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High-throughput screening

Margret Thorsteinsdottir, Unnur A Thorsteinsdottir, Finnur F Eiriksson, Hrafnhildur L Runolfsdottir, Inger M Sch Agustsdottir, Steinunn Oddsdottir, Baldur B Sigurdsson, Hordur K Hardarson, Nilesh R Kamble, Snorri Th Sigurdsson, Vidar O Edvardsson, Runolfur Palsson
Adenine phosphoribosyltransferase (APRT) deficiency is a hereditary disorder that leads to excessive urinary excretion of 2,8-dihydroxyadenine (DHA), causing nephrolithiasis and chronic kidney disease. Treatment with allopurinol or febuxostat reduces DHA production and attenuates the renal manifestations. Assessment of DHA crystalluria by urine microscopy is used for therapeutic monitoring, but lacks sensitivity. We report a high-throughput assay based on ultra-performance liquid chromatography coupled to tandem mass spectrometry (UPLC-MS/MS) for quantification of urinary DHA...
September 14, 2016: Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences
Huma Siddiqui, Tsute Chen, Ardita Aliko, Piotr M Mydel, Roland Jonsson, Ingar Olsen
BACKGROUND: Reduced salivation is considered a major clinical feature of most but not all cases of primary Sjögren's syndrome (pSS). Reduced saliva flow may lead to changes in the salivary microbiota. These changes have mainly been studied with culture that typically recovers only 65% of the bacteria present. OBJECTIVE: This study was to use high throughput sequencing, covering both cultivated and not-yet-cultivated bacteria, to assess the bacterial microbiota of whole saliva in pSS patients with normal salivation...
2016: Journal of Oral Microbiology
Dimitrios Spiliotopoulos, Amedeo Caflisch
We review the results of fragment-based high-throughput docking to the N-terminal bromodomain of BRD4 and the CREBBP bromodomain. In both docking campaigns the ALTA (anchor-based library tailoring) procedure was used to reduce the size of the initial library by selecting for flexible docking only the molecules that contain a fragment with favorable predicted binding energy. Ranking by a force field-based energy with solvation has resulted in small-molecule hits with low-micromolar affinity and favorable ligand efficiency...
March 2016: Drug Discovery Today. Technologies
Mikael Persson, Jorrit J Hornberg
High content screening enables parallel acquisition of multiple molecular and cellular readouts. In particular the predictive toxicology field has progressed from the advances in high content screening, as more refined end points that report on cellular health can be studied in combination, at the single cell level, and in relatively high throughput. Here, we discuss how high content screening has become an essential tool for Discovery Safety, the discipline that integrates safety and toxicology in the drug discovery process to identify and mitigate safety concerns with the aim to design drug candidates with a superior safety profile...
October 21, 2016: Chemical Research in Toxicology
Beate Schwer, Fahad Khalid, Stewart Shuman
Saccharomyces cerevisiae Dbr1 is a manganese-dependent RNA debranching enzyme that cleaves the 2'-5' phosphodiester bond of the lariat introns formed during pre-mRNA splicing. Dbr1 is a member of the binuclear metallophosphoesterase enzyme superfamily. We showed previously via alanine scanning that RNA debranching in vivo and in vitro depends on conserved active site residues His13, Asp40, Asn85, His86, His179, His231, and His233. Here, by extending the alanine scan, we added Cys11 to the ensemble of essential active site components...
October 7, 2016: RNA
Ying Qiao, Yong Mao, Jun Wang, Ruanni Chen, Yong-Quan Su, Jia Chen, Wei-Qiang Zheng
The white-spot disease caused by marine ciliate Cryptocryon irritans hindered the sustainable development of large yellow croaker Larimichthys crocea industry. Better understandings about the parasite-host interactions in the molecular level will facilitate the prevention of mass mortality of the L. crocea caused by white-spot disease. MicroRNAs (miRNAs) are a class of small RNA molecules about 20-22 nucleotides which post-transcriptionally regulated many protein-coding genes and involved in many biological processes, especially in host-pathogen responses...
October 17, 2016: Fish & Shellfish Immunology
Kishore Polireddy, Ruochen Dong, Peter R McDonald, Tao Wang, Brendan Luke, Ping Chen, Melinda Broward, Anuradha Roy, Qi Chen
BACKGROUND: Pancreatic cancer has an enrichment of stem-like cancer cells (CSCs) that contribute to chemoresistant tumors prone to metastasis and recurrence. Drug screening assays based on cytotoxicity cannot identify specific CSC inhibitors, because CSCs comprise only a small portion of cancer cell population, and it is difficult to propagate stable CSC populations in vitro for high-throughput screening (HTS) assays. Based on the important role of cancer cell epithelial-to-mesenchymal transition (EMT) in promoting CSCs, we hypothesized that inhibition of EMT can be a useful strategy for inhibiting CSCs, and therefore a feasible approach for HTS can be built for identification of CSC inhibitors, based on assays detecting EMT inhibition...
2016: PloS One
Li Zhou, Ji Wen, Zhao Huang, Edouard C Nice, Canhua Huang, Haiyuan Zhang, Qifu Li
Liver cancer is a major global health problem being the sixth most common cancer and the third cause of cancer-related death, with HCC representing more than 90% of primary liver cancers. Mounting evidence suggests that, compared with their normal counterparts, many types of cancer cell have increased levels of ROS. Therefore, cancer cells need to combat high levels of ROS, especially at early stages of tumour development. Recent studies have revealed that ROS-mediated regulation of redox-sensitive proteins (redox sensors) is involved in the pathogenesis and/or progression of many human diseases, including cancer...
October 20, 2016: Proteomics. Clinical Applications
Ingo Muegge, Prasenjit Mukherjee
A statistical analysis of 203 high-throughput screens was conducted studying the propensity of small molecules in the Boehringer Ingelheim screening deck to show biological activity after having tested inactive previously in a growing number of screening assays. Dark chemical matter (DCM) compounds, which have been tested and found inactive in 50 or more assays, exhibit hit rates that are comparable to those of compounds tested in much fewer assays. Only compounds tested inactive in 125 or more assays start showing a hit rate deterioration of up to 40% compared to compounds tested in less than 25 assays...
October 20, 2016: Journal of Medicinal Chemistry
Jingjing Li, Jin Gao, Lei Han, Yinjie Zhang, Wen Guan, Liang Zhou, Yan Yu, Wei Han
Identifying interactions between ligands and transmembrane receptors is crucial for understanding the endocrine system. However, the present approaches for this purpose are still not capable of high-throughput screening. In this report, a membrane-anchored ligand and receptor yeast two-hybrid (MALAR-Y2H) system was established. In the method, an extracellular ligand is linked with an intracellular split-ubiquitin reporter system via a chimeric transmembrane structure. Meanwhile, the prey proteins of transmembrane receptors are fused to the other half of the split-ubiquitin reporter system...
October 20, 2016: Scientific Reports
Joshua Bloom, Shan Sun, Yousef Al-Abed
Macrophage migration inhibitory factor (MIF) has emerged as a promising drug target in diseases including sepsis, rheumatoid arthritis, and cancer. MIF has multiple properties that favor development of specific, targeted therapies: it is expressed broadly among human cells, has noted roles in diverse inflammatory and oncological processes, and has intrinsic enzymatic activity amenable to high-throughput screening. Despite these advantages, anti-MIF therapy remains well behind other cytokine-targeted therapeutics, with no small molecules in the pipeline for clinical development and anti-MIF antibodies only recently beginning clinical trials...
October 20, 2016: Expert Opinion on Therapeutic Targets
Robyn T Rebbeck, Maram M Essawy, Florentin R Nitu, Benjamin D Grant, Gregory D Gillispie, David D Thomas, Donald M Bers, Razvan L Cornea
Using time-resolved fluorescence resonance energy transfer (FRET), we have developed and validated the first high-throughput screening (HTS) method to discover compounds that modulate an intracellular Ca(2+) channel, the ryanodine receptor (RyR), for therapeutic applications. Intracellular Ca(2+) regulation is critical for striated muscle function, and RyR is a central player. At resting [Ca(2+)], an increased propensity of channel opening due to RyR dysregulation is associated with severe cardiac and skeletal myopathies, diabetes, and neurological disorders...
October 19, 2016: Journal of Biomolecular Screening
Eugen Widmeier, Weizhen Tan, Merlin Airik, Friedhelm Hildebrandt
INTRODUCTION: Steroid-resistant nephrotic syndrome (SRNS) inevitably progresses to end-stage kidney disease, requiring dialysis or transplantation for survival. However, treatment modalities and drug discovery remain limited. Mutations in over 30 genes have been discovered as monogenic causes of SRNS. Most of these genes are predominantly expressed in the glomerular epithelial cell, the podocyte, placing it at the center of the pathogenesis of SRNS. Podocyte migration rate (PMR) represents a relevant intermediate phenotype of disease in monogenic causes of SRNS...
October 19, 2016: American Journal of Physiology. Renal Physiology
Tao He, Didier Surdez, Juha K Rantala, Saija Haapa-Paananen, Jozef Ban, Maximilian Kauer, Eleni Tomazou, Vidal Fey, Javier Alonso, Heinrich Kovar, Olivier Delattre, Kristiina Iljin
A translocation leading to the formation of an oncogenic EWS-ETS fusion protein defines Ewing sarcoma. The most frequent gene fusion, present in 85 percent of Ewing sarcomas, is EWS-FLI1. Here, a high-throughput RNA interference screen was performed to identify genes whose function is critical for EWS-FLI1 driven cell viability. In total, 6781 genes were targeted by siRNA molecules and the screen was performed both in presence and absence of doxycycline-inducible expression of the EWS-FLI1 shRNA in A673/TR/shEF Ewing sarcoma cells...
October 16, 2016: Gene
Yongchul G Chung, Diego A Gómez-Gualdrón, Peng Li, Karson T Leperi, Pravas Deria, Hongda Zhang, Nicolaas A Vermeulen, J Fraser Stoddart, Fengqi You, Joseph T Hupp, Omar K Farha, Randall Q Snurr
Discovery of new adsorbent materials with a high CO2 working capacity could help reduce CO2 emissions from newly commissioned power plants using precombustion carbon capture. High-throughput computational screening efforts can accelerate the discovery of new adsorbents but sometimes require significant computational resources to explore the large space of possible materials. We report the in silico discovery of high-performing adsorbents for precombustion CO2 capture by applying a genetic algorithm to efficiently search a large database of metal-organic frameworks (MOFs) for top candidates...
October 2016: Science Advances
Mohammad A Ghattas, Noor Raslan, Asil Sadeq, Mohammad Al Sorkhy, Noor Atatreh
Protein tyrosine phosphatases (PTP) play important roles in the pathogenesis of many diseases. The fact that no PTP inhibitors have reached the market so far has raised many questions about their druggability. In this study, the active sites of 17 PTPs were characterized and assessed for its ability to bind drug-like molecules. Consequently, PTPs were classified according to their druggability scores into four main categories. Only four members showed intermediate to very druggable pocket; interestingly, the rest of them exhibited poor druggability...
2016: Drug Design, Development and Therapy
Shuai Huang, Aruna Balgi, Yaping Pan, Meng Li, Xiaoran Zhang, Lilin Du, Ming Zhou, Michel Roberge, Xin Li
Nucleotide-binding leucine-rich repeat (NLR) proteins serve as immune receptors in both plants and animals. To identify components required for NLR-mediated immunity, we designed and carried out a chemical genetics screen to search for small molecules that can alter resistance responses in Arabidopsis thaliana. From 13,600 compounds, we identified Ro 8-4304 that is able to specifically suppress the severe autoimmune phenotypes of chs3-2D (chilling sensitive 3, 2D), including the arrested growth morphology and heightened PR (Pathogenesis Related) gene expression...
October 15, 2016: Molecular Plant
Partha Pratim Bose, Prakash Kumar
In high-throughput biotechnology and structural biology, molecular cloning is an essential prerequisite for attaining high yields of recombinant protein. However, a rapid, cost-effective, easy clone screening protocol is still required to identify colonies with desired insert along with a cross check method to certify the expression of the desired protein as the end product. We report an easy, fast, sensitive and cheap visual clone screening and protein expression cross check protocol employing gold nanoparticle based plasmonic detection phenomenon...
October 15, 2016: Analytical Biochemistry
Mark D Mathew, Neal D Mathew, Angela Miller, Mike Simpson, Vinci Au, Stephanie Garland, Marie Gestin, Mark L Edgley, Stephane Flibotte, Aruna Balgi, Jennifer Chiang, Guri Giaever, Pamela Dean, Audrey Tung, Michel Roberge, Calvin Roskelley, Tom Forge, Corey Nislow, Donald Moerman
BACKGROUND: The lack of new anthelmintic agents is of growing concern because it affects human health and our food supply, as both livestock and plants are affected. Two principal factors contribute to this problem. First, nematode resistance to anthelmintic drugs is increasing worldwide and second, many effective nematicides pose environmental hazards. In this paper we address this problem by deploying a high throughput screening platform for anthelmintic drug discovery using the nematode Caenorhabditis elegans as a surrogate for infectious nematodes...
October 2016: PLoS Neglected Tropical Diseases
Marko Poglitsch, Ashraf H Ahmed, Michael Resl, Andrea Stoller, Dunja Van Oyen, Cornelia Schwager, Claudia Aigner, Oliver Domenig, Michael Krebs, Manuel Haschke, Michael Stowasser
OBJECTIVE: Primary aldosteronism (PA) is form of hypertension characterized by production of aldosterone by the adrenal that is excessive and relatively autonomous of the renin-angiotensin system. Once detected, unilateral PA can be usually cured by surgical removal of the affected adrenal, while bilateral PA can be specifically treated by medications, which antagonize aldosterone action. Clinical guidelines of Endocrine Societies in Europe and the US recommend screening for PA among most hypertensive patients...
September 2016: Journal of Hypertension
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