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https://www.readbyqxmd.com/read/29342416/identification-of-novel-quinazolinedione-derivatives-as-ror%C3%AE-t-inverse-agonist
#1
Yoshiyuki Fukase, Ayumu Sato, Yoshihide Tomata, Atsuko Ochida, Mitsunori Kono, Kazuko Yonemori, Keiko Koga, Toshitake Okui, Masashi Yamasaki, Yasushi Fujitani, Hideyuki Nakagawa, Ryoukichi Koyama, Masaharu Nakayama, Robert Skene, Bi-Ching Sang, Isaac Hoffman, Junya Shirai, Satoshi Yamamoto
Novel small molecules were synthesized and evaluated as retinoic acid receptor-related orphan receptor-gamma t (RORγt) inverse agonists for the treatment of inflammatory and autoimmune diseases. A hit compound, 1, was discovered by high-throughput screening of our compound library. The structure-activity relationship (SAR) study of compound 1 showed that the introduction of a chlorine group at the 3-position of 4-cyanophenyl moiety increased the potency and a 3-methylpentane-1,5-diamide linker is favorable for the activity...
December 28, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/29341586/development-of-a-novel-cytopathic-effect-based-phenotypic-screening-assay-against-cryptosporidium
#2
Alexander T Chao, Boon Heng Lee, Kah Fei Wan, Jeremy Selva, Bin Zou, Peter Gedeck, David Beer, Thierry T Diagana, Ghislain Bonamy, Ujjini H Manjunatha
Cryptosporidiosis is a diarrheal disease predominantly caused by Cryptosporidium parvum (Cp) and Cryptosporidium hominis (Ch), apicomplexan parasites which infect the intestinal epithelial cells of their human hosts. The only approved drug for cryptosporidiosis is nitazoxanide, which shows limited efficacy in immunocompromised children, the most vulnerable patient population. Thus, new therapeutics and in vitro infection models are urgently needed to address the current unmet medical need. Toward this aim, we have developed novel cytopathic effect (CPE)-based Cp and Ch assays in human colonic tumor (HCT-8) cells and compared them to traditional imaging formats...
January 17, 2018: ACS Infectious Diseases
https://www.readbyqxmd.com/read/29341164/patient-derived-organoid-models-help-define-personalized-management-of-gastrointestinal-cancer
#3
REVIEW
M R Aberle, R A Burkhart, H Tiriac, S W M Olde Damink, C H C Dejong, D A Tuveson, R M van Dam
BACKGROUND: The prognosis of patients with different gastrointestinal cancers varies widely. Despite advances in treatment strategies, such as extensive resections and the addition of new drugs to chemotherapy regimens, conventional treatment strategies have failed to improve survival for many tumours. Although promising, the clinical application of molecularly guided personalized treatment has proven to be challenging. This narrative review focuses on the personalization of cancer therapy using patient-derived three-dimensional 'organoid' models...
January 2018: British Journal of Surgery
https://www.readbyqxmd.com/read/29340841/an-efficient-gene-disruption-method-using-a-positive-negative-split-selection-marker-and-agrobacterium-tumefaciens-mediated-transformation-for-nomuraea-rileyi
#4
Yu Su, Zhongkang Wang, Changwen Shao, Yuanli Luo, Li Wang, Youping Yin
Targeted gene disruption via Agrobacterium tumefaciens-mediated transformation (ATMT) and homologous recombination is the most common method used to identify and investigate the functions of genes in fungi. However, the gene disruption efficiency of this method is low due to ectopic integration. In this study, a high-efficiency gene disruption strategy based on ATMT and the split-marker method was developed for use in Nomuraea rileyi. The β-glucuronidase (gus) gene was used as a negative selection marker to facilitate the screening of putative transformants...
January 16, 2018: World Journal of Microbiology & Biotechnology
https://www.readbyqxmd.com/read/29338757/a-rapid-high-resolution-method-for-resolving-dna-topoisomers
#5
Lesley A Mitchenall, Rachel E Hipkin, Michael M Piperakis, Nicolas P Burton, Anthony Maxwell
OBJECTIVE: Agarose gel electrophoresis has been the mainstay technique for the analysis of DNA samples of moderate size. In addition to separating linear DNA molecules, it can also resolve different topological forms of plasmid DNAs, an application useful for the analysis of the reactions of DNA topoisomerases. However, gel electrophoresis is an intrinsically low-throughput technique and suffers from other potential disadvantages. We describe the application of the QIAxcel Advanced System, a high-throughput capillary electrophoresis system, to separate DNA topoisomers, and compare this technique with gel electrophoresis...
January 16, 2018: BMC Research Notes
https://www.readbyqxmd.com/read/29337372/crispr-cas9-edited-site-sequencing-cres-seq-an-efficient-and-high-throughput-method-for-the-selection-of-crispr-cas9-edited-clones
#6
Yaligara Veeranagouda, Delphine Debono-Lagneaux, Hamida Fournet, Gilbert Thill, Michel Didier
The emergence of clustered regularly interspaced short palindromic repeats-Cas9 (CRISPR-Cas9) gene editing systems has enabled the creation of specific mutants at low cost, in a short time and with high efficiency, in eukaryotic cells. Since a CRISPR-Cas9 system typically creates an array of mutations in targeted sites, a successful gene editing project requires careful selection of edited clones. This process can be very challenging, especially when working with multiallelic genes and/or polyploid cells (such as cancer and plants cells)...
January 16, 2018: Current Protocols in Molecular Biology
https://www.readbyqxmd.com/read/29337186/lipoprotein-signal-peptidase-inhibitors-with-antibiotic-properties-identified-through-design-of-a-robust-in%C3%A2-vitro-ht-platform
#7
Seiya Kitamura, Anna Owensby, Daniel Wall, Dennis W Wolan
As resistance to antibiotics increases, the exploration of new targets and strategies to combat pathogenic bacteria becomes more urgent. Ideal protein targets are required for viability across many species, are unique to prokaryotes to limit effects on the host, and have robust assays to quantitate activity and identify inhibitors. Lipoprotein signal peptidase (Lsp) is a transmembrane aspartyl protease required for lipoprotein maturation and comprehensively fits these criteria. Here, we have developed the first in vitro high-throughput assay to monitor proteolysis by Lsp...
January 10, 2018: Cell Chemical Biology
https://www.readbyqxmd.com/read/29337164/identification-of-novel-antivirals-inhibiting-recognition-of-venezuelan-equine-encephalitis-virus-capsid-protein-by-the-importin-%C3%AE-%C3%AE-1-heterodimer-through-high-throughput-screening
#8
David R Thomas, Lindsay Lundberg, Chelsea Pinkham, Sharon Shechter, Aaron Debono, Jonathan Baell, Kylie M Wagstaff, Caroline A Hick, Kylene Kehn-Hall, David A Jans
Although the alphavirus Venezuelan equine encephalitis virus (VEEV) has been the cause of multiple outbreaks resulting in extensive human and equine mortality and morbidity, there are currently no anti-VEEV therapeutics available. VEEV pathogenicity is largely dependent on targeting of the viral capsid protein (CP) to the host cell nucleus through the nuclear transporting importin (Imp) α/β1 heterodimer. Here we perform a high-throughput screen, combined with nested counterscreens to identify small molecules able to inhibit the Impα/β1:CP interaction for the first time...
January 11, 2018: Antiviral Research
https://www.readbyqxmd.com/read/29337119/sox10-single-transcription-factor-based-fast-and-efficient-generation-of%C3%A2-oligodendrocytes-from-human-pluripotent-stem-cells
#9
Juan Antonio García-León, Manoj Kumar, Ruben Boon, David Chau, Jennifer One, Esther Wolfs, Kristel Eggermont, Pieter Berckmans, Nilhan Gunhanlar, Femke de Vrij, Bas Lendemeijer, Benjamin Pavie, Nikky Corthout, Steven A Kushner, José Carlos Dávila, Ivo Lambrichts, Wei-Shou Hu, Catherine M Verfaillie
Scarce access to primary samples and lack of efficient protocols to generate oligodendrocytes (OLs) from human pluripotent stem cells (hPSCs) are hampering our understanding of OL biology and the development of novel therapies. Here, we demonstrate that overexpression of the transcription factor SOX10 is sufficient to generate surface antigen O4-positive (O4+) and myelin basic protein-positive OLs from hPSCs in only 22 days, including from patients with multiple sclerosis or amyotrophic lateral sclerosis. The SOX10-induced O4+ population resembles primary human OLs at the transcriptome level and can myelinate neurons in vivo...
January 10, 2018: Stem Cell Reports
https://www.readbyqxmd.com/read/29336544/identification-of-collateral-sensitivity-to-dihydroorotate-dehydrogenase-inhibitors-in-i-plasmodium-falciparum-i
#10
Leila Saxby Ross, Maria Jose Lafuente-Monasterio, Tomoyo Sakata-Kato, Rebecca E K Mandt, Francisco-Javier Gamo, Dyann F Wirth, Amanda K Lukens
Drug resistance has been reported for every antimalarial in use highlighting the need for new strategies to protect the efficacy of therapeutics in development. We have previously shown that resistance can be suppressed with a population biology trap: by identifying situations where resistance to one compound confers hypersensitivity to another (collateral sensitivity), we can design combination therapies that not only kill the parasite, but also guide its evolution away from resistance. We applied this concept to the Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) enzyme, a well validated antimalarial target with inhibitors in the development pipeline...
January 16, 2018: ACS Infectious Diseases
https://www.readbyqxmd.com/read/29336194/a-robust-multiplex-mass-spectrometric-assay-for-screening-small-molecule-inhibitors-of-cd73-with-diverse-inhibition-modalities
#11
Jessica McManus, Timothy He, Julie-Ann Gavigan, Ghislaine Marchand, Stephanie Vougier, Olivier Bedel, Paul Ferrari, Rosalia Arrebola, Timothy Gillespy, Richard C Gregory, Stuart Licht, Hong Cheng, Bailin Zhang, Gejing Deng
CD73/Ecto-5'-nucleotidase is a membrane-tethered ecto-enzyme that works in tandem with CD39 to convert extracellular adenosine triphosphate (ATP) into adenosine. CD73 is highly expressed on various types of cancer cells and on infiltrating suppressive immune cells, leading to an elevated concentration of adenosine in the tumor microenvironment, which elicits a strong immunosuppressive effect. In preclinical studies, targeting CD73 with anti-CD73 antibody results in favorable antitumor effects. Despite initial studies using antibodies, inhibition of CD73 catalytic activity using small-molecule inhibitors may be more effective in lowering extracellular adenosine due to better tumor penetration and distribution...
January 1, 2018: SLAS Discovery
https://www.readbyqxmd.com/read/29335539/brain-activity-patterns-in-high-throughput-electrophysiology-screen-predict-both%C3%A2-drug-efficacies-and-side-effects
#12
Peter M Eimon, Mostafa Ghannad-Rezaie, Gianluca De Rienzo, Amin Allalou, Yuelong Wu, Mu Gao, Ambrish Roy, Jeffrey Skolnick, Mehmet Fatih Yanik
Neurological drugs are often associated with serious side effects, yet drug screens typically focus only on efficacy. We demonstrate a novel paradigm utilizing high-throughput in vivo electrophysiology and brain activity patterns (BAPs). A platform with high sensitivity records local field potentials (LFPs) simultaneously from many zebrafish larvae over extended periods. We show that BAPs from larvae experiencing epileptic seizures or drug-induced side effects have substantially reduced complexity (entropy), similar to reduced LFP complexity observed in Parkinson's disease...
January 15, 2018: Nature Communications
https://www.readbyqxmd.com/read/29334378/supermultiplexed-optical-imaging-and-barcoding-with-engineered-polyynes
#13
Fanghao Hu, Chen Zeng, Rong Long, Yupeng Miao, Lu Wei, Qizhi Xu, Wei Min
Optical multiplexing has a large impact in photonics, the life sciences and biomedicine. However, current technology is limited by a 'multiplexing ceiling' from existing optical materials. Here we engineered a class of polyyne-based materials for optical supermultiplexing. We achieved 20 distinct Raman frequencies, as 'Carbon rainbow', through rational engineering of conjugation length, bond-selective isotope doping and end-capping substitution of polyynes. With further probe functionalization, we demonstrated ten-color organelle imaging in individual living cells with high specificity, sensitivity and photostability...
January 15, 2018: Nature Methods
https://www.readbyqxmd.com/read/29334207/screening-for-causative-mutations-of-major-prolificacy-genes-in-iranian-fat-tailed-sheep
#14
Ramin Abdoli, Seyed Ziaeddin Mirhoseini, Navid Ghavi Hossein-Zadeh, Pouya Zamani
Background: The presence of different missense mutations in sheep breeds have shown that the bone morphogenetic protein receptor 1B (BMPR1B), bone morphogenetic protein 15 (BMP15) and growth differentiation factor 9 (GDF9) genes play a vital role in ovulation rate and prolificacy in ewes. Therefore, the present study aims to investigate BMPR1B, BMP15 and GDF9 gene mutations in prolific ewes of Iranian fat-tailed Lori-Bakhtiari sheep. MATERIALS AND METHODS: In the present experimental study, genomic DNA was extracted from whole blood of 10 prolific Lori-Bakhtiari ewes with at least two twinning records in the first four parities to identify point mutations of the BMPR1B, BMP15 and GDF9 genes, using DNA sequencing...
April 2018: International Journal of Fertility & Sterility
https://www.readbyqxmd.com/read/29332810/sensitive-fluorescence-sensing-of-t4-polynucleotide-kinase-activity-and-inhibition-based-on-dna-polydopamine-nanospheres-platform
#15
Yao Cen, Wen-Jing Deng, Ru-Qin Yu, Xia Chu
5'-Polynucleotide kinase (PNK) is a crucial enzyme that catalyzes the phosphorylation of nucleic acid with 5'-OH termini and this phosphorylation reaction has been involved in many important cellular activities. The evaluation of PNK activity has received an increasing attention due to the significance of PNK. Here, the polydopamine nanospheres (PDANS) could adsorb single-stranded DNA (ssDNA) through π-π stacking or hydrogen bonding between nucleobases and aromatic groups of PDANS, while the interaction between double-stranded DNA (dsDNA) with PDANS was weakened due to the changed conformation...
April 1, 2018: Talanta
https://www.readbyqxmd.com/read/29331267/identification-and-initial-optimization-of-inhibitors-of-clostridium-difficile-c-difficile-toxin-b-tcdb
#16
Jeffrey J Letourneau, Ilana L Stroke, David W Hilbert, Laurie J Sturzenbecker, Brett A Marinelli, Jorge G Quintero, Joan Sabalski, Linh Ma, David J Diller, Philip D Stein, Maria L Webb
The discovery, synthesis and preliminary structure-activity relationship (SAR) of a novel class of inhibitors of Clostridium difficile (C. difficile) toxin B (TcdB) is described. A high throughput screening (HTS) campaign resulted in the identification of moderately active screening hits 1-5 the most potent of which was compound 1 (IC50 = 0.77 µM). In silico docking of an early analog offered suggestions for structural modification which resulted in the design and synthesis of highly potent analogs 13j(IC50 = 1 nM) and 13 l(IC50 = 7 nM) which were chosen as leads for further optimization...
January 5, 2018: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/29330186/effect-of-plasmid-design-and-type-of-integration-event-on-recombinant-protein-expression-in-pichia-pastoris
#17
Thomas Vogl, Leigh Gebbie, Robin W Palfreyman, Robert Speight
Pichia pastoris (syn. Komagataella phaffii) is one of the most common eukaryotic expression systems for heterologous protein production. Expression cassettes are typically integrated in the genome to obtain stable expression strains. In contrast to Saccharomyces cerevisiae, where short overhangs are sufficient to target highly specific integration, long overhangs are more efficient in P. pastoris and ectopic integration of foreign DNA can occur. Here, we aimed to elucidate the influence of ectopic integration by high throughput screening of >700 transformants and whole genome sequencing of 27 transformants...
January 12, 2018: Applied and Environmental Microbiology
https://www.readbyqxmd.com/read/29330113/runt-related-transcription-factor-1-runx1-deficiency-attenuates-inflammation-induced-pro-inflammatory-and-pro-labour-mediators-in-myometrium
#18
Martha Lappas
Identifying new targets that regulate myometrial activation are required to develop effective treatments to stop preterm labor. Inflammation, which can be induced by sterile or infective insults, plays a role in initiating and maintaining uterine contractions. Several high throughput transcription screening studies have identified an upregulation of runt-related transcription factor 1 (RUNX1) mRNA expression in myometrium with labor. The role of RUNX1 in labor, however, is not known. We report increased RUNX1 during late gestation which was further augmented in labor, suggesting that RUNX1 may be involved in the transition of the myometrium from a quiescent into a contractile state in preparation for labor...
January 9, 2018: Molecular and Cellular Endocrinology
https://www.readbyqxmd.com/read/29329925/phenotypic-and-molecular-characterisation-of-a-serum-free-miniature-erythroid-differentiation-system-suitable-for-high-throughput-screening-and-single-cell-assays
#19
Sachith Mettananda, Kevin Clark, Chris A Fisher, Jackie A Sloane-Stanley, Richard J Gibbons, Douglas R Higgs
In vitro erythroid differentiation systems are used to study the mechanisms underlying normal and abnormal erythropoiesis and to test the effects of various extracellular factors on erythropoiesis. The use of serum or conditioned medium in liquid cultures, and seeding cultures with heterogeneous peripheral blood mononuclear cells confound the reproducibility of these systems. Newer erythroid differentiation culture systems have overcome some of these limitations by using a fully defined, serum-free, medium and initiating cultures using purified CD34+ cells...
January 9, 2018: Experimental Hematology
https://www.readbyqxmd.com/read/29329553/inhibitors-of-the-integrase-transportin-sr2-interaction-block-hiv-nuclear-import
#20
Jonas Demeulemeester, Jolien Blokken, Stéphanie De Houwer, Lieve Dirix, Hugo Klaassen, Arnaud Marchand, Patrick Chaltin, Frauke Christ, Zeger Debyser
BACKGROUND: Combination antiretroviral therapy efficiently suppresses HIV replication in infected patients, transforming HIV/AIDS into a chronic disease. Viral resistance does develop however, especially under suboptimal treatment conditions such as poor adherence. As a consequence, continued exploration of novel targets is paramount to identify novel antivirals that do not suffer from cross-resistance with existing drugs. One new promising class of targets are HIV protein-cofactor interactions...
January 12, 2018: Retrovirology
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