bluuebunny/crossref_metadata_2025_split huggingface dataset:
High-throughput screening identified selective inhibitors of exosome biogenesis and secretion: A drug repurposing strategy for advanced cancer
Authors: Datta Amrita , Kim Hogyoung , McGee Lauren , Johnson Adedoyin E. , Talwar Sudha , Marugan Juan , Southall Noel , Hu Xin , Lal Madhu , Mondal Debasis , Ferrer Marc , Abdel-Mageed Asim B. 
Published: May 2018

AbstractTargeting exosome biogenesis and release may have potential clinical implications for cancer therapy. Herein, we have optimized a quantitative high throughput screen (qHTS) assay to identify compounds that modulate exosome biogenesis and/or release by aggressive prostate cancer (PCa) CD63-GFP-expressing C4-2B cells. A total of 4,580 compounds were screened from the LOPAC library (a collection of 1,280 pharmacologically active compounds) and the NPC library (NCGC collection of 3,300 compounds approved for clinical use). Twenty-two compounds were found to be either potent activators or inhibitors of intracellular GFP signal in the CD63-GFP-expressing C4-2B cells. The activity of lead compounds in modulating the secretion of exosomes was validated by a tunable resistive pulse sensing (TRPS) system (qNano-IZON) and flow cytometry. The mechanism of action of the lead compounds in modulating exosome biogenesis and/or secretion were delineated by immunoblot analysis of protein markers of the endosomal sorting complex required for transport (ESCRT)-dependent and ESCRT-independent pathways. The lead compounds tipifarnib, neticonazole, climbazole, ketoconazole, and triademenol were validated as potent inhibitors and sitafloxacin, forskolin, SB218795, fenoterol, nitrefazole and pentetrazol as activators of exosome biogenesis and/or secretion in PC cells. Our findings implicate the potential utility of drug-repurposing as novel adjunct therapeutic strategies in advanced cancer.
Multiple implications of an active site phenylalanine in the catalysis of aryl-alcohol oxidase
Authors: Carro Juan , Amengual-Rigo Pep , Sancho Ferran , Medina Milagros , Guallar Victor , Ferreira Patricia , Martínez Angel T. 
Published: May 2018

AbstractAryl-alcohol oxidase (AAO) has demonstrated to be an enzyme with a bright future ahead due to its biotechnological potential in deracemisation of chiral compounds, production of bioplastic precursors and other reactions of interest. Expanding our understanding on the AAO reaction mechanisms, through the investigation of its structure-function relationships, is crucial for its exploitation as an industrial biocatalyst. In this regard, previous computational studies suggested an active role for AAO Phe397 at the active-site entrance. This residue is located in a loop that partially covers the access to the cofactor forming a bottleneck together with two other aromatic residues. Kinetic and affinity spectroscopic studies, complemented with computational simulations using the recently developed adaptive-PELE technology, reveal that the Phe397 residue is important for product release and to help the substrates attain a catalytically relevant position within the active-site cavity. Moreover, removal of aromaticity at the 397 position impairs the oxygen-reduction activity of the enzyme. Experimental and computational findings agree very well in the timing of product release from AAO, and the simulations help to understand the experimental results. This highlights the potential of adaptive-PELE to provide answers to the questions raised by the empirical results in the study of enzyme mechanisms.
Dissecting Clinical and Metabolomics Associations of Left Atrial Phasic Function by Cardiac Magnetic Resonance Feature Tracking
Authors: Koh Angela S. , Gao Fei , Leng Shuang , Kovalik Jean-Paul , Zhao Xiaodan , Tan Ru San , Fridianto Kevin Timothy , Ching Jianhong , Chua Serene JM , Yuan Jian-Min , Koh Woon-Puay , Zhong Liang 
Published: May 2018

AbstractAmong community cohorts, associations between clinical and metabolite factors and complex left atrial (LA) phasic function assessed by cardiac magnetic resonance (CMR) feature tracking (FT) are unknown. Longitudinal LA strain comprising reservoir strain (εs), conduit strain (εe) and booster strain (εa) and their corresponding peak strain rates (SRs, SRe, SRa) were measured using CMR FT. Targeted mass spectrometry measured 83 circulating metabolites in serum. Sparse Principal Component Analysis was used for data reduction. Among community adults (n = 128, 41% female) (mean age: 70.5 ± 11.6 years), age was significantly associated with εs (β = −0.30, p < 0.0001), εe (β = −0.3, p < 0.0001), SRs (β = −0.02, p < 0.0001), SRe (β = 0.04, p < 0.0001) and SRe/SRa (β = −0.01, p = 0.012). In contrast, heart rate was significantly associated with εa (β = 0.1, p = 0.001) and SRa (β = −0.02, p < 0.0001). Serine was significantly associated with εs (β = 10.1, p = 0.015), SRs (β = 0.5, p = 0.033) and SRa (β = −0.9, p = 0.016). Citrulline was associated with εs (β = −4.0, p = 0.016), εa (β = −3.4, p = 0.002) and SRa (β = 0.4, p = 0.019). Valine was associated with ratio of SRe:SRa (β = −0.4, p = 0.039). Medium and long chain dicarboxyl carnitines were associated with εs (β = −0.6, p = 0.038). Phases of LA function were differentially associated with clinical and metabolite factors. Metabolite signals may be used to advance mechanistic understanding of LA disease in future studies.
Network-guided genomic and metagenomic analysis of the faecal microbiota of the critically endangered kakapo
Authors: Waite David W. , Dsouza Melissa , Sekiguchi Yuji , Hugenholtz Philip , Taylor Michael W. 
Published: May 2018

AbstractThe kakapo is a critically endangered, herbivorous parrot endemic to New Zealand. The kakapo hindgut hosts a dense microbial community of low taxonomic diversity, typically dominated by Escherichia fergusonii, and has proven to be a remarkably stable ecosystem, displaying little variation in core membership over years of study. To elucidate mechanisms underlying this robustness, we performed 16S rRNA gene-based co-occurrence network analysis to identify potential interactions between E. fergusonii and the wider bacterial community. Genomic and metagenomic sequencing were employed to facilitate interpretation of potential interactions observed in the network. E. fergusonii maintained very few correlations with other members of the microbiota, and isolates possessed genes for the generation of energy from a wide range of carbohydrate sources, including plant fibres such as cellulose. We surmise that this dominant microorganism is abundant not due to ecological interaction with other members of the microbiota, but its ability to metabolise a wide range of nutrients in the gut. This research represents the first concerted effort to understand the functional roles of the kakapo microbiota, and leverages metagenomic data to contextualise co-occurrence patterns. By combining these two techniques we provide a means for studying the diversity-stability hypothesis in the context of bacterial ecosystems.
Long-Term Administration of Conjugated Estrogen and Bazedoxifene Decreased Murine Fecal β-Glucuronidase Activity Without Impacting Overall Microbiome Community
Authors: Chen Karen Lee Ann , Liu Xiaoji , Zhao Yiru Chen , Hieronymi Kadriye , Rossi Gianluigi , Auvil Loretta Sue , Welge Michael , Bushell Colleen , Smith Rebecca Lee , Carlson Kathryn E. , Kim Sung Hoon , Katzenellenbogen John A. , Miller Michael Joseph , Madak-Erdogan Zeynep 
Published: May 2018

AbstractConjugated estrogens (CE) and Bazedoxifene (BZA) combination is used to alleviate menopause-associated symptoms in women. CE+BZA undergo first-pass-metabolism in the liver and deconjugation by gut microbiome via β-glucuronidase (GUS) enzyme inside the distal gut. To date, the impact of long-term exposure to CE+BZA on the gut microbiome or GUS activity has not been examined. Our study using an ovariectomized mouse model showed that CE+BZA administration did not affect the overall cecal or fecal microbiome community except that it decreased the abundance ofAkkermansia, which was identified as a fecal biomarker correlated with weight gain. The fecal GUS activity was reduced significantly and was positively correlated with the abundance of Lactobacillaceae in the fecal microbiome. We further confirmed inEscherichia coliK12 andLactobacillus gasseriADH that Tamoxifen-, 4-hydroxy-Tamoxifen- and Estradiol-Glucuronides competed for GUS activity. Our study for the first time demonstrated that long-term estrogen supplementation directly modulated gut microbial GUS activity. Our findings implicate that long-term estrogen supplementation impacts composition of gut microbiota and microbial activity, which affects estrogen metabolism in the gut. Thus, it is possible to manipulate such activity to improve the efficacy and safety of long-term administered estrogens for postmenopausal women or breast cancer patients.
Multiple Reaction Monitoring for quantitative laccase kinetics by LC-MS
Authors: Perna Valentina , Agger Jane W. , Holck Jesper , Meyer Anne S. 
Published: May 2018

AbstractLaccases (EC 1.10.3.2) are enzymes known for their ability to catalyse the oxidation of phenolic compounds using molecular oxygen as the final electron acceptor. Lignin is a natural phenylpropanoids biopolymer whose degradation in nature is thought to be aided by enzymatic oxidation by laccases. Laccase activity is often measured spectrophotometrically on compounds such as syringaldazine and ABTS which poorly relate to lignin. We employed natural phenolic hydroxycinnamates having different degree of methoxylations, p-coumaric, ferulic and sinapic acid, and a lignin model OH-dilignol compound as substrates to assess enzyme kinetics by HPLC-MS on two fungal laccases Trametes versicolor laccase, Tv and Ganoderma lucidum laccase, Gl. The method allowed accurate kinetic measurements and detailed insight into the product profiles of both laccases. Both Tv and Gl laccase are active on the hydroxycinnammates and show a preference for substrate with methoxylations. Product profiles were dominated by the presence of dimeric and trimeric species already after 10 minutes of reaction and similar profiles were obtained with the two laccases. This new HPLC-MS method is highly suitable and accurate as a new method for assaying laccase activity on genuine phenolic substrates, as well as a tool for examining laccase oxidation product profiles.
Effects of Low-level Brodifacoum Exposure on the Feline Immune Response
Authors: Kopanke Jennifer H. , Horak Katherine E. , Musselman Esther , Miller Craig A. , Bennett Kristine , Olver Christine S. , Volker Steven F. , VandeWoude Sue , Bevins Sarah N. 
Published: May 2018

AbstractAnticoagulant rodenticides have been implicated as a potential inciting factor in the development of mange in wild felids, but a causative association between anticoagulant rodenticide exposure and immune suppression has not been established. Specific-pathogen-free domestic cats were exposed to brodifacoum over a 6-week period to determine whether chronic, low-level exposure altered the feline immune response. Cats were vaccinated with irrelevant antigens at different points during the course of the experiment to assess recall and direct immune responses. Measures of immune response included delayed-type hypersensitivity tests and cell proliferation assays. IgE and antigen-specific antibodies were quantified via ELISA assays, and cytokine induction following exposure to vaccine antigens was also analyzed. While cats had marked levels of brodifacoum present in blood during the study, no cats developed coagulopathies or hematologic abnormalities. Brodifacoum-exposed cats had transient, statistically significant decreases in the production of certain cytokines, but all other measures of immune function remained unaffected throughout the study period. This study indicates that cats may be more resistant to clinical effects of brodifacoum exposure than other species and suggests that the gross impacts of environmentally realistic brodifacoum exposure on humoral and cell-mediated immunity against foreign antigen exposures in domestic cats are minimal.
An individual differences approach to semantic cognition: Divergent effects of age on representation, retrieval and selection
Authors: Hoffman Paul 
Published: May 2018

AbstractSemantic cognition refers to the appropriate use of acquired knowledge about the world. This requires representation of knowledge as well as control processes which ensure that currently-relevant aspects of knowledge are retrieved and selected. Although these abilities can be impaired selectively following brain damage, the relationship between them in healthy individuals is unclear. It is also commonly assumed that semantic cognition is preserved in later life, because older people have greater reserves of knowledge. However, this claim overlooks the possibility of decline in semantic control processes. Here, semantic cognition was assessed in 100 young and older adults. Despite having a broader knowledge base, older people showed specific impairments in semantic control, performing more poorly than young people when selecting among competing semantic representations. Conversely, they showed preserved controlled retrieval of less salient information from the semantic store. Breadth of semantic knowledge was positively correlated with controlled retrieval but was unrelated to semantic selection ability, which was instead correlated with non-semantic executive function. These findings indicate that three distinct elements contribute to semantic cognition: semantic representations that accumulate throughout the lifespan, processes for controlled retrieval of less salient semantic information, which appear age-invariant, and mechanisms for selecting task-relevant aspects of semantic knowledge, which decline with age and may relate more closely to domain-general executive control.
The conserved RNA recognition motif and C3H1 domain of the Not4 ubiquitin ligase regulate in vivo ligase function
Authors: Chen Hongfeng , Sirupangi Tirupataiah , Wu Zhao-Hui , Johnson Daniel L. , Laribee R. Nicholas 
Published: May 2018

AbstractThe Ccr4-Not complex controls RNA polymerase II (Pol II) dependent gene expression and proteasome function. The Not4 ubiquitin ligase is a Ccr4-Not subunit that has both a RING domain and a conserved RNA recognition motif and C3H1 domain (referred to as the RRM-C domain) with unknown function. We demonstrate that while individual Not4 RING or RRM-C mutants fail to replicate the proteasomal defects found in Not4 deficient cells, mutation of both exhibits a Not4 loss of function phenotype. Transcriptome analysis revealed that the Not4 RRM-C affects a specific subset of Pol II-regulated genes, including those involved in transcription elongation, cyclin-dependent kinase regulated nutrient responses, and ribosomal biogenesis. The Not4 RING, RRM-C, or RING/RRM-C mutations cause a generalized increase in Pol II binding at a subset of these genes, yet their impact on gene expression does not always correlate with Pol II recruitment which suggests Not4 regulates their expression through additional mechanisms. Intriguingly, we find that while the Not4 RRM-C is dispensable for Ccr4-Not association with RNA Pol II, the Not4 RING domain is required for these interactions. Collectively, these data elucidate previously unknown roles for the conserved Not4 RRM-C and RING domains in regulating Ccr4-Not dependent functionsin vivo.
RNA synthesis is modulated by G-quadruplex formation in Hepatitis C virus negative RNA strand
Authors: Jaubert Chloé , Bedrat Amina , Bartolucci Laura , Di Primo Carmelo , Ventura Michel , Mergny Jean-Louis , Amrane Samir , Andreola Marie-Line 
Published: May 2018

AbstractDNA and RNA guanine-rich oligonucleotides can form non-canonical structures called G-quadruplexes or “G4” that are based on the stacking of G-quartets. The role of DNA and RNA G4 is documented in eukaryotic cells and in pathogens such as viruses. Yet, G4 have been identified only in a few RNA viruses, including the Flaviviridae family. In this study, we analysed the last 157 nucleotides at the 3′end of the HCV (−) strand. This sequence is known to be the minimal sequence required for an efficient RNA replication. Using bioinformatics and biophysics, we identified a highly conserved G4-prone sequence located in the stem-loop IIy’ of the negative strand. We also showed that the formation of this G-quadruplex inhibits the in vitro RNA synthesis by the RdRp. Furthermore, Phen-DC3, a specific G-quadruplex binder, is able to inhibit HCV viral replication in cells in conditions where no cytotoxicity was measured. Considering that this domain of the negative RNA strand is well conserved among HCV genotypes, G4 ligands could be of interest for new antiviral therapies.
Exploring a possible connection between U.S. tornado activity and Arctic sea ice
Authors: Trapp Robert J. , Hoogewind Kimberly A. 
Published: May 2018

AbstractThe significant losses in Arctic sea ice over the past few decades appear to have been accompanied by changes in global-scale and regional-scale atmospheric circulation. Such circulation changes have in turn been used to support arguments that low Arctic sea-ice extent (SIE) has helped to promote extreme weather events within the mid-latitudes. The contemporaneous variability in U.S. tornado incidence over the past decade provides motivation to explore whether the essence of these arguments also applies to tornadoes. Here, robust statistical correlations are found between tornado activity and SIE during boreal summer, specifically in July. The statistical relationship is supported by the presence of anomalous regional circulation and storm track that are unfavorable (favorable) for tornado-bearing thunderstorm formation when SIE is low (high).
15-GHz radio emission from nearby low-luminosity active galactic nuclei
Authors: Saikia Payaswini , Körding Elmar , Coppejans Deanne L. , Falcke Heino , Williams David , Baldi Ranieri D. , Mchardy Ian , Beswick Rob 
Published: May 2018

We present a sub-arcsec resolution radio imaging survey of a sample of 76 low-luminosity active galactic nuclei (LLAGN) that were previously not detected with the Very Large Array at 15 GHz. Compact, parsec-scale radio emission has been detected above a flux density of 40 μ Jy in 60% (45 of 76) of the LLAGN sample. We detect 20 out of 31 (64%) low-ionization nuclear emission-line region (LINER) nuclei, ten out of 14 (71%) low-luminosity Seyfert galaxies, and 15 out of 31 (48%) transition objects. We use this sample to explore correlations between different emission lines and the radio luminosity. We also populate the X-ray and the optical fundamental plane of black hole activity and further refine its parameters. We obtain a fundamental plane relation of log LR = 0.48 (±0.04) log LX + 0.79 (±0.03) log M and an optical fundamental plane relation of log LR = 0.63 (±0.05) log L[O III] + 0.67 (±0.03) log M after including all the LLAGN detected at high resolution at 15 GHz, and the best-studied hard-state X-ray binaries (luminosities are given in erg s−1 while the masses are in units of solar mass). Finally, we find conclusive evidence that the nuclear 15 GHz radio luminosity function (RLF) of all the detected Palomar Sample LLAGN has a turnover at the low-luminosity end, and is best-fitted with a broken power law. The break in the power law occurs at a critical mass accretion rate of 1.2 × 10−3 M⊙ yr−1, which translates to an Eddington ratio of ṁEdd ~ 5.1 × 10−5, assuming a black hole mass of 109 M⊙. The local group stands closer to the extrapolation of the higher-luminosity sources, and the classical Seyferts agree with the nuclear RLF of the LLAGN in the local universe.
Detection and Quantitation of Cleaved and Uncleaved High Molecular Weight Kininogen in Plasma by Ligand Blotting with Radiolabeled Plasma Prekallikrein or Factor XI
Authors: Lämmle Bernhard , Zuraw Bruce L , Heeb Mary Jo , Schwarz Hans Peter , Berrettini Mauro , Curd John G , Griffin John H 
Published: May 2018

SummaryA method for the quantitative assay of native single chain and kallikrein cleaved two-chain high molecular weight (HMW)-kininogen in plasma is described. Sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) of whole plasma is followed by electrotransfer of the electropherogram to nitrocellulose membranes and detection of the blotted HMW-kininogen with its physiologic ligands, radiolabeled plasma prekallikrein or radiolabeled factor XI. Using unreduced SDS-PAGE cleaved two-chain HMW-kininogen (Mr ∼107,000 and 95,000), is elec-trophoretically separated from uncleaved single chain HMW-kininogen (Mr ∼150,000). Counting the radioactivity of the nitrocellulose pieces corresponding to cleaved HMW-kininogen permits its quantitative measurement by comparison with standards consisting of decreasing amounts of fully dextran sulfate activated normal human plasma. Single chain HMW-kininogen is similarly assayed using reduced SDS-PAGE and unactivated normal human plasma standards.This technique is highly specific and sensitive to about 50 ng of either cleaved or uncleaved HMW-kininogen. Varying amounts of cleaved HMW-kininogen were found in a small series of plasmas from patients suffering from various inflammatory conditions. Higher levels of in vivo cleaved HMW-kininogen were observed during acute attacks of hereditary angioedema due to Cl-inhibitor deficiency. This technique may be useful for the assessment of the degree of in vitro or in vivo activation of the contact system.
Impairment of Phosphatidylinositol Metabolism in a Patient with a Bleeding Disorder Associated with Defects of Initial Platelet Responses
Authors: Lages Bruce , Weiss Harvey J 
Published: May 2018

SummaryPhosphoinositide/polyphosphoinositide (PI/PPI) metabolism, measured by the increase of 3H-phosphatidic acid (PA) and the decrease of 3H-phosphatidylinositol (PI) in 3H-arachidonate- labeled platelet suspensions, was assessed in five patients whose platelet functional defects included impaired initial rates of ADP, epinephrine and U44069 aggregation in platelet-rich plasma (PRP). In one patient, 3H-PA formation induced by collagen and thrombin was reduced or absent on two of three occasions, and the decrease in 3H-PI was reduced on one of these two occasions in response to collagen and A23187, and on all 3 occasions in response to thrombin. The variations in the formation of 3H-PA in this patient on different occasions broadly paralleled the variations in the initial rates of ADP and U44069 aggregation and in epinephrine aggregation seen in PRP. No such abnormalities of PI metabolism were found in four other patients with similar, but not identical, functional defects. These results suggest an impairment affecting metabolism of PI/PPI via the PI/PPI cycle in this patient's platelets. The association of abnormalities of PI metabolism with defects of initial platelet responses provides further support for a physiological role of phosphoinositide metabolism in the early activation mechanisms of platelets.
Prostacyclin Release in the Coronary Circulation During Sustained Stimulation in In Vitro and in In Vivo Experimental Systems
Authors: Prosdocimi M , Finesso M , Banzatto N , Zanetti A , de Gaetano G , Dejana E 
Published: May 2018

SummaryProstacyclin release from rat isolated perfused hearts and from dog coronary circulation was studied by measuring immunoreac- tive 6-keto-PGFlalpha (6-keto-PGFla) in heart perfusate and in plasma obtained from the great cardiac vein respectively.