Effects of an Oxycodone Conjugate Vaccine on Oxycodone Self-Administration and Oxycodone-Induced Brain Gene Expression in Rats

Prescription opioid abuse is an increasing public health concern in the USA. A vaccine comprising a hapten (OXY) conjugated to the carrier protein keyhole limpet hemocyanin (OXY-KLH) has been shown to attenuate the antinociceptive effects of oxycodone. Here, the vaccine's ability to prevent acquisition of intravenous (i.v.) oxycodone self-administration was studied in rats. Effects of vaccination on oxycodone-induced changes in the expression of several genes within the mesolimbic system, which are regulated by chronic opiate use, were also examined. Vaccination with OXY-KLH reduced the proportion of rats acquiring i.v. self-administration of oxycodone under a fixed ratio (FR) 3 schedule of reinforcement compared to control rats immunized with the unconjugated KLH carrier protein. Vaccination significantly reduced the mean number of infusions at FR3, total number of infusions, and total oxycodone intake during the entire protocol. Compared to oxycodone self-administering control rats immunized with the carrier alone, rats vaccinated with the OXY-KLH immunogen showed increased levels of adenylate cyclase 5 (Adcy5) and decreased levels of early growth response protein 2 (Egr2) and the early immediate gene c-Fos in the striatum. These data suggest that vaccination with OXY-KLH can attenuate the reinforcing effects of oxycodone at a clinically-relevant exposure level. Analysis of mRNA expression identified some addiction-relevant markers that may be of interest in understanding oxycodone effects or the protection provided by vaccination

KSRP-PMR1-exosome association determines parathyroid hormone mRNA levels and stability in transfected cells

<p>Abstract</p> <p>Background</p> <p>Parathyroid hormone (PTH) gene expression is regulated post-transcriptionally through the binding of the <it>trans-</it>acting proteins AU rich binding factor 1 (AUF1), Upstream of N-<it>ras </it>(Unr) and KH-type splicing regulatory protein (KSRP) to an AU rich element (ARE) in PTH mRNA 3'-UTR. AUF1 and Unr stabilize PTH mRNA while KSRP, recruiting the exoribonucleolytic complex exosome, promotes PTH mRNA decay.</p> <p>Results</p> <p>PTH mRNA is cleaved by the endoribonuclease polysomal ribonuclease 1 (PMR1) in an ARE-dependent manner. Moreover, PMR1 co-immunoprecipitates with PTH mRNA, the exosome and KSRP. Knock-down of either exosome components or KSRP by siRNAs prevents PMR1-mediated cleavage of PTH mRNA.</p> <p>Conclusion</p> <p>PTH mRNA is a target for the endonuclease PMR1. The PMR1 mediated decrease in PTH mRNA levels involves the PTH mRNA 3'-UTR ARE, KSRP and the exosome. This represents an unanticipated mechanism by which the decay of an ARE-containing mRNA is facilitated by KSRP and is dependent on both the exosome and an endoribonuclease.</p

Pattern recognition in lymphoid malignancies using CytoGPS and Mercator

BACKGROUND: There have been many recent breakthroughs in processing and analyzing large-scale data sets in biomedical informatics. For example, the CytoGPS algorithm has enabled the use of text-based karyotypes by transforming them into a binary model. However, such advances are accompanied by new problems of data sparsity, heterogeneity, and noisiness that are magnified by the large-scale multidimensional nature of the data. To address these problems, we developed the Mercator R package, which processes and visualizes binary biomedical data. We use Mercator to address biomedical questions of cytogenetic patterns relating to lymphoid hematologic malignancies, which include a broad set of leukemias and lymphomas. Karyotype data are one of the most common form of genetic data collected on lymphoid malignancies, because karyotyping is part of the standard of care in these cancers. RESULTS: In this paper we combine the analytic power of CytoGPS and Mercator to perform a large-scale multidimensional pattern recognition study on 22,741 karyotype samples in 47 different hematologic malignancies obtained from the public Mitelman database. CONCLUSION: Our findings indicate that Mercator was able to identify both known and novel cytogenetic patterns across different lymphoid malignancies, furthering our understanding of the genetics of these diseases

MUSTANG: 90 GHz Science with the Green Bank Telescope

MUSTANG is a 90 GHz bolometer camera built for use as a facility instrument on the 100 m Robert C. Byrd Green Bank radio telescope (GBT). MUSTANG has an 8 by 8 focal plane array of transition edge sensor bolometers read out using time-domain multiplexed SQUID electronics. As a continuum instrument on a large single dish MUSTANG has a combination of high resolution (8") and good sensitivity to extended emission which make it very competitive for a wide range of galactic and extragalactic science. Commissioning finished in January 2008 and some of the first science data have been collected.Comment: 9 Pages, 5 figures, Presented at the SPIE conference on astronomical instrumentation in 200

Reviews

The International Relations of Middle-earth: Learning from The Lord of the Rings. Abigail E. Ruane and Patrick James. Reviewed by Robert T. Tally Jr Moments of Grace and Spiritual Warfare in The Lord of the Rings. Anne Marie Gazzolo. Reviewed by Damien Bador. The Wizard of Oz as American Myth: A Critical Study of Six Versions of the Story, 1900-2007. Alissa Burger. Reviewed by Hugh H. Davis. Plain to the Inward Eye: Selected Essays on C.S. Lewis. Don W. King. Reviewed by Holly Ordway. Tolkien\u27s Poetry. Ed. Julian Eilmann and Allan Turner. Reviewed by Joe R. Christopher. The Lion\u27s World: A Journey into the Heart of Narnia. Rowan Williams. Reviewed by Melody Green. C. S. Lewis - A Life: Eccentric Genius, Reluctant Prophet. Alister McGrath. Reviewed by Gregory Bassham. Seven: An Anglo-American Literary Review. Ed. Marjorie Lamp Mead. Reviewed by Janet Brennan Croft. Supernatural Studies: Official Publication of the Supernatural Studies Association. Ed. Margo Collins and Deborah Christie. Reviewed by Janet Brennan Croft. Fastitocalon: Studies in Fantasticism Ancient to Modern. Ed. Thomas Honegger and Fanfan Chen. Reviewed by Janet Brennan Croft. Wormwood: Literature of the Fantastic, Supernatural and Decadent. Edited by Mark Valentine. Reviewed by Janet Brennan Croft

Investigating knowledge management factors affecting Chinese ICT firms performance: An integrated KM framework

This is an Author's Accepted Manuscript of an article published in the Journal of Information Systems Management, 28(1), 19 - 29, 2011, copyright Taylor & Francis, available online at: http://www.tandfonline.com/10.1080/10580530.2011.536107.This article sets out to investigate the critical factors of Knowledge Management (KM) which are considered to have an impact on the performance of Chinese information and communication technology (ICT) firms. This study confirms that the cultural environment of an enterprise is central to its success in the context of China. It shows that a collaborated, trusted, and learning environment within ICT firms will have a positive impact on their KM performance

Monitoring the kinetics of the pH driven transition of the anthrax toxin prepore to the pore by biolayer interferometry and surface plasmon resonance

Domain 2 of the anthrax protective antigen (PA) prepore heptamer unfolds and refolds during endosome acidification to generate an extended 100 Å beta barrel pore that inserts into the endosomal membrane. The PA pore facilitates the pH dependent unfolding and translocation of bound toxin enzymic components, lethal factor (LF) and/or edema factor (EF), from the endosome into the cytoplasm. We constructed immobilized complexes of the prepore with the PA-binding domain of LF (LFN) to monitor the real-time prepore to pore kinetic transition using surface plasmon resonance (SPR) and bio-layer interferometry (BLI). The kinetics of this transition increased as the solution pH was decreased from pH 7.5 to pH 5.0, mirroring acidification of the endosome. Once transitioned, the LFN-PA pore complex was removed from the BLI biosensor tip and deposited onto EM grids, where the PA pore formation was confirmed by negative stain electron microscopy. When the soluble receptor domain (ANTRX2/CMG2) binds the immobilized PA prepore, the transition to the pore state was observed only after the pH was lowered to early or late endosomal pH conditions (5.5 to 5.0 respectively). Once the pore formed, the soluble receptor readily dissociated from the PA pore. Separate binding experiments with immobilized PA pores and soluble receptor indicate that the receptor has a weakened propensity to bind to the transitioned pore. This immobilized anthrax toxin platform can be used to identify or validate potential antimicrobial lead compounds capable of regulating and/or inhibiting anthrax toxin complex formation or pore transitions