/read/28719188/phage-selection-of-cyclic-peptides-for-application-in-research-and-drug-development
#9
Kaycie Deyle, Xu-Dong Kong, Christian Heinis
Cyclic peptides can bind to protein targets with high affinities and selectivities, which makes them an attractive modality for the development of research reagents and therapeutics. Additional properties, including low inherent toxicity, efficient chemical synthesis, and facile modification with labels or immobilization reagents, increase their attractiveness. Cyclic peptide ligands against a wide range of protein targets have been isolated from natural sources such as bacteria, fungi, plants, and animals...
July 18, 2017: Accounts of Chemical Research
https://www.readbyqxmd.com/read/28715190/chemical-topic-modeling-exploring-molecular-data-sets-using-a-common-text-mining-approach
#10
Nadine Schneider, Nikolas Fechner, Gregory A Landrum, Nikolaus Stiefl
Big data is one of the key transformative factors which increasingly influences all aspects of modern life. Although this transformation brings vast opportunities it also generates novel challenges, not the least of which is organizing and searching this data deluge. The field of medicinal chemistry is not different: more and more data are being generated, for instance, by technologies such as DNA encoded libraries, peptide libraries, text mining of large literature corpora, and new in silico enumeration methods...
August 9, 2017: Journal of Chemical Information and Modeling
https://www.readbyqxmd.com/read/28714473/prioritizing-multiple-therapeutic-targets-in-parallel-using-automated-dna-encoded-library-screening
#11
Carl A Machutta, Christopher S Kollmann, Kenneth E Lind, Xiaopeng Bai, Pan F Chan, Jianzhong Huang, Lluis Ballell, Svetlana Belyanskaya, Gurdyal S Besra, David Barros-Aguirre, Robert H Bates, Paolo A Centrella, Sandy S Chang, Jing Chai, Anthony E Choudhry, Aaron Coffin, Christopher P Davie, Hongfeng Deng, Jianghe Deng, Yun Ding, Jason W Dodson, David T Fosbenner, Enoch N Gao, Taylor L Graham, Todd L Graybill, Karen Ingraham, Walter P Johnson, Bryan W King, Christopher R Kwiatkowski, Joël Lelièvre, Yue Li, Xiaorong Liu, Quinn Lu, Ruth Lehr, Alfonso Mendoza-Losana, John Martin, Lynn McCloskey, Patti McCormick, Heather P O'Keefe, Thomas O'Keeffe, Christina Pao, Christopher B Phelps, Hongwei Qi, Keith Rafferty, Genaro S Scavello, Matt S Steiginga, Flora S Sundersingh, Sharon M Sweitzer, Lawrence M Szewczuk, Amy Taylor, May Fern Toh, Juan Wang, Minghui Wang, Devan J Wilkins, Bing Xia, Gang Yao, Jean Zhang, Jingye Zhou, Christine P Donahue, Jeffrey A Messer, David Holmes, Christopher C Arico-Muendel, Andrew J Pope, Jeffrey W Gross, Ghotas Evindar
The identification and prioritization of chemically tractable therapeutic targets is a significant challenge in the discovery of new medicines. We have developed a novel method that rapidly screens multiple proteins in parallel using DNA-encoded library technology (ELT). Initial efforts were focused on the efficient discovery of antibacterial leads against 119 targets from Acinetobacter baumannii and Staphylococcus aureus. The success of this effort led to the hypothesis that the relative number of ELT binders alone could be used to assess the ligandability of large sets of proteins...
July 17, 2017: Nature Communications
https://www.readbyqxmd.com/read/28689404/discovery-of-a-covalent-kinase-inhibitor-from-a-dna-encoded-small-molecule-library-%C3%A3-protein-library-selection
#12
Alix I Chan, Lynn M McGregor, Tara Jain, David R Liu
We previously reported interaction determination using unpurified proteins (IDUP), a method to selectively amplify DNA sequences encoding ligand:target pairs from a mixture of DNA-linked small molecules and unpurified protein targets in cell lysates. In this study, we applied IDUP to libraries of DNA-encoded bioactive compounds and DNA-tagged human kinases to identify ligand:protein binding partners out of 32 096 possible combinations in a single solution-phase library × library experiment. The results recapitulated known small molecule:protein interactions and also revealed that ethacrynic acid is a novel ligand and inhibitor of MAP2K6 kinase...
July 20, 2017: Journal of the American Chemical Society
https://www.readbyqxmd.com/read/28682059/poisson-statistics-of-combinatorial-library-sampling-predict-false-discovery-rates-of-screening
#13
Andrew B MacConnell, Brian M Paegel
Microfluidic droplet-based screening of DNA-encoded one-bead-one-compound combinatorial libraries is a miniaturized, potentially widely distributable approach to small molecule discovery. In these screens, a microfluidic circuit distributes library beads into droplets of activity assay reagent, photochemically cleaves the compound from the bead, then incubates and sorts the droplets based on assay result for subsequent DNA sequencing-based hit compound structure elucidation. Pilot experimental studies revealed that Poisson statistics describe nearly all aspects of such screens, prompting the development of simulations to understand system behavior...
August 14, 2017: ACS Combinatorial Science
https://www.readbyqxmd.com/read/28677085/role-of-saccharomyces-cerevisiae-tan1-trna-acetyltransferase-in-eukaryotic-initiation-factor-2b-eif2b-mediated-translation-control-and-stress-response
#14
Sonum Sharma, Anuradha Sourirajan, Kamal Dev
Eukaryotic initiation factor 2B (eIF2B) controls the first step of translation by catalyzing guanine nucleotide exchange on eukaryotic initiation factor 2 (eIF2). Mutations in the genes encoding eIF2B subunits inhibit the nucleotide exchange and eventually slow down the process of translation, causing vanishing white matter disease. We constructed a Saccharomyces cerevisiae genomic DNA library in YEp24 vector and screened it for the identification of extragenic suppressors of eIF2B mutations, corresponding to human eIF2B mutations...
July 2017: 3 Biotech
https://www.readbyqxmd.com/read/28674833/cloning-purification-and-characterization-of-tripeptidyl-peptidase-from-streptomyces-herbaricolor-ty-21
#15
Keisuke Ekino, Shinichi Yonei, Hiroshi Oyama, Takuji Oka, Yoshiyuki Nomura, Takashi Shin
Tripeptidyl peptidase (TPP) is an exopeptidase that sequentially hydrolyzes tripeptides from the N-terminus of oligopeptides or polypeptides. We performed screening for isolating novel TPP-producing microorganisms from soil samples. TPP activity was observed in the culture supernatant of Streptomyces herbaricolor TY-21 by using Ala-Ala-Phe-p-nitroanilide (pNA) as the substrate. TPP from the culture supernatant was purified to approximately 790-fold. It was shown to cleave oxidized insulin B-chain, thereby with releasing tripeptide units, but not the N-terminal-protected peptide, Cbz-Ala-Ala-Phe-pNA...
July 3, 2017: Applied Biochemistry and Biotechnology
https://www.readbyqxmd.com/read/28674000/genome-wide-screen-for-genes-involved-in-edna-release-during-biofilm-formation-by-staphylococcus-aureus
#16
Alicia S DeFrancesco, Nadezda Masloboeva, Adnan K Syed, Aaron DeLoughery, Niels Bradshaw, Gene-Wei Li, Michael S Gilmore, Suzanne Walker, Richard Losick
Staphylococcus aureus is a leading cause of both nosocomial and community-acquired infection. Biofilm formation at the site of infection reduces antimicrobial susceptibility and can lead to chronic infection. During biofilm formation, a subset of cells liberate cytoplasmic proteins and DNA, which are repurposed to form the extracellular matrix that binds the remaining cells together in large clusters. Using a strain that forms robust biofilms in vitro during growth under glucose supplementation, we carried out a genome-wide screen for genes involved in the release of extracellular DNA (eDNA)...
July 18, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28607440/an-arabidopsis-mutant-with-high-operating-efficiency-of-photosystem-ii-and-low-chlorophyll-fluorescence
#17
Niels van Tol, Martijn Rolloos, Dieuwertje Augustijn, A Alia, Huub J de Groot, Paul J J Hooykaas, Bert J van der Zaal
The overall light energy to biomass conversion efficiency of plant photosynthesis is generally regarded as low. Forward genetic screens in Arabidopsis have yielded very few mutants with substantially enhanced photochemistry. Here, we report the isolation of a novel Arabidopsis mutant with a high operating efficiency of Photosystem II (φPSII) and low chlorophyll fluorescence from a library of lines harboring T-DNA constructs encoding artificial transcription factors. This mutant was named Low Chlorophyll Fluorescence 1 (LCF1)...
June 12, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28600885/immunolocalization-of-tar-dna-binding-protein-of-43%C3%A2-kda-tdp-43-in-mouse-seminiferous-epithelium
#18
Hari Prasad Osuru, Patcharin Pramoonjago, Mayuresh M Abhyankar, Eric Swanson, LaToya Ann Roker, Helen Cathro, Prabhakara P Reddi
TAR DNA-binding protein of 43 kDa (TDP-43) is an evolutionarily conserved, ubiquitously expressed, multi-functional DNA/RNA-binding protein with roles in gene transcription, mRNA splicing, stability, transport, micro RNA biogenesis, and suppression of transposons. Aberrant expression of TDP-43 in testis and sperm was recently shown to be associated with male infertility, which highlights the need to understand better the expression of TDP-43 in the testis. We previously cloned TDP-43 from a mouse testis cDNA library, and showed that it functions as a transcriptional repressor and regulates the precise spatiotemporal expression of the Acrv1 gene, which encodes the acrosomal protein SP-10, during spermatogenesis...
June 10, 2017: Molecular Reproduction and Development
https://www.readbyqxmd.com/read/28597662/chitosan-hyaluronic-acid-nanoparticles-rational-design-revisited-for-rna-delivery
#19
Enrique Lallana, Julio M Rios de la Rosa, Annalisa Tirella, Maria Pelliccia, Arianna Gennari, Ian J Stratford, Sanyogitta Puri, Marianne Ashford, Nicola Tirelli
Chitosan/hyaluronic acid (HA) nanoparticles can be used to deliver an RNA/DNA cargo to cells overexpressing HA receptors such as CD44. For these systems, unequivocal links have not been established yet between chitosan macromolecular (molecular weight; degree of deacetylation, i.e., charge density) and nanoparticle variables (complexation strength, i.e., stability; nucleic acid protection; internalization rate) on one hand, and transfection efficiency on the other hand. Here, we have focused on the role of avidity on transfection efficiency in the CD44-expressing HCT-116 as a cellular model; we have employed two differently sized payloads (a large luciferase-encoding mRNA and a much smaller anti-Luc siRNA), and a small library of chitosans (variable molecular weight and degree of deactylation)...
June 19, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/28596758/a-functional-metagenomic-analysis-of-tetracycline-resistance-in-cheese-bacteria
#20
Ana B Flórez, Lucía Vázquez, Baltasar Mayo
Metagenomic techniques have been successfully used to monitor antibiotic resistance genes in environmental, animal and human ecosystems. However, despite the claim that the food chain plays a key role in the spread of antibiotic resistance, metagenomic analysis has scarcely been used to investigate food systems. The present work reports a functional metagenomic analysis of the prevalence and evolution of tetracycline resistance determinants in a raw-milk, blue-veined cheese during manufacturing and ripening...
2017: Frontiers in Microbiology
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