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Library Discovery

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https://www.readbyqxmd.com/read/28446608/model-enabled-gene-search-megs-allows-fast-and-direct-discovery-of-enzymatic-and-transport-gene-functions-in-the-marine-bacterium-vibrio-fischeri
#1
Shu Pan, Kiel Nikolakakis, Paul A Adamczyk, Min Pan, Edward G Ruby, Jennifer L Reed
While genomes can be rapidly sequenced, the functions of many genes are incompletely or erroneously annotated because of a lack of experimental evidence or prior functional knowledge in sequence databases. To address this weakness, we describe here a model-enabled gene search (MEGS) approach that (i) identifies metabolic functions either missing from an organism's genome annotation or incorrectly assigned to an ORF, by using discrepancies between metabolic model predictions and experimental culturing data; (ii) designs functional selection experiments for these specific metabolic functions; and (iii) selects a candidate gene(s) responsible for these functions from a genomic library and directly interrogates this gene's function experimentally...
April 26, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28446605/crispr-cas9-mediated-gene-knockout-screens-and-target-identification-via-whole-genome-sequencing-uncover-host-genes-required-for-picornavirus-infection
#2
Heon Seok Kim, Kyungjin Lee, Sangsu Bae, Jeongbin Park, Chong-Kyo Lee, Meehyein Kim, Eunji Kim, Minju Kim, Seokjoong Kim, Chonsaeng Kim, Jin-Soo Kim
Several groups have used genome-wide libraries of lentiviruses encoding small-guide RNAs (sgRNAs) for genetic screens. In most cases, sgRNA expression cassettes are integrated into cells by using lentiviruses, and target genes are statistically estimated by the readout of sgRNA sequences after targeted sequencing. We present a new virus-free method for human gene-knockout screens using a genome-wide library of CRISPR/Cas9 sgRNAs based on plasmids, and target gene identification via whole-genome sequencing (WGS) confirming authentic mutations rather than statistical estimating through targeted amplicon sequencing...
April 26, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28446504/feasibility-of-ultra-high-throughput-functional-screening-of-melanoma-biopsies-for-discovery-of-novel-cancer-drug-combinations
#3
Adam A Friedman, Yun Xia, Lorenzo Trippa, Long P Le, Vivien Igras, Dennie T Frederick, Jennifer A Wargo, Kenneth K Tanabe, Donald P Lawrence, Donna S Neuberg, Keith T Flaherty, David Fisher
Purpose: Successful development of targeted therapy combinations for cancer patients depends on first discovering such combinations in predictive preclinical models. Stable cell lines and mouse xenograft models can have genetic and phenotypic drift and may take too long to generate to be useful as a personalized medicine tool. <p>Experimental Design: To overcome these limitations, we have used a platform of ultra-high-throughput functional screening of primary biopsies preserving both cancer and stroma cell populations from melanoma patients to nominate such novel combinations from a library of  thousands of drug combinations in a patient-specific manner within days of biopsy...
April 26, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28445411/discovery-of-farnesoid-x-receptor-antagonists-based-on-a-library-of-oleanolic-acid-3-o-esters-through-diverse-substituent-design-and-molecular-docking-methods
#4
Shao-Rong Wang, Tingting Xu, Kai Deng, Chi-Wai Wong, Jinsong Liu, Wei-Shuo Fang
The pentacyclic triterpene oleanolic acid (OA, 1) with known farnesoid X receptor (FXR) modulatory activity was modified at its C-3 position to find new FXR-interacting agents. A diverse substitution library of OA derivatives was constructed in silico through a 2D fingerprint similarity cluster strategy. With further docking analysis, four top-scored OA 3-O-ester derivatives were selected for synthesis. The bioassay results indicated that all four compounds 3 inhibited chenodeoxycholic acid (CDCA)-induced FXR transactivation in a concentration-dependent mode...
April 26, 2017: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/28445046/lead-discovery-of-dual-g-quadruplex-stabilizers-and-poly-adp-ribose-polymerases-parps-inhibitors-a-new-avenue-in-anticancer-treatment
#5
Erica Salvati, Lorenzo Botta, Jussara Amato, Francesco Saverio Di Leva, Pasquale Zizza, Antimo Gioiello, Bruno Pagano, Grazia Graziani, Madalena Tarsounas, Antonio Randazzo, Ettore Novellino, Annamaria Biroccio, Sandro Cosconati
G-quadruplex stabilizers are an established opportunity in anticancer chemotherapy. To circumvent the antiproliferative effects of G4 ligands, cancer cells recruit PARP enzymes at telomeres. Herein, starting from the structural similarity of a potent G4 ligand previously discovered by our group and a congeneric PARP inhibitor, a library of derivatives was synthesized to discover the first dual G4/PARP ligand. We demonstrate that a properly decorated thieno[3,2-c]quinolin-4(5H)-one stabilizes the G4 fold in vitro and in cells, induces a DNA damage response localized to telomeres, inhibits PARylation in cells and has an antiproliferative effect in BRCA2 deficient tumor cells...
April 26, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28443514/compound-libraries-recent-advances-and-their-applications-in-drug-discovery
#6
Zhen Gong, Guoping Hu, Qiang Li, Zhiguo Liu, Fei Wang, Xuejin Zhang, Jian Xiong, Peng Li, Yan Xu, Rujian Ma, Shuhui Chen, Jian Li
Hit identification is the starting point of small-molecule drug discovery and is therefore very important to the pharmaceutical industry. One of the most important approaches to identify a new hit is to screen a compound library using an in vitro assay. High-throughput screening has made great contributions to drug discovery since the 1990s but requires expensive equipment and facilities, and its success depends on the size of the compound library. Recent progress in the development of compound libraries has provided more efficient ways to identify new hits for novel drug targets, thereby helping to promote the development of the pharmaceutical industry, especially for first-in-class drugs...
April 25, 2017: Current Drug Discovery Technologies
https://www.readbyqxmd.com/read/28443097/large-diversity-of-functional-nanobodies-from-a-camelid-immune-library-revealed-by-an-alternative-analysis-of-next-generation-sequencing-data
#7
Pieter Deschaght, Ana Paula Vintém, Marc Logghe, Miguel Conde, David Felix, Rob Mensink, Juliana Gonçalves, Jorn Audiens, Yanik Bruynooghe, Rita Figueiredo, Diana Ramos, Robbe Tanghe, Daniela Teixeira, Liesbeth Van de Ven, Catelijne Stortelers, Bruno Dombrecht
Next-generation sequencing (NGS) has been applied successfully to the field of therapeutic antibody discovery, often outperforming conventional screening campaigns which tend to identify only the more abundant selective antibody sequences. We used NGS to mine the functional nanobody repertoire from a phage-displayed camelid immune library directed to the recepteur d'origine nantais (RON) receptor kinase. Challenges to this application of NGS include accurate removal of read errors, correct identification of related sequences, and establishing meaningful inclusion criteria for sequences-of-interest...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/28442630/discovering-relationships-between-nuclear-receptor-signaling-pathways-genes-and-tissues-in-transcriptomine
#8
Lauren B Becnel, Scott A Ochsner, Yolanda F Darlington, Apollo McOwiti, Wasula H Kankanamge, Michael Dehart, Alexey Naumov, Neil J McKenna
We previously developed a web tool, Transcriptomine, to explore expression profiling data sets involving small-molecule or genetic manipulations of nuclear receptor signaling pathways. We describe advances in biocuration, query interface design, and data visualization that enhance the discovery of uncharacterized biology in these pathways using this tool. Transcriptomine currently contains about 45 million data points encompassing more than 2000 experiments in a reference library of nearly 550 data sets retrieved from public archives and systematically curated...
April 25, 2017: Science Signaling
https://www.readbyqxmd.com/read/28442262/an-integrated-chemical-biology-approach-reveals-the-mechanism-of-action-of-hiv-replication-inhibitors
#9
Nicholas Pagano, Peter Teriete, Margrith E Mattmann, Li Yang, Beth A Snyder, Zhaohui Cai, Marintha L Heil, Nicholas D P Cosford
Continuous flow (microfluidic) chemistry was employed to prepare a small focused library of dihydropyrimidinone (DHPM) derivatives. Compounds in this class have been reported to exhibit activity against the human immunodeficiency virus (HIV), but their molecular target had not been identified. We tested the initial set of DHPMs in phenotypic assays providing a hit (1i) that inhibited the replication of the human immunodeficiency virus HIV in cells. Flow chemistry-driven optimization of 1i led to the identification of HIV replication inhibitors such as 1l with cellular potency comparable with the clinical drug nevirapine (NVP)...
April 8, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28439825/small-rna-profiling-by-next-generation-sequencing-using-high-definition-adapters
#10
Martina Billmeier, Ping Xu
Small RNAs (sRNAs) as key regulators of gene expression play fundamental roles in many biological processes. Next-generation sequencing (NGS) has become an important tool for sRNA discovery and profiling. However, NGS data often show bias for or against certain sequences which is mainly caused by adapter oligonucleotides that are ligated to sRNAs more or less efficiently by RNA ligases. In order to reduce ligation bias, High-definition (HD) adapters for the Illumina sequencing platform were developed. However, a large amount of direct 5' and 3' adapter ligation products are often produced when the current commercially available kits are used for cloning with HD adapters...
2017: Methods in Molecular Biology
https://www.readbyqxmd.com/read/28439545/accelerated-discovery-of-new-magnets-in-the-heusler-alloy-family
#11
Stefano Sanvito, Corey Oses, Junkai Xue, Anurag Tiwari, Mario Zic, Thomas Archer, Pelin Tozman, Munuswamy Venkatesan, Michael Coey, Stefano Curtarolo
Magnetic materials underpin modern technologies, ranging from data storage to energy conversion to contactless sensing. However, the development of a new high-performance magnet is a long and often unpredictable process, and only about two dozen magnets are featured in mainstream applications. We describe a systematic pathway to the design of novel magnetic materials, which demonstrates a high throughput and discovery speed. On the basis of an extensive electronic structure library of Heusler alloys containing 236,115 prototypical compounds, we filtered those displaying magnetic order and established whether they can be fabricated at thermodynamic equilibrium...
April 2017: Science Advances
https://www.readbyqxmd.com/read/28439316/epigenetic-assays-for-chemical-biology-and-drug-discovery
#12
REVIEW
Sheraz Gul
The implication of epigenetic abnormalities in many diseases and the approval of a number of compounds that modulate specific epigenetic targets in a therapeutically relevant manner in cancer specifically confirms that some of these targets are druggable by small molecules. Furthermore, a number of compounds are currently in clinical trials for other diseases including cardiovascular, neurological and metabolic disorders. Despite these advances, the approved treatments for cancer only extend progression-free survival for a relatively short time and being associated with significant side effects...
2017: Clinical Epigenetics
https://www.readbyqxmd.com/read/28438136/normalized-long-read-rna-sequencing-in-chicken-reveals-transcriptome-complexity-similar-to-human
#13
Richard I Kuo, Elizabeth Tseng, Lel Eory, Ian R Paton, Alan L Archibald, David W Burt
BACKGROUND: Despite the significance of chicken as a model organism, our understanding of the chicken transcriptome is limited compared to human. This issue is common to all non-human vertebrate annotations due to the difficulty in transcript identification from short read RNAseq data. While previous studies have used single molecule long read sequencing for transcript discovery, they did not perform RNA normalization and 5'-cap selection which may have resulted in lower transcriptome coverage and truncated transcript sequences...
April 24, 2017: BMC Genomics
https://www.readbyqxmd.com/read/28437733/the-establishment-of-in%C3%A2-vitro-culture-and-drug-screening-systems-for-a-newly-isolated-strain-of-trypanosoma-equiperdum
#14
Keisuke Suganuma, Shino Yamasaki, Nthatisi Innocentia Molefe, Peter Simon Musinguzi, Batdorj Davaasuren, Ehab Mossaad, Sandagdorj Narantsatsral, Banzragch Battur, Badgar Battsetseg, Noboru Inoue
Dourine is caused by Trypanosoma equiperdum via coitus with an infected horse. Although dourine is distributed in Equidae worldwide and is listed as an internationally important animal disease by the World Organization for Animal Health (OIE), no effective treatment strategies have been established. In addition, there are no reports on drug discovery, because no drug screening system exists for this parasite. A new T. equiperdum strain was recently isolated from the genital organ of a stallion that showed typical symptoms of dourine...
April 13, 2017: International Journal for Parasitology, Drugs and Drug Resistance
https://www.readbyqxmd.com/read/28436590/identification-of-small-molecules-using-accurate-mass-ms-ms-search
#15
REVIEW
Tobias Kind, Hiroshi Tsugawa, Tomas Cajka, Yan Ma, Zijuan Lai, Sajjan S Mehta, Gert Wohlgemuth, Dinesh Kumar Barupal, Megan R Showalter, Masanori Arita, Oliver Fiehn
Tandem mass spectral library search (MS/MS) is the fastest way to correctly annotate MS/MS spectra from screening small molecules in fields such as environmental analysis, drug screening, lipid analysis, and metabolomics. The confidence in MS/MS-based annotation of chemical structures is impacted by instrumental settings and requirements, data acquisition modes including data-dependent and data-independent methods, library scoring algorithms, as well as post-curation steps. We critically discuss parameters that influence search results, such as mass accuracy, precursor ion isolation width, intensity thresholds, centroiding algorithms, and acquisition speed...
April 24, 2017: Mass Spectrometry Reviews
https://www.readbyqxmd.com/read/28435886/discovery-of-a-novel-antifungal-agent-in-the-pathogen-box
#16
François L Mayer, James W Kronstad
Human fungal pathogens cause over 2 million infections per year and are major drivers of morbidity and mortality. Cryptococcus neoformans and Candida albicans are two of the most common fungal pathogens of humans, together accounting for a staggering 1.4 million infections annually, with very high mortality rates. Patients with dysfunctional immune systems, such as individuals with HIV/AIDS, are particularly susceptible to fungal infections. Unfortunately, relatively few antifungal drugs are currently available and fungi frequently develop resistance, further complicating treatment approaches...
March 2017: MSphere
https://www.readbyqxmd.com/read/28435537/integrated-platform-for-expedited-synthesis-purification-testing-of-small-molecule-libraries
#17
Aleksandra Baranczak, Noah P Tu, Jasmina Marjanovic, Philip A Searle, Anil Vasudevan, Stevan W Djuric
The productivity of medicinal chemistry programs can be significantly increased through the introduction of automation, leading to shortened discovery cycle times. Herein, we describe a platform that consolidates synthesis, purification, quantitation, dissolution, and testing of small molecule libraries. The system was validated through the synthesis and testing of two libraries of binders of polycomb protein EED, and excellent correlation of obtained data with results generated through conventional approaches was observed...
April 13, 2017: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28435528/discovery-of-highly-selective-inhibitors-of-the-immunoproteasome-low-molecular-mass-polypeptide-2-lmp2-subunit
#18
Henry W B Johnson, Janet L Anderl, Erin K Bradley, John Bui, Jeffrey Jones, Shirin Arastu-Kapur, Lisa M Kelly, Eric Lowe, David C Moebius, Tony Muchamuel, Christopher Kirk, Zhengping Wang, Dustin McMinn
Building upon the success of bortezomib (VELCADE) and carfilzomib (KYPROLIS), the design of a next generation of inhibitors targeting specific subunits within the immunoproteasome is of interest for the treatment of autoimmune disease. There are three catalytic subunits within the immunoproteasome (low molecular mass polypeptide-7, -2, and multicatalytic endopeptidase complex subunit-1; LMP7, LMP2, and MECL-1), and a campaign was undertaken to design a potent and selective LMP2 inhibitor with sufficient properties to allow for sustained inhibition in vivo...
April 13, 2017: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28433433/design-selection-and-development-of-cyclic-peptide-ligands-for-human-erythropoietin
#19
William S Kish, Hiroyuki Sachi, Amith D Naik, Matthew K Roach, Benjamin G Bobay, Robert K Blackburn, Stefano Menegatti, Ruben G Carbonell
This work presents the selection and characterization of erythropoietin (EPO)-binding cyclic peptide ligands. The sequences were selected by screening a focused library of cyclic depsipeptides cyclo[(Nα-Ac)Dap(A)-X1-X6-AE], whose structure and amino acid compositions were tailored to mimic the EPO receptor. The sequences identified through library screening were synthesized on chromatographic resin and characterized via binding-and-elution studies against EPO to select a pool of candidate ligands. Sequences with higher hydrophobicity consistently showed stronger binding to EPO, with the exception of FSLLSH, which was noted for its lower hydrophobicity and high EPO binding...
April 12, 2017: Journal of Chromatography. A
https://www.readbyqxmd.com/read/28432195/n-terminal-proteomics-assisted-profiling-of-the-unexplored-translation-initiation-landscape-in-arabidopsis-thaliana
#20
Patrick Willems, Elvis Ndah, Veronique Jonckheere, Simon Stael, Adriaan Sticker, Lennart Martens, Frank Van Breusegem, Kris Gevaert, Petra Van Damme
Proteogenomics is an emerging research field yet lacking a uniform method of analysis. Proteogenomic studies in which N-terminal proteomics and ribosome profiling are combined, suggest that a high number of protein start sites are currently missing in genome annotations. We constructed a proteogenomic pipeline specific for the analysis of N-terminal proteomics data, with the aim of discovering novel translational start sites outside annotated protein coding regions. In summary, unidentified MS/MS spectra were matched to a specific N-terminal peptide library encompassing protein N-termini encoded in the Arabidopsis thaliana genome...
April 21, 2017: Molecular & Cellular Proteomics: MCP
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