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Journal of Biomolecular Screening

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https://www.readbyqxmd.com/read/27932699/a-systematic-investigation-of-the-best-buffers-for-use-in-screening-by-maldi-mass-spectrometry
#1
Jessica Chandler, Carl Haslam, Neil Hardy, Melanie Leveridge, Peter Marshall
Matrix-assisted laser desorption/ionization-mass spectrometry (MALDI-MS) offers a label-free alternative for the screening of biochemical targets in both 1536- and 6144-assay formats, as well as potentially providing increased sensitivity, reproducibility, and the simultaneous detection of multiple assay components within a specified m/z range. Ion suppression effects are one of the principal limitations reported for MS analysis. Within MALDI-MS screening, it has been identified that certain biochemical components incorporated into the assay (e...
December 8, 2016: Journal of Biomolecular Screening
https://www.readbyqxmd.com/read/27932698/identification-of-inhibitors-of-the-association-of-zap-70-with-the-t-cell-receptor-by-high-throughput-screen
#2
Patrick R Visperas, Christopher G Wilson, Jonathan A Winger, Qingrong Yan, Kevin Lin, Michelle R Arkin, Arthur Weiss, John Kuriyan
ZAP-70 is a critical molecule in the transduction of T cell antigen receptor signaling and the activation of T cells. Upon activation of the T cell antigen receptor, ZAP-70 is recruited to the intracellular ζ-chains of the T cell receptor, where ZAP-70 is activated and colocalized with its substrates. Inhibitors of ZAP-70 could potentially function as treatments for autoimmune diseases or organ transplantation. In this work, we present the design, optimization, and implementation of a screen for inhibitors that would disrupt the interaction between ZAP-70 and the T cell antigen receptor...
December 8, 2016: Journal of Biomolecular Screening
https://www.readbyqxmd.com/read/27932697/htra3-isoform-specific-elisas-for-early-detection-of-preeclampsia
#3
Yao Wang, Ying Li, Jonathan Hyett, Fabricio da Silva Costa, Guiying Nie
Preeclampsia is a serious disorder of human pregnancy occurring after 20 weeks of gestation. It can be divided into subtypes of early onset (<34 weeks of gestation) and late onset (>34 weeks). Presymptomatic detection to identify those at high risk is important for managing this disease. HtrA3, a serine protease with high expression in the developing placenta, exists in long (HtrA3-L) and short (HtrA3-S) isoforms. They are identical, except HtrA3-S lacks the C-terminal PDZ domain. We have previously shown by Western blot analysis that serum HtrA3 levels at the end of the first trimester are significantly higher in women who later develop preeclampsia than in controls...
December 8, 2016: Journal of Biomolecular Screening
https://www.readbyqxmd.com/read/28071153/novel-chemical-scaffolds-for-inhibition-of-rifamycin-resistant-rna-polymerase-discovered-from-high-throughput-screening
#4
Nathan T Scharf, Vadim Molodtsov, Arrin Kontos, Katsuhiko S Murakami, George A Garcia
Rifampin has been a cornerstone of tuberculosis (TB) treatment since its introduction. The rise of multidrug-resistant and extensively drug-resistant TB makes the development of novel therapeutics effective against these strains an urgent need. Site-specific mutations in the target enzyme of rifampin, RNA polymerase (RNAP) comprises the majority (~97%) of rifamycin-resistant (Rif(R)) strains of Mycobacterium tuberculosis (MTB). To identify novel inhibitors of bacterial RNAP, an in vitro plasmid-based transcription assay that uses malachite green (MG) to detect transcribed RNA containing MG aptamers was developed...
December 1, 2016: Journal of Biomolecular Screening
https://www.readbyqxmd.com/read/28027450/enabling-1536-well-high-throughput-cell-based-screening-through-the-application-of-novel-centrifugal-plate-washing
#5
Sinead Knight, Helen Plant, Lisa McWilliams, David Murray, Rebecca Dixon-Steele, Anet Varghese, Paul Harper, Anna Ramne, Paula McArdle, Susanna Engberg, Neil Bennett, Carolyn Blackett, Mark Wigglesworth
Cell-based assays have long been important within hit discovery paradigms; however, improving the disease relevance of the assay system can positively affect the translation of small-molecule drug discovery, especially if adopted in the initial hit identification assay. Consequently, there is an increasing need for disease-relevant assay systems capable of running at large scale, including the use of induced pluripotent stem cells and donor-derived primary cells. Major hurdles to adopting these assays for high-throughput screening are the cost, availability of cells, and complex protocols...
December 1, 2016: Journal of Biomolecular Screening
https://www.readbyqxmd.com/read/28027449/novel-chemical-scaffolds-for-inhibition-of-rifamycin-resistant-rna-polymerase-discovered-from-high-throughput-screening
#6
Nathan T Scharf, Vadim Molodtsov, Arrin Kontos, Katsuhiko S Murakami, George A Garcia
Rifampin has been a cornerstone of tuberculosis (TB) treatment since its introduction. The rise of multidrug-resistant and extensively drug-resistant TB makes the development of novel therapeutics effective against these strains an urgent need. Site-specific mutations in the target enzyme of rifampin, RNA polymerase (RNAP) comprises the majority (~97%) of rifamycin-resistant (Rif(R)) strains of Mycobacterium tuberculosis (MTB). To identify novel inhibitors of bacterial RNAP, an in vitro plasmid-based transcription assay that uses malachite green (MG) to detect transcribed RNA containing MG aptamers was developed...
December 1, 2016: Journal of Biomolecular Screening
https://www.readbyqxmd.com/read/28027448/induced-pluripotent-hd-monkey-stem-cells-derived-neural-cells-for-drug-discovery
#7
Tanut Kunkanjanawan, Richard Carter, Kwan-Sung Ahn, Jinjing Yang, Rangsun Parnpai, Anthony W S Chan
Huntington's disease (HD) is a neurodegenerative disease caused by an expansion of CAG trinucleotide repeat (polyglutamine [polyQ]) in the huntingtin ( HTT) gene, which leads to the formation of mutant HTT (mHTT) protein aggregates. In the nervous system, an accumulation of mHTT protein results in glutamate-mediated excitotoxicity, proteosome instability, and apoptosis. Although HD pathogenesis has been extensively studied, effective treatment of HD has yet to be developed. Therapeutic discovery research in HD has been reported using yeast, cells derived from transgenic animal models and HD patients, and induced pluripotent stem cells from patients...
December 1, 2016: Journal of Biomolecular Screening
https://www.readbyqxmd.com/read/27909235/a-simple-and-sensitive-high-content-assay-for-the-characterization-of-antiproliferative-therapeutic-antibodies
#8
Andreas Stengl, David Hörl, Heinrich Leonhardt, Jonas Helma
Monoclonal antibodies (mAbs) have become a central class of therapeutic agents in particular as antiproliferative compounds. Their often complex modes of action require sensitive assays during early, functional characterization. Current cell-based proliferation assays often detect metabolites that are indicative of metabolic activity but do not directly account for cell proliferation. Measuring DNA replication by incorporation of base analogues such as 5-bromo-2'-deoxyuridine (BrdU) fills this analytical gap but was previously restricted to bulk effect characterization in enzyme-linked immunosorbent assay formats...
December 1, 2016: Journal of Biomolecular Screening
https://www.readbyqxmd.com/read/27909234/a-high-throughput-screening-strategy-for-development-of-rnf8-ubc13-protein-protein-interaction-inhibitors
#9
Elisabeth Weber, Ina Rothenaigner, Stefanie Brandner, Kamyar Hadian, Kenji Schorpp
The ubiquitin-proteasome system plays an essential role in a broad range of cellular signaling pathways. Ubiquitination is a posttranslational protein modification that involves the action of an enzymatic cascade (E1, E2, and E3 enzymes) for the covalent attachment of ubiquitin to target proteins. The emerging knowledge of the molecular mechanisms and correlation of deregulation of the ubiquitin system in human diseases is uncovering new opportunities for therapeutics development. The E3 ligase RNF8 acts in cooperation with the heterodimeric E2 enzyme Ubc13/Uev1a to generate ubiquitin conjugates at the sides of DNA double-strand breaks, and recent findings suggest RNF8 as a potential therapeutic target for the treatment of breast cancer...
December 1, 2016: Journal of Biomolecular Screening
https://www.readbyqxmd.com/read/27899692/jenkins-ci-an-open-source-continuous-integration-system-as-a-scientific-data-and-image-processing-platform
#10
Ioannis K Moutsatsos, Imtiaz Hossain, Claudia Agarinis, Fred Harbinski, Yann Abraham, Luc Dobler, Xian Zhang, Christopher J Wilson, Jeremy L Jenkins, Nicholas Holway, John Tallarico, Christian N Parker
High-throughput screening generates large volumes of heterogeneous data that require a diverse set of computational tools for management, processing, and analysis. Building integrated, scalable, and robust computational workflows for such applications is challenging but highly valuable. Scientific data integration and pipelining facilitate standardized data processing, collaboration, and reuse of best practices. We describe how Jenkins-CI, an "off-the-shelf," open-source, continuous integration system, is used to build pipelines for processing images and associated data from high-content screening (HCS)...
November 29, 2016: Journal of Biomolecular Screening
https://www.readbyqxmd.com/read/27899691/high-throughput-spectral-and-lifetime-based-fret-screening-in-living-cells-to-identify-small-molecule-effectors-of-serca
#11
Tory M Schaaf, Kurt C Peterson, Benjamin D Grant, Prachi Bawaskar, Samantha Yuen, Ji Li, Joseph M Muretta, Gregory D Gillispie, David D Thomas
A robust high-throughput screening (HTS) strategy has been developed to discover small-molecule effectors targeting the sarco/endoplasmic reticulum calcium ATPase (SERCA), based on a fluorescence microplate reader that records both the nanosecond decay waveform (lifetime mode) and the complete emission spectrum (spectral mode), with high precision and speed. This spectral unmixing plate reader (SUPR) was used to screen libraries of small molecules with a fluorescence resonance energy transfer (FRET) biosensor expressed in living cells...
November 29, 2016: Journal of Biomolecular Screening
https://www.readbyqxmd.com/read/27879398/spectral-unmixing-plate-reader-high-throughput-high-precision-fret-assays-in-living-cells
#12
Tory M Schaaf, Kurt C Peterson, Benjamin D Grant, David D Thomas, Gregory D Gillispie
We have developed a microplate reader that records a complete high-quality fluorescence emission spectrum on a well-by-well basis under true high-throughput screening (HTS) conditions. The read time for an entire 384-well plate is less than 3 min. This instrument is particularly well suited for assays based on fluorescence resonance energy transfer (FRET). Intramolecular protein biosensors with genetically encoded green fluorescent protein (GFP) donor and red fluorescent protein (RFP) acceptor tags at positions sensitive to structural changes were stably expressed and studied in living HEK cells...
November 22, 2016: Journal of Biomolecular Screening
https://www.readbyqxmd.com/read/27872202/genome-wide-overexpression-screen-identifies-genes-able-to-bypass-p16-mediated-senescence-in-melanoma
#13
Won Jae Lee, Dubravka Škalamera, Mareike Dahmer-Heath, Konstanin Shakhbazov, Max V Ranall, Carly Fox, Duncan Lambie, Alexander J Stevenson, Paul Yaswen, Thomas J Gonda, Brian Gabrielli
Malignant melanomas often arise from nevi, which result from initial oncogene-induced hyperproliferation of melanocytes that are maintained in a CDKN2A/p16-mediated senescent state. Thus, genes that can bypass this senescence barrier are likely to contribute to melanoma development. We have performed a gain-of-function screen of 17,030 lentivirally expressed human open reading frames (ORFs) in a melanoma cell line containing an inducible p16 construct to identify such genes. Genes known to bypass p16-induced senescence arrest, including the human papilloma virus 18 E7 gene (HPV18E7), and genes such as the p16-binding CDK6 with expected functions, as well as panel of novel genes, were identified, including high-mobility group box (HMGB) proteins...
November 21, 2016: Journal of Biomolecular Screening
https://www.readbyqxmd.com/read/27872201/identification-of-chemical-compounds-that-inhibit-protein-synthesis-in-pseudomonas-aeruginosa
#14
Stephanie O Palmer, Yanmei Hu, Megan Keniry, James M Bullard
Four inhibitory compounds were identified using a poly-uridylic acid (polyU) mRNA-directed aminoacylation/translation (A/T) protein synthesis system composed of phenylalanyl-tRNA synthetases (PheRS), ribosomes, and ribosomal factors from Pseudomonas aeruginosa in an in vitro screen of a synthetic compound library. The compounds were specific for inhibition of bacterial protein synthesis. In enzymatic assays, the compounds inhibited protein synthesis with IC50 values ranging from 20 to 60 μM. Minimum inhibitory concentrations (MICs) were determined in cultures for a panel of pathogenic organisms, including Enterococcus faecalis, Escherichia coli, Haemophilus influenzae, P...
November 21, 2016: Journal of Biomolecular Screening
https://www.readbyqxmd.com/read/27827304/development-of-an-hts-compatible-assay-for-discovery-of-melanoma-related-microphthalmia-transcription-factor-disruptors-using-alphascreen-technology
#15
Jing Wang, Pengfei Fang, Peter Chase, Sagi Tshori, Ehud Razin, Timothy P Spicer, Louis Scampavia, Peter Hodder, Min Guo
Microphthalmia transcription factor (MITF) is a master transcription factor expressed in melanocytes, essential for melanocyte survival, differentiation, and pigment formation, and is a key oncogenic factor in melanoma initiation, migration, and treatment resistance. Although identified as an important therapeutic target for melanoma, clinical inhibitors directly targeting the MITF protein are not available. Based on the functional state of MITF, we have designed an MITF dimerization-based AlphaScreen (MIDAS) assay that sensitively and specifically mirrors the dimerization of MITF in vitro...
November 8, 2016: Journal of Biomolecular Screening
https://www.readbyqxmd.com/read/27821623/optimization-of-a-luminescence-based-high-throughput-screening-assay-for-detecting-apyrase-activity
#16
John R Veloria, Ashwini K Devkota, Eun Jeong Cho, Kevin N Dalby
Apyrase is a calcium-activated enzyme that catalyzes the conversion of adenosine triphosphate (ATP) to adenosine diphosphate (ADP), adenosine monophosphate (AMP), and Pi It is currently used in studies involving cancer and platelet aggregation in humans, as well as herbicide resistance in plants. Inhibitors of apyrase are being investigated for their use to suppress tumors and combat herbicide resistance. Only a few inhibitors of apyrase have been reported, many of which were identified through automated screening using a 96-well plate format and colorimetric phosphate detection...
November 7, 2016: Journal of Biomolecular Screening
https://www.readbyqxmd.com/read/27810952/high-content-screening-of-raw-actinomycete-extracts-for-the-identification-of-antituberculosis-activities
#17
Jinyeong Heo, Jiyoun Nam, Jichan Jang, David Shum, Constantin Radu, Jinhua Cheng, Hanki Lee, Joo-Won Suh, Vincent Delorme
The feasibility and relevance of screening a library of raw actinomycete extracts (ECUM library) for the identification of antituberculosis activities was assessed on 11,088 extracts using a multiple-screening approach. Each extract was first tested at two concentrations against noninfected macrophages as a control, then against Mycobacterium tuberculosis growing in broth medium as well as infecting murine macrophages. The screening results indicated a library of good quality with an apparent low proportion of cytotoxic extracts...
November 3, 2016: Journal of Biomolecular Screening
https://www.readbyqxmd.com/read/27803177/bioluminescent-assays-for-glucose-and-glutamine-metabolism-high-throughput-screening-for-changes-in-extracellular-and-intracellular-metabolites
#18
Donna Leippe, Mary Sobol, Gediminas Vidugiris, James J Cali, Jolanta Vidugiriene
Cancer cell metabolism is a complex, dynamic network of regulated pathways. Interrogation of this network would benefit from rapid, sensitive techniques that are adaptable to high-throughput formats, facilitating novel compound screening. This requires assays that have minimal sample preparation and are adaptable to lower-volume 384-well formats and automation. Here we describe bioluminescent glucose, lactate, glutamine, and glutamate detection assays that are well suited for high-throughput analysis of two major metabolic pathways in cancer cells: glycolysis and glutaminolysis...
November 1, 2016: Journal of Biomolecular Screening
https://www.readbyqxmd.com/read/27789755/a-genome-wide-arrayed-cdna-screen-to-identify-functional-modulators-of-%C3%AE-7-nicotinic-acetylcholine-receptors
#19
Elizabeth B Rex, Nikhil Shukla, Shenyan Gu, David Bredt, Daniel DiSepio
Cellular signaling is in part regulated by the composition and subcellular localization of a series of protein interactions that collectively form a signaling complex. Using the α7 nicotinic acetylcholine receptor (α7nAChR) as a proof-of-concept target, we developed a platform to identify functional modulators (or auxiliary proteins) of α7nAChR signaling. The Broad cDNA library was transiently cotransfected with α7nAChR cDNA in HEK293T cells in a high-throughput fashion. Using this approach in combination with a functional assay, we identified positive modulators of α7nAChR activity...
October 27, 2016: Journal of Biomolecular Screening
https://www.readbyqxmd.com/read/27789754/unified-software-solution-for-efficient-spr-data-analysis-in-drug-research
#20
Göran Dahl, Stephan Steigele, Per Hillertz, Anna Tigerström, Anders Egnéus, Alexander Mehrle, Martin Ginkel, Fredrik Edfeldt, Geoff Holdgate, Nichole O'Connell, Bernd Kappler, Annette Brodte, Philip B Rawlins, Gareth Davies, Eva-Lotta Westberg, Rutger H A Folmer, Stephan Heyse
Surface plasmon resonance (SPR) is a powerful method for obtaining detailed molecular interaction parameters. Modern instrumentation with its increased throughput has enabled routine screening by SPR in hit-to-lead and lead optimization programs, and SPR has become a mainstream drug discovery technology. However, the processing and reporting of SPR data in drug discovery are typically performed manually, which is both time-consuming and tedious. Here, we present the workflow concept, design and experiences with a software module relying on a single, browser-based software platform for the processing, analysis, and reporting of SPR data...
October 27, 2016: Journal of Biomolecular Screening
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