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High-throughput screening

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https://www.readbyqxmd.com/read/28346890/high-throughput-system-wide-engineering-and-screening-for-microbial-biotechnology
#1
REVIEW
Yannick Vervoort, Alicia Gutiérrez Linares, Miguel Roncoroni, Chengxun Liu, Jan Steensels, Kevin J Verstrepen
Genetic engineering and screening of large number of cells or populations is a crucial bottleneck in today's systems biology and applied (micro)biology. Instead of using standard methods in bottles, flasks or 96-well plates, scientists are increasingly relying on high-throughput strategies that miniaturize their experiments to the nanoliter and picoliter scale and the single-cell level. In this review, we summarize different high-throughput system-wide genome engineering and screening strategies for microbes...
March 24, 2017: Current Opinion in Biotechnology
https://www.readbyqxmd.com/read/28346741/small-molecules-targeting-human-n-acetylmannosamine-kinase
#2
Stephan Hinderlich, Martin Neuenschwander, Paul-Robin Wratil, Andreas Oder, Michael Lisurek, Long D Nguyen, Jens Peter von Kries, Christian Hackenberger
N-Acetylmannosamine kinase (MNK) plays a key role in the biosynthesis of sialic acids and glycosylation of proteins. Sialylated glycoconjugates affect a large number of biological processes, including immune modulation and cancer transformation. For the search of effective inhibitors of MNK we applied high-throughput screening of drug-like small molecules. Applying different orthogonal assays for their validation we identified four potential MNK-specific inhibitors with IC50 values in the low micromolar range...
March 27, 2017: Chembiochem: a European Journal of Chemical Biology
https://www.readbyqxmd.com/read/28346404/chemical-screening-identifies-atm-as-a-target-for-alleviating-senescence
#3
Hyun Tae Kang, Joon Tae Park, Kobong Choi, Yongsub Kim, Hyo Jei Claudia Choi, Chul Won Jung, Young-Sam Lee, Sang Chul Park
Senescence, defined as irreversible cell-cycle arrest, is the main driving force of aging and age-related diseases. Here, we performed high-throughput screening to identify compounds that alleviate senescence and identified the ataxia telangiectasia mutated (ATM) inhibitor KU-60019 as an effective agent. To elucidate the mechanism underlying ATM's role in senescence, we performed a yeast two-hybrid screen and found that ATM interacted with the vacuolar ATPase V1 subunits ATP6V1E1 and ATP6V1G1. Specifically, ATM decreased E-G dimerization through direct phosphorylation of ATP6V1G1...
March 27, 2017: Nature Chemical Biology
https://www.readbyqxmd.com/read/28346107/a-high-throughput-method-for-measuring-drug-residence-time-using-the-transcreener-adp-assay
#4
Meera Kumar, Robert G Lowery
Analysis of drug-target residence times during drug development can result in improved efficacy, increased therapeutic window, and reduced side effects. Residence time can be estimated as the reciprocal of the dissociation rate ( koff) of an inhibitor from its target. The traditional methods for measuring koff require synthesis of labeled ligands or low-throughput label-free methods. To provide an alternative that is better suited to an automated high-throughput screening (HTS) environment, we adapted a classic "jump dilution" catalytic assay method for determination of koff values for kinase inhibitor drugs...
February 1, 2017: SLAS Discov
https://www.readbyqxmd.com/read/28346103/discovery-of-novel-gq-biased-lpa1-negative-allosteric-modulators
#5
Yuji Shimizu, Masaharu Nakayama
Lysophosphatidic acid (LPA) activates the G-protein-coupled receptor LPA1, which regulates various cellular processes, including cell proliferation and migration. Although LPA1 transduces cellular responses via Gq, Gi, and G12/13, associations between these signaling molecules and cellular phenotypes remain poorly characterized due to the lack of signal-specific pharmacological tools. Here, we characterized novel signal-biased modulators using multiple assays, including label-free impedance assays. LPA caused dramatic changes in cellular impedance in LPA1-expressing recombinant cells, which were susceptible to G-protein and protein kinase inhibitors...
February 1, 2017: SLAS Discov
https://www.readbyqxmd.com/read/28346100/robotic-mammosphere-assay-for-high-throughput-screening-in-triple-negative-breast-cancer
#6
P A Fitzpatrick, N Akrap, E M V Söderberg, H Harrison, G J Thomson, G Landberg
In order to identify novel treatment principles specifically affecting cancer stem cells in triple-negative breast cancer, we have developed a high-throughput screening method based on the mammosphere and anoikis resistance assays allowing us to screen compounds using a functional readout. The assay was validated against manual protocols and through the use of positive controls, such as the response to hypoxia and treatment with the known cancer stem cell-targeting compound salinomycin. Manual and robotic procedures were compared and produced similar results in cell handling, cell cultures, and counting techniques, with no statistically significant difference produced from either method...
February 1, 2017: SLAS Discov
https://www.readbyqxmd.com/read/28346099/development-of-novel-cell-lines-for-high-throughput-screening-to-detect-estrogen-related-receptor-alpha-modulators
#7
Christina T Teng, Jui-Hua Hsieh, Jinghua Zhao, Ruili Huang, Menghang Xia, Negin Martin, Xiaohua Gao, Darlene Dixon, Scott S Auerbach, Kristine L Witt, B Alex Merrick
Estrogen-related receptor alpha (ERRα), the first orphan nuclear receptor discovered, is crucial for the control of cellular energy metabolism. ERRα and its coactivator, peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), are required for rapid energy production in response to environmental challenges. They have been implicated in the etiology of metabolic disorders such as type 2 diabetes and metabolic syndrome. ERRα also plays a role in the pathogenesis of breast cancer. Identification of compounds that modulate ERRα signaling may elucidate environmental factors associated with these diseases...
January 1, 2017: SLAS Discov
https://www.readbyqxmd.com/read/28346096/a-novel-multiparametric-drug-scoring-method-for-high-throughput-screening-of-3d-multicellular-tumor-spheroids-using-the-celigo-image-cytometer
#8
Scott Cribbes, Sarah Kessel, Scott McMenemy, Jean Qiu, Leo Li-Ying Chan
Three-dimensional (3D) tumor models have been increasingly used to investigate and characterize cancer drug compounds. The ability to perform high-throughput screening of 3D multicellular tumor spheroids (MCTS) can highly improve the efficiency and cost-effectiveness of discovering potential cancer drug candidates. Previously, the Celigo Image Cytometer has demonstrated a novel method for high-throughput screening of 3D multicellular tumor spheroids. In this work, we employed the Celigo Image Cytometer to examine the effects of 14 cancer drug compounds on 3D MCTS of the glioblastoma cell line U87MG in 384-well plates...
January 1, 2017: SLAS Discov
https://www.readbyqxmd.com/read/28346095/identification-by-high-throughput-screening-of-pseudomonas-acyl-coenzyme-a-synthetase-inhibitors
#9
Lorenzo Turcano, Daniela Visaggio, Emanuela Frangipani, Antonino Missineo, Matteo Andreini, Sergio Altamura, Paolo Visca, Alberto Bresciani
Pseudomonas infections are common among hospitalized, immunocompromised, and chronic lung disease patients. These infections are recalcitrant to common antibacterial therapies due to inherent antibiotic resistance. To meet the need of new anti- Pseudomonas drugs, a sensitive, homogenous, and robust assay was developed with the aim of identifying inhibitors of acyl-coenzyme A synthetases (ACSs) from Pseudomonas. Given the importance of fatty acids for in vivo nutrition of Pseudomonas, such inhibitors might have the potential to reduce the bacterial fitness during infection...
January 1, 2017: SLAS Discov
https://www.readbyqxmd.com/read/28346094/drug-library-screening-for-the-identification-of-ionophores-that-correct-the-mistrafficking-disorder-associated-with-oxalosis-kidney-disease
#10
Shurong Hou, Franck Madoux, Louis Scampavia, Jo Ann Janovick, P Michael Conn, Timothy P Spicer
Primary hyperoxaluria is the underlying cause of oxalosis and is a life-threatening autosomal recessive disease, for which treatment may require dialysis or dual liver-kidney transplantation. The most common primary hyperoxaluria type 1 (PH1) is caused by genetic mutations of a liver-specific enzyme alanine:glyoxylate aminotransferase (AGT), which results in the misrouting of AGT from the peroxisomes to the mitochondria. Pharmacoperones are small molecules with the ability to modify misfolded proteins and route them correctly within the cells, which may present an effective strategy to treat AGT misrouting in PH1 disorders...
January 1, 2017: SLAS Discov
https://www.readbyqxmd.com/read/28346093/a-label-free-continuous-fluorescence-based-assay-for-monitoring-ornithine-decarboxylase-activity-with-a-synthetic-putrescine-receptor
#11
Mohamed Nilam, Philip Gribbon, Jeanette Reinshagen, Kathrin Cordts, Edzard Schwedhelm, Werner M Nau, Andreas Hennig
Polyamines play an important role in cell growth, differentiation, and cancer development, and the biosynthetic pathway of polyamines is established as a drug target for the treatment of parasitic diseases, neoplasia, and cancer chemoprevention. The key enzyme in polyamine biosynthesis is ornithine decarboxylase (ODC). We report herein an analytical method for the continuous fluorescence monitoring of ODC activity based on the supramolecular receptor cucurbit[6]uril (CB6) and the fluorescent dye trans-4-[4-(dimethylamino)styryl]-1-methylpyridinium iodide (DSMI)...
January 1, 2017: SLAS Discov
https://www.readbyqxmd.com/read/28346092/screening-for-protein-protein-interaction-inhibitors-using-a-bioluminescence-resonance-energy-transfer-bret-based-assay-in-yeast
#12
Caroline Corbel, Sara Sartini, Elisabetta Levati, Pierre Colas, Laurent Maillet, Cyril Couturier, Barbara Montanini, Stéphane Bach
The bioluminescence resonance energy transfer (BRET) technology is a widely used live cell-based method for monitoring protein-protein interactions as well as conformational changes within proteins or molecular complexes. Considering the emergence of protein-protein interactions as a new promising class of therapeutic targets, we have adapted the BRET method in budding yeast. In this technical note, we describe the advantages of using this simple eukaryotic model rather than mammalian cells to perform high-throughput screening of chemical compound collections: genetic tractability, tolerance to solvent, rapidity, and no need of expensive robotic systems...
January 1, 2017: SLAS Discov
https://www.readbyqxmd.com/read/28346091/a-high-throughput-screening-model-of-the-tumor-microenvironment-for-ovarian-cancer-cell-growth
#13
Madhu Lal-Nag, Lauren McGee, Rajarshi Guha, Ernst Lengyel, Hilary A Kenny, Marc Ferrer
The tumor microenvironment plays an important role in the processes of tumor growth, metastasis, and drug resistance. We have used a multilayered 3D primary cell culture model that reproduces the human ovarian cancer metastatic microenvironment to study the effect of the microenvironment on the pharmacological responses of different classes of drugs on cancer cell proliferation. A collection of oncology drugs was screened to identify compounds that inhibited the proliferation of ovarian cancer cells growing as monolayers or forming spheroids, on plastic and on a 3D microenvironment culture model of the omentum metastatic site, and also cells already in preformed spheroids...
January 1, 2017: SLAS Discov
https://www.readbyqxmd.com/read/28346089/a-chemogenomic-screening-platform-used-to-identify-chemotypes-perturbing-hsp90-pathways
#14
Fiona M Thomas, Kourtney M Goode, Bartek Rajwa, Andrew B Bieberich, Larisa V Avramova, Tony R Hazbun, V Jo Davisson
Compounds that modulate the heat shock protein (HSP) network have potential in a broad range of research applications and diseases. A yeast-based liquid culture assay that measured time-dependent turbidity enabled the high-throughput screening of different Saccharomyces cerevisae strains to identify HSP modulators with unique molecular mechanisms. A focused set of four strains, with differing sensitivities to Hsp90 inhibitors, was used to screen a compound library of 3680 compounds. Computed turbidity curve functions were used to classify strain responses and sensitivity to chemical effects across the compound library...
January 1, 2017: SLAS Discov
https://www.readbyqxmd.com/read/28346088/a-1536-well-3d-viability-assay-to-assess-the-cytotoxic-effect-of-drugs-on-spheroids
#15
Franck Madoux, Allison Tanner, Michelle Vessels, Lynsey Willetts, Shurong Hou, Louis Scampavia, Timothy P Spicer
Evaluation of drug cytotoxicity traditionally relies on use of cell monolayers, which are easily miniaturized to the 1536-well plate format. Three-dimensional (3D) cell culture models have recently gained popularity thanks to their ability to better mimic the complexity of in vivo systems. Despite growing interest in these more physiologically relevant and highly predictive cell-based models for compound profiling and drug discovery, 3D assays are currently performed in a medium- to low-throughput format, either in 96-well or 384-well plates...
January 1, 2017: SLAS Discov
https://www.readbyqxmd.com/read/28346087/pubchem-bioassay
#16
Yanli Wang, Tiejun Cheng, Stephen H Bryant
High-throughput screening (HTS) is now routinely conducted for drug discovery by both pharmaceutical companies and screening centers at academic institutions and universities. Rapid advance in assay development, robot automation, and computer technology has led to the generation of terabytes of data in screening laboratories. Despite the technology development toward HTS productivity, fewer efforts were devoted to HTS data integration and sharing. As a result, the huge amount of HTS data was rarely made available to the public...
January 1, 2017: SLAS Discov
https://www.readbyqxmd.com/read/28345579/inhibition-of-delta-secretase-improves-cognitive-functions-in-mouse-models-of-alzheimer-s-disease
#17
Zhentao Zhang, Obiamaka Obianyo, Elfriede Dall, Yuhong Du, Haian Fu, Xia Liu, Seong Su Kang, Mingke Song, Shan-Ping Yu, Chiara Cabrele, Mario Schubert, Xiaoguang Li, Jian-Zhi Wang, Hans Brandstetter, Keqiang Ye
δ-secretase, also known as asparagine endopeptidase (AEP) or legumain, is a lysosomal cysteine protease that cleaves both amyloid precursor protein (APP) and tau, mediating the amyloid-β and tau pathology in Alzheimer's disease (AD). Here we report the therapeutic effect of an orally bioactive and brain permeable δ-secretase inhibitor in mouse models of AD. We performed a high-throughput screen and identified a non-toxic and selective δ-secretase inhibitor, termed compound 11, that specifically blocks δ-secretase but not other related cysteine proteases...
March 27, 2017: Nature Communications
https://www.readbyqxmd.com/read/28345451/the-impact-of-advanced-proteomics-in-the-search-for-markers-and-therapeutic-targets-of-bladder-cancer
#18
Hongshuo Zhang, Yue Fan, Lingling Xia, Chunhui Gao, Xin Tong, Hanfu Wang, Lili Sun, Tuo Ji, Mingyu Jin, Bing Gu, Bo Fan
Bladder cancer is the most common cancer of the urinary tract and can be avoided through proper surveillance and monitoring. Several genetic factors are known to contribute to the progression of bladder cancer, many of which produce molecules that serve as cancer biomarkers. Blood, urine, and tissue are commonly analyzed for the presence of biomarkers, which can be derived from either the nucleus or the mitochondria. Recent advances in proteomics have facilitated the high-throughput profiling of data generated from bladder cancer-related proteins or peptides in parallel with high sensitivity and specificity, providing a wealth of information for biomarker discovery and validation...
March 2017: Tumour Biology: the Journal of the International Society for Oncodevelopmental Biology and Medicine
https://www.readbyqxmd.com/read/28344635/the-combination-of-gas-phase-fluorophore-technology-and-automation-to-enable-high-throughput-analysis-of-plant-respiration
#19
Andrew P Scafaro, A Clarissa A Negrini, Brendan O'Leary, F Azzahra Ahmad Rashid, Lucy Hayes, Yuzhen Fan, You Zhang, Vincent Chochois, Murray R Badger, A Harvey Millar, Owen K Atkin
BACKGROUND: Mitochondrial respiration in the dark (Rdark) is a critical plant physiological process, and hence a reliable, efficient and high-throughput method of measuring variation in rates of Rdark is essential for agronomic and ecological studies. However, currently methods used to measure Rdark in plant tissues are typically low throughput. We assessed a high-throughput automated fluorophore system of detecting multiple O2 consumption rates. The fluorophore technique was compared with O2-electrodes, infrared gas analysers (IRGA), and membrane inlet mass spectrometry, to determine accuracy and speed of detecting respiratory fluxes...
2017: Plant Methods
https://www.readbyqxmd.com/read/28341739/modifiers-of-prion-protein-biogenesis-and-recycling-identified-by-a-highly-parallel-endocytosis-kinetics-assay
#20
Boris A Ballmer, Rita Moos, Prisca Liberali, Lucas Pelkmans, Simone Hornemann, Adriano Aguzzi
The cellular prion protein, PrP(C), is attached by a glycosylphosphatidylinositol anchor to the outer leaflet of the plasma membrane. Its misfolded isoform PrP(Sc) is the causative agent of prion diseases. Conversion of PrP(C) into PrP(Sc) is thought to take place at the cell surface or in endo-lysosomal organelles. Understanding the intracellular trafficking of PrP(C) may therefore help elucidating the conversion process. Here we describe a time-resolved fluorescence resonance energy transfer (FRET) assay reporting membrane expression and real-time internalization rates of PrP(C) The assay is suitable for high-throughput genetic and pharmaceutical screens for modulators of PrP(C) trafficking...
March 24, 2017: Journal of Biological Chemistry
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