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Library Discovery

Moran N Cabili, Knox Carey, Stephanie O M Dyke, Anthony J Brookes, Marc Fiume, Francis Jeanson, Giselle Kerry, Alex Lash, Heidi Sofia, Dylan Spalding, Anne-Marie Tasse, Susheel Varma, Ravi Pandya
The volume of genomics and health data is growing rapidly, driven by sequencing for both research and clinical use. However, under current practices, the data is fragmented into many distinct datasets, and researchers must go through a separate application process for each dataset. This is time-consuming both for the researchers and the data stewards, and it reduces the velocity of research and new discoveries that could improve human health. We propose to simplify this process, by introducing a standard Library Card that identifies and authenticates researchers across all participating datasets...
March 14, 2018: Scientific Data
A Samdani, Umashankar Vetrivel
High throughput virtual screening plays a crucial role in hit identification during the drug discovery process. With the rapid increase in the chemical libraries, virtual screening process becomes computationally challenging, thereby posing a demand for efficiently parallelized software pipelines. Here we present a GNU Parallel based pipeline-POAP that is programmed to run Open Babel and AutoDock suite under highly optimized parallelization. The ligand preparation module is a unique feature in POAP, as it offers extensive options for geometry optimization, conformer generation, parallelization and also quarantines erroneous datasets for seamless operation...
March 1, 2018: Computational Biology and Chemistry
Karthikeyan Mohanraj, Bagavathy Shanmugam Karthikeyan, R P Vivek-Ananth, R P Bharath Chand, S R Aparna, Pattulingam Mangalapandi, Areejit Samal
Phytochemicals of medicinal plants encompass a diverse chemical space for drug discovery. India is rich with a flora of indigenous medicinal plants that have been used for centuries in traditional Indian medicine to treat human maladies. A comprehensive online database on the phytochemistry of Indian medicinal plants will enable computational approaches towards natural product based drug discovery. In this direction, we present, IMPPAT, a manually curated database of 1742 Indian Medicinal Plants, 9596 Phytochemicals, And 1124 Therapeutic uses spanning 27074 plant-phytochemical associations and 11514 plant-therapeutic associations...
March 12, 2018: Scientific Reports
Jee Youn Hwang, Kesavan Markkandan, Mun Gyeong Kwon, Jung Soo Seo, Seung-Il Yoo, Seong Don Hwang, Maeng-Hyun Son, Junhyung Park
Olive flounder (Paralichthys olivaceus) is one of the most valuable marine aquatic species in South Korea and faces tremendous exposure to the viral hemorrhagic septicemia virus (VHSV). Given the growing importance of flounder, it is therefore essential to understand the host defense of P. olivaceus against VHSV infection, but studies on its immune mechanism are hindered by the lack of genomic resources. In this study, the P. olivaceus was infected with disease-causing VHSV isolates, ADC-VHS2012-11 and ADC-VHS2014-5 which showed moderate virulent (20% mortality) and high virulent (65% mortality), in order to investigate the effect of difference in pathogenicity in head kidney during 1, 3, 7 days of post-infection using Illumina sequencing...
March 9, 2018: Fish & Shellfish Immunology
Faiza H Waghu, Shaini Joseph, Sanket Ghawali, Elvis A Martis, Taruna Madan, Kareenhalli V Venkatesh, Susan Idicula-Thomas
Antimicrobial peptides (AMPs) are gaining attention as substitutes for antibiotics in order to combat the risk posed by multi-drug resistant pathogens. Several research groups are engaged in design of potent anti-infective agents using natural AMPs as templates. In this study, a library of peptides with high sequence similarity to Myeloid Antimicrobial Peptide (MAP) family were screened using popular online prediction algorithms. These peptide variants were designed in a manner to retain the conserved residues within the MAP family...
2018: Frontiers in Microbiology
Amelie Perron, Yoshihiro Nishikawa, Jun Iwata, Hiromi Shimojo, Junichiro Takaya, Kumiko Kobayashi, Itaru Imayoshi, Naasson Mbambi Mbenza, Mihoko Takenoya, Ryoichiro Kageyama, Yuzo Kodama, Motonari Uesugi
The transcription factor Hes family bHLH transcription factor 1 (Hes1) is a downstream effector of Notch signaling and plays a crucial role in orchestrating developmental processes during the embryonic stage. However, its aberrant signaling in adulthood is linked to the pathogenesis of cancer. In the present study, we report the discovery of small organic molecules (JI051 and JI130) that impair the ability of Hes1 to repress transcription. Hes1 interacts with the transcriptional corepressor transducing-like enhancer of split 1 (TLE1) via an interaction domain comprising two tryptophan residues, prompting us to search a chemical library of 1,800 small molecules enriched for indole-like π-electron-rich pharmacophores for a compound that blocks Hes1-mediated transcriptional repression...
March 9, 2018: Journal of Biological Chemistry
Laura L Burger, Charlotte Vanacker, Chayarndorn Phumsatitpong, Elizabeth R Wagenmaker, Luhong Wang, David P Olson, Suzanne M Moenter
GnRH neurons are a nexus of fertility regulation. We utilized translating ribosome affinity purification coupled with RNA sequencing to examine mRNAs of GnRH neurons in adult intact and gonadectomized (GDX) male and female mice. GnRH neuron ribosomes were tagged with green fluorescent protein (GFP) and GFP-labeled polysomes isolated by immunoprecipitation, producing one RNA fraction enhanced for GnRH neuron transcripts and one RNA fraction depleted. cDNA libraries were created from each fraction and 50-base, paired-end sequencing done and differential expression (enhanced fraction/depleted fraction) determined with a threshold of >1...
March 7, 2018: Endocrinology
Alfonso T Garcia-Sosa
Leishmaniasis, malaria, and fungal diseases are burdens on individuals and populations and can present severe complications. Easily accessible chemical treatments for these diseases are increasingly sought-after. Targeting the parasite N-myristoyl transferase while avoiding the human enzyme and other anti-targets may allow the prospect of compounds with pan-activity against these diseases, which would simplify treatments and costs. Developing chemical libraries, both virtual and physical, that have been filtered and flagged early on in the drug discovery process (before virtual screening) could reduce attrition rates of compounds being developed and failing late in development stages due to problems of side-effects or toxicity...
March 8, 2018: Current Computer-aided Drug Design
Marissa Mattar, Craig R McCarthy, Amanda R Kulick, Besnik Qeriqi, Sean Guzman, Elisa de Stanchina
Patient-derived xenograft (PDX) models have recently emerged as a highly desirable platform in oncology and are expected to substantially broaden the way in vivo studies are designed and executed and to reshape drug discovery programs. However, acquisition of patient-derived samples, and propagation, annotation and distribution of PDXs are complex processes that require a high degree of coordination among clinic, surgery and laboratory personnel, and are fraught with challenges that are administrative, procedural and technical...
2018: Frontiers in Oncology
Michael Gotrik, Gurpreet Sekhon, Saumya Saurabh, Margaret Nakamoto, Michael Eisenstein, H Tom Soh
RNA aptamers that generate a strong fluorescence signal upon binding a nonfluorescent small-molecule dye offer a powerful means for the selective imaging of individual RNA species. Unfortunately, conventional in vitro discovery methods are not efficient at generating such fluorescence-enhancing aptamers, because they primarily exert selective pressure based on target affinity-a characteristic that correlates poorly with fluorescence enhancement. Thus, only a handful of fluorescence-enhancing aptamers have been reported to date...
March 5, 2018: Journal of the American Chemical Society
Larissa Buedenbender, Leesa J Habener, Tanja Grkovic, D İpek Kurtböke, Sandra Duffy, Vicky M Avery, Anthony R Carroll
Microbial products are a promising source for drug leads as a result of their unique structural diversity. However, reisolation of already known natural products significantly hampers the discovery process, and it is therefore important to incorporate effective microbial isolate selection and dereplication protocols early in microbial natural product studies. We have developed a systematic approach for prioritization of microbial isolates for natural product discovery based on heteronuclear single-quantum correlation-total correlation spectroscopy (HSQC-TOCSY) nuclear magnetic resonance profiles in combination with antiplasmodial activity of extracts...
March 2, 2018: Journal of Natural Products
Matteo Forloni, Alex Y Liu, Narendra Wajapeyee
"Random mutagenesis" is a technique that allows researchers to develop large libraries of variants of a particular DNA sequence. Once developed, these libraries can then be used for several purposes, including structure-function and directed evolution studies. Random mutagenesis is different from other mutagenesis techniques in that it does not require the researcher to have any prior knowledge about the structural properties of the DNA sequence being targeted, thus allowing for the unbiased discovery of novel or beneficial mutations...
March 1, 2018: Cold Spring Harbor Protocols
Sophie Lamarre, Pierre Frasse, Mohamed Zouine, Delphine Labourdette, Elise Sainderichin, Guojian Hu, Véronique Le Berre-Anton, Mondher Bouzayen, Elie Maza
RNA-Seq is a widely used technology that allows an efficient genome-wide quantification of gene expressions for, for example, differential expression (DE) analysis. After a brief review of the main issues, methods and tools related to the DE analysis of RNA-Seq data, this article focuses on the impact of both the replicate number and library size in such analyses. While the main drawback of previous relevant studies is the lack of generality, we conducted both an analysis of a two-condition experiment (with eight biological replicates per condition) to compare the results with previous benchmark studies, and a meta-analysis of 17 experiments with up to 18 biological conditions, eight biological replicates and 100 million (M) reads per sample...
2018: Frontiers in Plant Science
Karel Schoonvaere, Guy Smagghe, Frédéric Francis, Dirk C de Graaf
Bees are associated with a remarkable diversity of microorganisms, including unicellular parasites, bacteria, fungi, and viruses. The application of next-generation sequencing approaches enables the identification of this rich species composition as well as the discovery of previously unknown associations. Using high-throughput polyadenylated ribonucleic acid (RNA) sequencing, we investigated the metatranscriptome of eight wild bee species ( Andrena cineraria, Andrena fulva, Andrena haemorrhoa, Bombus terrestris, Bombus cryptarum, Bombus pascuorum, Osmia bicornis , and Osmia cornuta ) sampled from four different localities in Belgium...
2018: Frontiers in Microbiology
Swechha Mishra, Sangeeta Singh
Background: In experimental therapy of cancer, survivin is considered to be one of the well-established targets. Studies have found that it is overexpression in most of the human tumors, but it is rarely found in normal tissues. It is having varied structural and functional role. It controls cell division and cellular stress response and also regulates metastasis and migration of cancerous cells. It has also been recognized as a biomarker which makes it unconventional drug target. In spite of being one of the centrally active components in metastasis and invasion, their clinical use is minimal...
January 2018: Pharmacognosy Magazine
Yoichi Kadoh, Haruko Miyoshi, Takehiko Matsumura, Yoshihito Tanaka, Mitsuya Hongu, Mayumi Kimura, Kei Takedomi, Kenji Omori, Jun Kotera, Takashi Sasaki, Tamaki Kobayashi, Hiroyuki Taniguchi, Yumi Watanabe, Koki Kojima, Toshiaki Sakamoto, Toshiyuki Himiyama, Eiji Kawanishi
Phosphodiesterase (PDE) 10A is a dual hydrolase of cAMP and cGMP and highly expressed in striatal medium spiny neurons. Inhibition of PDE10A modulates the activity of medium spiny neurons (MSN) via the regulation of cAMP and cGMP. Signal control of MSN is considered associated with psychotic symptoms. Therefore PDE10A inhibitor is expected as a therapeutic method for psychosis disease such as schizophrenia. Avanafil (1) is a PDE5 inhibitor (treatment for erectile dysfunction) discovered by our company. We paid attention to the homology of PDE10A and PDE5 and took advantage of PDE5 inhibitor library to discover PDE10A inhibitors, and found a series of compounds that exhibit higher potency for PDE10A than PDE5...
2018: Chemical & Pharmaceutical Bulletin
Colin S Maxwell, Thomas Jacobsen, Ryan Marshall, Vincent Noireaux, Chase L Beisel
The RNA-guided nucleases derived from the CRISPR-Cas systems in bacteria and archaea have found numerous applications in biotechnology, including genome editing, imaging, and gene regulation. However, the discovery of novel Cas nucleases has outpaced their characterization and subsequent exploitation. A key step in characterizing Cas nucleases is determining which protospacer-adjacent motif (PAM) sequences they recognize. Here, we report advances to an in vitro method based on an E. coli cell-free transcription-translation system (TXTL) to rapidly elucidate PAMs recognized by Cas nucleases...
February 24, 2018: Methods: a Companion to Methods in Enzymology
Panagiotis Lagarias, Eleni Vrontaki, George Lambrinidis, Dimitrios Stamatis, Marino Convertino, Gabriella Ortore, Thomas Mavromoustakos, Karl-Norbert Klotz, Antonios Kolocouris
An intense effort is made by pharmaceutical and academic research laboratories to identify and develop selective antagonists for each adenosine receptor (AR) subtype as potential clinical candidates for "soft" treatment of various diseases. Crystal structures of subtypes A2A and A1ARs offer exciting opportunities for structure-based drug design. In the first part of the present work, Maybridge HitFinderTM library of 14400 compounds was utilized to apply a combination of structure-based against the crystal structure of A2AAR and ligand-based methodologies...
February 27, 2018: Journal of Chemical Information and Modeling
Hartmut Beck, Mario Jeske, Kai Thede, Friederike Stoll, Ingo Flamme, Metin Akbaba, Jens-Kerim Ergüden, Gunter Karig, Jörg Keldenich, Felix Oehme, Hans-Christian Militzer, Ingo V Hartung, Uwe Thuss
Small molecule inhibitors of hypoxia inducible factor prolyl hydroxylases (HIF-PHs) are currently under clinical development as novel treatment option for chronic kidney disease (CKD) associated anemia. Inhibition of HIF-PH mimics hypoxia and leads to increased EPO expression and subsequently increased erythropoiesis. Herein we describe the discovery, synthesis, SAR and proposed binding mode of novel 2,4-diheteroaryl-1,2-dihydro-3H-pyrazol-3-ones as orally bioavailable HIF-PH inhibitors for the treatment of anemia...
February 27, 2018: ChemMedChem
Sergei A Filichkin, Michael Hamilton, Palitha D Dharmawardhana, Sunil K Singh, Christopher Sullivan, Asa Ben-Hur, Anireddy S N Reddy, Pankaj Jaiswal
Abiotic stresses affect plant physiology, development, growth, and alter pre-mRNA splicing. Western poplar is a model woody tree and a potential bioenergy feedstock. To investigate the extent of stress-regulated alternative splicing (AS), we conducted an in-depth survey of leaf, root, and stem xylem transcriptomes under drought, salt, or temperature stress. Analysis of approximately one billion of genome-aligned RNA-Seq reads from tissue- or stress-specific libraries revealed over fifteen millions of novel splice junctions...
2018: Frontiers in Plant Science
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