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https://www.readbyqxmd.com/read/29342358/synthesis-and-biological-characterization-of-aryl-uracil-inhibitors-of-hepatitis-c-virus-ns5b-polymerase-discovery-of-abt-072-a-trans-stilbene-analog-with-good-oral-bioavailability
#1
John Randolph, A Chris Krueger, Pamela Donner, John K Pratt, Dachun Liu, Christopher E Motter, Todd W Rockway, Mike D Tufano, Rolf Wagner, Hock B Lim, Jill M Beyer, Rubina Mondal, Neeta S Panchal, Lynn Colletti, Yaya Liu, Gennadiy Koev, Warren M Kati, Lisa E Hernandez, David W A Beno, Kenton L Longenecker, Kent D Stewart, Emily O Dumas, Akhteruzzaman Molla, Clarence Maring
ABT-072 is a non-nucleoside HCV NS5B polymerase inhibitor that was discovered as part of a program to identify new direct-acting antivirals (DAAs) for the treatment of HCV infection. This compound was identified during a medicinal chemistry effort to improve on an original lead, inhibitor 1, which we described in a previous publication. Replacement of the amide linkage in 1 with a trans-olefin resulted in improved compound permeability and solubility, and provided much better pharmacokinetic properties in preclinical species...
January 17, 2018: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29342309/prognostic-power-of-a-tumor-differentiation-gene-signature-for-bladder-urothelial-carcinomas
#2
Qianxing Mo, Fotis Nikolos, Fengju Chen, Zoe Tramel, Yu-Cheng Lee, Kazukuni Hayashi, Jing Xiao, Jianjun Shen, Keith Syson Chan
Background: Muscle-invasive bladder cancers (MIBCs) cause approximately 150 000 deaths per year worldwide. Survival for MIBC patients is heterogeneous, with no clinically validated molecular markers that predict clinical outcome. Non-MIBCs (NMIBCs) generally have favorable outcome; however, a portion progress to MIBC. Hence, development of a prognostic tool that can guide decision-making is crucial for improving clinical management of bladder urothelial carcinomas. Methods: Tumor grade is defined by pathologic evaluation of tumor cell differentiation, and it often associates with clinical outcome...
January 12, 2018: Journal of the National Cancer Institute
https://www.readbyqxmd.com/read/29342301/subtyping-bladder-cancers-biology-vs-bioinformatics
#3
David J McConkey, Woonyoung Choi
No abstract text is available yet for this article.
January 12, 2018: Journal of the National Cancer Institute
https://www.readbyqxmd.com/read/29342297/an-exact-goodness-of-fit-test-based-on-the-occupancy-problems-to-study-zero-inflation-and-zero-deflation-in-biological-dosimetry-data
#4
Amanda Fernández-Fontelo, Pedro Puig, Elizabeth A Ainsbury, Manuel Higueras
The goal in biological dosimetry is to estimate the dose of radiation that a suspected irradiated individual has received. For that, the analysis of aberrations (most commonly dicentric chromosome aberrations) in scored cells is performed and dose response calibration curves are built. In whole body irradiation (WBI) with X- and gamma-rays, the number of aberrations in samples is properly described by the Poisson distribution, although in partial body irradiation (PBI) the excess of zeros provided by the non-irradiated cells leads, for instance, to the Zero-Inflated Poisson distribution...
January 12, 2018: Radiation Protection Dosimetry
https://www.readbyqxmd.com/read/29342277/finding-nemo-hybrid-assembly-with-oxford-nanopore-and-illumina-reads-greatly-improves-the-clownfish-amphiprion-ocellaris-genome-assembly
#5
Mun Hua Tan, Christopher M Austin, Michael P Hammer, Yin Peng Lee, Laurence J Croft, Han Ming Gan
Background: Some of the most widely recognised coral-reef fishes are clownfish or anemonefishes, members of the family Pomacentridae (subfamily: Amphiprioninae). They are popular aquarium species due to their bright colours, adaptability to captivity and fascinating behavior. Their breeding biology (sequential hermaphrodites) and symbiotic mutualism with sea anemones have attracted much scientific interest. Moreover, there are some curious geographic-based phenotypes which warrant investigation...
January 12, 2018: GigaScience
https://www.readbyqxmd.com/read/29342245/structure-function-relationships-of-olfactory-and-taste-receptors
#6
Maik Behrens, Loïc Briand, Claire A de March, Hiroaki Matsunami, Atsuko Yamashita, Wolfgang Meyerhof, Simone Weyand
The field of chemical senses has made major progress in understanding the cellular mechanisms of olfaction and taste in the past two decades. However, the molecular understanding of odour and taste recognition is still lagging far behind and will require solving multiple structures of the relevant full-length receptors in complex with native ligands to achieve this goal. However, the development of multiple complimentary strategies for the structure determination of G protein-coupled receptors (GPCRs) makes this goal realistic...
January 12, 2018: Chemical Senses
https://www.readbyqxmd.com/read/29342233/quantumclone-clonal-assessment-of-functional-mutations-in-cancer-based-on-a-genotype-aware-method-for-clonal-reconstruction
#7
Paul Deveau, Leo Colmet Daage, Derek Oldridge, Virginie Bernard, Angela Bellini, Mathieu Chicard, Nathalie Clement, Eve Lapouble, Valerie Combaret, Anne Boland, Vincent Meyer, Jean-Francois Deleuze, Isabelle Janoueix-Lerosey, Emmanuel Barillot, Olivier Delattre, John Maris, Gudrun Schleiermacher, Valentina Boeva
Motivation: In cancer, clonal evolution is assessed based on information coming from single nucleotide variants and copy number alterations. Nonetheless, existing methods often fail to accurately combine information from both sources to truthfully reconstruct clonal populations in a given tumor sample or in a set of tumor samples coming from the same patient. Moreover, previously published methods detect clones from a single set of variants. As a result, compromises have to be done between stringent variant filtering (reducing dispersion in variant allele frequency estimates, VAFs) and using all biologically relevant variants...
January 12, 2018: Bioinformatics
https://www.readbyqxmd.com/read/29342213/circulating-neutrophil-transcriptome-may-reveal-intracranial-aneurysm-signature
#8
Vincent M Tutino, Kerry E Poppenberg, Kaiyu Jiang, James N Jarvis, Yijun Sun, Ashish Sonig, Adnan H Siddiqui, Kenneth V Snyder, Elad I Levy, John Kolega, Hui Meng
BACKGROUND: Unruptured intracranial aneurysms (IAs) are typically asymptomatic and undetected except for incidental discovery on imaging. Blood-based diagnostic biomarkers could lead to improvements in IA management. This exploratory study examined circulating neutrophils to determine whether they carry RNA expression signatures of IAs. METHODS: Blood samples were collected from patients receiving cerebral angiography. Eleven samples were collected from patients with IAs and 11 from patients without IAs as controls...
2018: PloS One
https://www.readbyqxmd.com/read/29342203/biological-pathways-underlying-the-association-of-red-cell-distribution-width-and-adverse-clinical-outcome-results-of-a-prospective-cohort-study
#9
Giedre Zurauskaite, Marc Meier, Alaadin Voegeli, Daniel Koch, Sebastian Haubitz, Alexander Kutz, Luca Bernasconi, Andreas Huber, Mario Bargetzi, Beat Mueller, Philipp Schuetz
BACKGROUND: Red cell distribution width (RDW) predicts disease outcome in several patient populations, but its prognostic value in addition to other disease parameters in unselected medical inpatients remains unclear. Our aim was to investigate the association of admission RDW levels and mortality adjusted for several disease pathways in unselected medical patients from a previous multicenter study. METHODS: We included consecutive adult, medical patients at the time point of hospital admission through the emergency department into this observational, cohort study...
2018: PloS One
https://www.readbyqxmd.com/read/29342193/analysis-of-copy-number-loss-of-the-erbb4-receptor-tyrosine-kinase-in-glioblastoma
#10
DeAnalisa C Jones, Adriana Scanteianu, Matthew DiStefano, Mehdi Bouhaddou, Marc R Birtwistle
Current treatments for glioblastoma multiforme (GBM)-an aggressive form of brain cancer-are minimally effective and yield a median survival of 14.6 months and a two-year survival rate of 30%. Given the severity of GBM and the limitations of its treatment, there is a need for the discovery of novel drug targets for GBM and more personalized treatment approaches based on the characteristics of an individual's tumor. Most receptor tyrosine kinases-such as EGFR-act as oncogenes, but publicly available data from the Cancer Cell Line Encyclopedia (CCLE) indicates copy number loss in the ERBB4 RTK gene across dozens of GBM cell lines, suggesting a potential tumor suppressor role...
2018: PloS One
https://www.readbyqxmd.com/read/29342181/optimization-of-mneongreen-for-homo-sapiens-increases-its-fluorescent-intensity-in-mammalian-cells
#11
Emiko Tanida-Miyake, Masato Koike, Yasuo Uchiyama, Isei Tanida
Green fluorescent protein (GFP) is tremendously useful for investigating many cellular and intracellular events. The monomeric GFP mNeonGreen is about 3- to 5-times brighter than GFP and monomeric enhanced GFP and shows high photostability. The maturation half-time of mNeonGreen is about 3-fold faster than that of monomeric enhanced GFP. However, the cDNA sequence encoding mNeonGreen contains some codons that are rarely used in Homo sapiens. For better expression of mNeonGreen in human cells, we synthesized a human-optimized cDNA encoding mNeonGreen and generated an expression plasmid for humanized mNeonGreen under the control of the cytomegalovirus promoter...
2018: PloS One
https://www.readbyqxmd.com/read/29342145/the-gram-negative-bacterial-periplasm-size-matters
#12
Samuel I Miller, Nina R Salama
Gram-negative bacteria are surrounded by two membrane bilayers separated by a space termed the periplasm. The periplasm is a multipurpose compartment separate from the cytoplasm whose distinct reducing environment allows more efficient and diverse mechanisms of protein oxidation, folding, and quality control. The periplasm also contains structural elements and important environmental sensing modules, and it allows complex nanomachines to span the cell envelope. Recent work indicates that the size or intermembrane distance of the periplasm is controlled by periplasmic lipoproteins that anchor the outer membrane to the periplasmic peptidoglycan polymer...
January 2018: PLoS Biology
https://www.readbyqxmd.com/read/29342141/monitoring-t-cell-dendritic-cell-interactions-in-vivo-by-intercellular-enzymatic-labelling
#13
Giulia Pasqual, Aleksey Chudnovskiy, Jeroen M J Tas, Marianna Agudelo, Lawrence D Schweitzer, Ang Cui, Nir Hacohen, Gabriel D Victora
Interactions between different cell types are essential for multiple biological processes, including immunity, embryonic development and neuronal signalling. Although the dynamics of cell-cell interactions can be monitored in vivo by intravital microscopy, this approach does not provide any information on the receptors and ligands involved or enable the isolation of interacting cells for downstream analysis. Here we describe a complementary approach that uses bacterial sortase A-mediated cell labelling across synapses of immune cells to identify receptor-ligand interactions between cells in living mice, by generating a signal that can subsequently be detected ex vivo by flow cytometry...
January 17, 2018: Nature
https://www.readbyqxmd.com/read/29342140/atomic-structure-of-the-eukaryotic-intramembrane-ras-methyltransferase-icmt
#14
Melinda M Diver, Leanne Pedi, Akiko Koide, Shohei Koide, Stephen B Long
The maturation of RAS GTPases and approximately 200 other cellular CAAX proteins involves three enzymatic steps: addition of a farnesyl or geranylgeranyl prenyl lipid to the cysteine (C) in the C-terminal CAAX motif, proteolytic cleavage of the AAX residues and methylation of the exposed prenylcysteine residue at its terminal carboxylate. This final step is catalysed by isoprenylcysteine carboxyl methyltransferase (ICMT), a eukaryote-specific integral membrane enzyme that resides in the endoplasmic reticulum...
January 17, 2018: Nature
https://www.readbyqxmd.com/read/29342135/structures-of-%C3%AE-klotho-reveal-a-zip-code-like-mechanism-for-endocrine-fgf-signalling
#15
Sangwon Lee, Jungyuen Choi, Jyotidarsini Mohanty, Leiliane P Sousa, Francisco Tome, Els Pardon, Jan Steyaert, Mark A Lemmon, Irit Lax, Joseph Schlessinger
Canonical fibroblast growth factors (FGFs) activate FGF receptors (FGFRs) through paracrine or autocrine mechanisms in a process that requires cooperation with heparan sulfate proteoglycans, which function as co-receptors for FGFR activation. By contrast, endocrine FGFs (FGF19, FGF21 and FGF23) are circulating hormones that regulate critical metabolic processes in a variety of tissues. FGF19 regulates bile acid synthesis and lipogenesis, whereas FGF21 stimulates insulin sensitivity, energy expenditure and weight loss...
January 17, 2018: Nature
https://www.readbyqxmd.com/read/29342118/microbial-degradation-behavior-in-seawater-of-polyester-blends-containing-poly-3-hydroxybutyrate-co-3-hydroxyhexanoate-phbhhx
#16
Hitoshi Sashiwa, Ryuji Fukuda, Tetsuo Okura, Shunsuke Sato, Atsuyoshi Nakayama
The microbial degradation behavior of poly(3-hydroxybutyrate-co-3-hydroxyhexanoate) (PHBHHx) and its compound with several polyesters such as poly(butylene adipate-co-telephtharate) (PBAT), poly(butylene succinate) (PBS), and polylactic acid (PLA) in seawater was tested by a biological oxygen demand (BOD) method. PHBHHx showed excellent biodegradation in seawater in this study. In addition, the biodegradation rate of several blends was much influenced by the weight ratio of PHBHHx in their blends and decreased in accordance with the decrement of PHBHHX ratio...
January 17, 2018: Marine Drugs
https://www.readbyqxmd.com/read/29342112/useful-bicistronic-reporter-system-for-studying-poly-a-site-defining-cis-elements-and-regulation-of-alternative-polyadenylation
#17
Zhongyuan Deng, Shen Zhang, Shaohua Gu, Xinzhi Ni, Wenxian Zeng, Xianchun Li
The link between polyadenylation (pA) and various biological, behavioral, and pathological events of eukaryotes underlines the need to develop in vivo polyadenylation assay methods for characterization of the cis-acting elements, trans-acting factors and environmental stimuli that affect polyadenylation efficiency and/or relative usage of two alternative polyadenylation (APA) sites. The current protein-based CAT or luciferase reporter systems can measure the polyadenylation efficiency of a single pA site or candidate cis element but not the choice of two APA sites...
January 17, 2018: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/29342104/synthesis-anti-proliferative-activity-evaluation-and-3d-qsar-study-of-naphthoquinone-derivatives-as-potential-anti-colorectal-cancer-agents
#18
Julio Acuña, Jhoan Piermattey, Daneiva Caro, Sven Bannwitz, Luis Barrios, Jairo López, Yanet Ocampo, Ricardo Vivas-Reyes, Fabio Aristizábal, Ricardo Gaitán, Klaus Müller, Luis Franco
Colorectal cancer (CRC) is a disease with high incidence and mortality, constituting the fourth most common cause of death from cancer worldwide. Naphthoquinones are attractive compounds due to their biological and structural properties. In this work, 36 naphthoquinone derivatives were synthesized and their activity evaluated against HT-29 cells. Overall, high to moderate anti-proliferative activity was observed in most members of the series, with 15 compounds classified as active (1.73 < IC50 < 18.11 μM)...
January 17, 2018: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/29342010/the-ever-expanding-saga-of-the-proprotein-convertases-and-their-roles-in-body-homeostasis-emphasis-on-novel-proprotein-convertase-subtilisin-kexin-number-9-functions-and-regulation
#19
Nabil G Seidah, Michel Chrétien, Majambu Mbikay
PURPOSE OF REVIEW: The nine members of the proprotein convertase family play major physiological roles during development and in the adult, and their dysregulation leads to various diseases. The primary objective of this article is to review recent findings on the clinical importance of some of these convertases concentrating mostly on PCSK9, the ninth member of the convertase family. This includes the transcriptional and translational regulation of PCSK9, its ability to enhance the degradation of LDL receptor (LDLR), and the implication of PCSK9 in inflammation and sepsis...
January 15, 2018: Current Opinion in Lipidology
https://www.readbyqxmd.com/read/29341931/bioinspired-capsules-based-on-nanocellulose-xyloglucan-and-pectin-the-influence-of-capsule-wall-composition-on-permeability-properties
#20
T Paulraj, A V Riazanova, A J Svagan
Materials based on renewable biopolymers, selective permeability and stimuli-responsive release/loading properties play an important role in biomedical applications. Here, in order to mimic the plant primary cell-wall, microcapsules have been fabricated using cell wall polysaccharides, namely pectin, xyloglucan and cellulose nanofibers. For the first time, a large amount of xyloglucan was successfully included in such capsules. These capsules demonstrated stimuli-responsive (ON/OFF) permeability and biocompatibility...
January 13, 2018: Acta Biomaterialia
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