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https://www.readbyqxmd.com/read/29038372/a-radio-counterpart-to-a-neutron-star-merger
#1
G Hallinan, A Corsi, K P Mooley, K Hotokezaka, E Nakar, M M Kasliwal, D L Kaplan, D A Frail, S T Myers, T Murphy, K De, D Dobie, J R Allison, K W Bannister, V Bhalerao, P Chandra, T E Clarke, S Giacintucci, A Y Q Ho, A Horesh, N E Kassim, S R Kulkarni, E Lenc, F J Lockman, C Lynch, D Nichols, S Nissanke, N Palliyaguru, W M Peters, T Piran, J Rana, E M Sadler, L P Singer
Gravitational waves have been detected from a binary neutron star merger event, GW170817. The detection of electromagnetic radiation from the same source has shown that the merger occurred in the outskirts of the galaxy NGC 4993, at a distance of 40 megaparsecs from Earth. We report the detection of a counterpart radio source that appears 16 days after the event, allowing us to diagnose the energetics and environment of the merger. The observed radio emission can be explained by either a collimated ultra-relativistic jet viewed off-axis, or a cocoon of mildly relativistic ejecta...
October 16, 2017: Science
https://www.readbyqxmd.com/read/28892032/semi-automated-analysis-of-mouse-skeletal-muscle-morphology-and-fiber-type-composition
#2
Sidharth Tyagi, Donald Beqollari, Chang Seok Lee, Lori A Walker, Roger A Bannister
For years, distinctions between skeletal muscle fiber types were best visualized by myosin-ATPase staining. More recently, immunohistochemical staining of myosin heavy chain (MyHC) isoforms has emerged as a finer discriminator of fiber-type. Type I, type IIA, type IIX and type IIB fibers can now be identified with precision based on their MyHC profile; however, manual analysis of these data can be slow and down-right tedious. In this regard, rapid, accurate assessment of fiber-type composition and morphology is a very desirable tool...
August 31, 2017: Journal of Visualized Experiments: JoVE
https://www.readbyqxmd.com/read/28832395/multiple-sites-and-actions-of-gabapentin-induced-relief-of-ongoing-experimental-neuropathic-pain
#3
Kirsty Bannister, Chaoling Qu, Edita Navratilova, Janice Oyarzo, Jennifer Yanhua Xie, Tamara King, Anthony H Dickenson, Frank Porreca
Gabapentin (GBP) is a first-line therapy for neuropathic pain, but its mechanisms and sites of action remain uncertain. We investigated GBP-induced modulation of neuropathic pain following spinal nerve ligation (SNL) in rats. Intravenous or intrathecal GBP reversed evoked mechanical hypersensitivity and produced conditioned place preference (CPP) and dopamine (DA) release in the nucleus accumbens (NAc) selectively in SNL rats. Spinal GBP also significantly inhibited dorsal horn wide-dynamic-range neuronal responses to a range of evoked stimuli in SNL rats...
December 2017: Pain
https://www.readbyqxmd.com/read/28659436/broad-spectrum-antiviral-gs-5734-inhibits-both-epidemic-and-zoonotic-coronaviruses
#4
Timothy P Sheahan, Amy C Sims, Rachel L Graham, Vineet D Menachery, Lisa E Gralinski, James B Case, Sarah R Leist, Krzysztof Pyrc, Joy Y Feng, Iva Trantcheva, Roy Bannister, Yeojin Park, Darius Babusis, Michael O Clarke, Richard L Mackman, Jamie E Spahn, Christopher A Palmiotti, Dustin Siegel, Adrian S Ray, Tomas Cihlar, Robert Jordan, Mark R Denison, Ralph S Baric
Emerging viral infections are difficult to control because heterogeneous members periodically cycle in and out of humans and zoonotic hosts, complicating the development of specific antiviral therapies and vaccines. Coronaviruses (CoVs) have a proclivity to spread rapidly into new host species causing severe disease. Severe acute respiratory syndrome CoV (SARS-CoV) and Middle East respiratory syndrome CoV (MERS-CoV) successively emerged, causing severe epidemic respiratory disease in immunologically naïve human populations throughout the globe...
June 28, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/28522587/preclinical-evaluation-of-medi0641-a-pyrrolobenzodiazepine-conjugated-antibody-drug-conjugate-targeting-5t4
#5
Jay Harper, Christopher Lloyd, Nazzareno Dimasi, Dorin Toader, Rose Marwood, Leeanne Lewis, David Bannister, Jelena Jovanovic, Ryan Fleming, Francois D'Hooge, Shenlan Mao, Allison M Marrero, Martin Korade, Patrick Strout, Linda Xu, Cui Chen, Leslie Wetzel, Shannon Breen, Lilian van Vlerken-Ysla, Sanjoo Jalla, Marlon Rebelatto, Haihong Zhong, Elaine M Hurt, Mary Jane Hinrichs, Keven Huang, Philip W Howard, David A Tice, Robert E Hollingsworth, Ronald Herbst, Adeela Kamal
Antibody-drug conjugates (ADC) are used to selectively deliver cytotoxic agents to tumors and have the potential for increased clinical benefit to cancer patients. 5T4 is an oncofetal antigen overexpressed on the cell surface in many carcinomas on both bulk tumor cells as well as cancer stem cells (CSC), has very limited normal tissue expression, and can internalize when bound by an antibody. An anti-5T4 antibody was identified and optimized for efficient binding and internalization in a target-specific manner, and engineered cysteines were incorporated into the molecule for site-specific conjugation...
May 18, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28442704/discovery-of-an-enzyme-and-substrate-selective-inhibitor-of-adam10-using-an-exosite-binding-glycosylated-substrate
#6
Franck Madoux, Daniela Dreymuller, Jean-Phillipe Pettiloud, Radleigh Santos, Christoph Becker-Pauly, Andreas Ludwig, Gregg B Fields, Thomas Bannister, Timothy P Spicer, Mare Cudic, Louis D Scampavia, Dmitriy Minond
ADAM10 and ADAM17 have been shown to contribute to the acquired drug resistance of HER2-positive breast cancer in response to trastuzumab. The majority of ADAM10 and ADAM17 inhibitor development has been focused on the discovery of compounds that bind the active site zinc, however, in recent years, there has been a shift from active site to secondary substrate binding site (exosite) inhibitor discovery in order to identify non-zinc-binding molecules. In the present work a glycosylated, exosite-binding substrate of ADAM10 and ADAM17 was utilized to screen 370,276 compounds from the MLPCN collection...
December 5, 2016: Scientific Reports
https://www.readbyqxmd.com/read/28336563/complex-multifault-rupture-during-the-2016-mw-7-8-kaik%C3%A5-ura-earthquake-new-zealand
#7
Ian J Hamling, Sigrún Hreinsdóttir, Kate Clark, John Elliott, Cunren Liang, Eric Fielding, Nicola Litchfield, Pilar Villamor, Laura Wallace, Tim J Wright, Elisabetta D'Anastasio, Stephen Bannister, David Burbidge, Paul Denys, Paula Gentle, Jamie Howarth, Christof Mueller, Neville Palmer, Chris Pearson, William Power, Philip Barnes, David J A Barrell, Russ Van Dissen, Robert Langridge, Tim Little, Andrew Nicol, Jarg Pettinga, Julie Rowland, Mark Stirling
On 14 November 2016, northeastern South Island of New Zealand was struck by a major moment magnitude (Mw) 7.8 earthquake. Field observations, in conjunction with interferometric synthetic aperture radar, Global Positioning System, and seismology data, reveal this to be one of the most complex earthquakes ever recorded. The rupture propagated northward for more than 170 kilometers along both mapped and unmapped faults before continuing offshore at the island's northeastern extent. Geodetic and field observations reveal surface ruptures along at least 12 major faults, including possible slip along the southern Hikurangi subduction interface; extensive uplift along much of the coastline; and widespread anelastic deformation, including the ~8-meter uplift of a fault-bounded block...
April 14, 2017: Science
https://www.readbyqxmd.com/read/28124907/discovery-and-synthesis-of-a-phosphoramidate-prodrug-of-a-pyrrolo-2-1-f-triazin-4-amino-adenine-c-nucleoside-gs-5734-for-the-treatment-of-ebola-and-emerging-viruses
#8
Dustin Siegel, Hon C Hui, Edward Doerffler, Michael O Clarke, Kwon Chun, Lijun Zhang, Sean Neville, Ernest Carra, Willard Lew, Bruce Ross, Queenie Wang, Lydia Wolfe, Robert Jordan, Veronica Soloveva, John Knox, Jason Perry, Michel Perron, Kirsten M Stray, Ona Barauskas, Joy Y Feng, Yili Xu, Gary Lee, Arnold L Rheingold, Adrian S Ray, Roy Bannister, Robert Strickley, Swami Swaminathan, William A Lee, Sina Bavari, Tomas Cihlar, Michael K Lo, Travis K Warren, Richard L Mackman
The recent Ebola virus (EBOV) outbreak in West Africa was the largest recorded in history with over 28,000 cases, resulting in >11,000 deaths including >500 healthcare workers. A focused screening and lead optimization effort identified 4b (GS-5734) with anti-EBOV EC50 = 86 nM in macrophages as the clinical candidate. Structure activity relationships established that the 1'-CN group and C-linked nucleobase were critical for optimal anti-EBOV potency and selectivity against host polymerases. A robust diastereoselective synthesis provided sufficient quantities of 4b to enable preclinical efficacy in a non-human-primate EBOV challenge model...
March 9, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/27922333/environmentally-relevant-chronic-low-dose-tritium-and-gamma-exposures-do-not-increase-somatic-intrachromosomal-recombination-in-pkz1-mouse-spleen
#9
Laura Bannister, Mandy Serran, Lindsey Bertrand, Dmitry Klokov, Heather Wyatt, Melinda Blimkie, Yann Gueguen, Nicholas Priest, Jean-René Jourdain, Pamela Sykes
The toxicity of tritium is a public health concern given its presence and mobility in the environment. For risk predictions using radiological protection models, it is essential to allocate an appropriate radiation weighting factor (WR). This in turn should be consistent with the observed relative biological effectiveness (RBE) of tritium beta radiation. Although the International Commission on Radiological Protection (ICRP) currently recommends a WR of 1 for the calculation of committed effective dose for X rays, gamma rays and electrons of all energies, including tritium energies, there are concerns that tritium health risks are underestimated and that current regulatory tritium drinking water standards need revision...
December 2016: Radiation Research
https://www.readbyqxmd.com/read/27920432/discovery-of-an-enzyme-and-substrate-selective-inhibitor-of-adam10-using-an-exosite-binding-glycosylated-substrate
#10
Franck Madoux, Daniela Dreymuller, Jean-Phillipe Pettiloud, Radleigh Santos, Christoph Becker-Pauly, Andreas Ludwig, Gregg B Fields, Thomas Bannister, Timothy P Spicer, Mare Cudic, Louis D Scampavia, Dmitriy Minond
ADAM10 and ADAM17 have been shown to contribute to the acquired drug resistance of HER2-positive breast cancer in response to trastuzumab. The majority of ADAM10 and ADAM17 inhibitor development has been focused on the discovery of compounds that bind the active site zinc, however, in recent years, there has been a shift from active site to secondary substrate binding site (exosite) inhibitor discovery in order to identify non-zinc-binding molecules. In the present work a glycosylated, exosite-binding substrate of ADAM10 and ADAM17 was utilized to screen 370,276 compounds from the MLPCN collection...
December 2016: Scientific Reports
https://www.readbyqxmd.com/read/27906103/progressive-impairment-of-cav1-1-function-in-the-skeletal-muscle-of-mice-expressing-a-mutant-type-1-cu-zn-superoxide-dismutase-g93a-linked-to-amyotrophic-lateral-sclerosis
#11
Donald Beqollari, Christin F Romberg, Gabriella Dobrowolny, Martina Martini, Andrew A Voss, Antonio Musarò, Roger A Bannister
BACKGROUND: Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disorder that is typically fatal within 3-5 years of diagnosis. While motoneuron death is the defining characteristic of ALS, the events that underlie its pathology are not restricted to the nervous system. In this regard, ALS muscle atrophies and weakens significantly before presentation of neurological symptoms. Since the skeletal muscle L-type Ca(2+) channel (CaV1.1) is a key regulator of both mass and force, we investigated whether CaV1...
June 23, 2016: Skeletal Muscle
https://www.readbyqxmd.com/read/27677938/initiating-and-imaging-the-coherent-surface-dynamics-of-charge-carriers-in-real-space
#12
K R Rusimova, N Bannister, P Harrison, D Lock, S Crampin, R E Palmer, P A Sloan
The tip of a scanning tunnelling microscope is an atomic-scale source of electrons and holes. As the injected charge spreads out, it can induce adsorbed molecules to react. By comparing large-scale 'before' and 'after' images of an adsorbate covered surface, the spatial extent of the nonlocal manipulation is revealed. Here, we measure the nonlocal manipulation of toluene molecules on the Si(111)-7 × 7 surface at room temperature. Both the range and probability of nonlocal manipulation have a voltage dependence...
2016: Nature Communications
https://www.readbyqxmd.com/read/27553432/olaparib-does-not-cause-clinically-relevant-qt-qtc-interval-prolongation-in-patients-with-advanced-solid-tumours-results-from-two-phase-i-studies
#13
RANDOMIZED CONTROLLED TRIAL
Helen Swaisland, Ruth Plummer, Karen So, Sally Garnett, Wendy Bannister, Marc-Antoine Fabre, Corina Dota, Anitra Fielding
BACKGROUND: Some therapeutic agents in oncology can be causally associated with specific cardiovascular events including QT/QTc interval prolongation. We investigated the effect of multiple dosing of the oral poly (ADP-ribose)-polymerase (PARP) inhibitor, olaparib (tablet formulation) on QT/QTc interval. METHODS: Two phase I, open-label, three-part studies (NCT01921140 [study 4] and NCT01900028 [study 7]) were conducted in adults with refractory/resistant advanced solid tumours...
October 2016: Cancer Chemotherapy and Pharmacology
https://www.readbyqxmd.com/read/27340545/progressive-impairment-of-cav1-1-function-in-the-skeletal-muscle-of-mice-expressing-a-mutant-type-1-cu-zn-superoxide-dismutase-g93a-linked-to-amyotrophic-lateral-sclerosis
#14
Donald Beqollari, Christin F Romberg, Gabriella Dobrowolny, Martina Martini, Andrew A Voss, Antonio Musarò, Roger A Bannister
BACKGROUND: Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disorder that is typically fatal within 3-5 years of diagnosis. While motoneuron death is the defining characteristic of ALS, the events that underlie its pathology are not restricted to the nervous system. In this regard, ALS muscle atrophies and weakens significantly before presentation of neurological symptoms. Since the skeletal muscle L-type Ca(2+) channel (CaV1.1) is a key regulator of both mass and force, we investigated whether CaV1...
2016: Skeletal Muscle
https://www.readbyqxmd.com/read/27294782/functional-interdependence-of-brd4-and-dot1l-in-mll-leukemia
#15
Omer Gilan, Enid Y N Lam, Isabelle Becher, Dave Lugo, Ester Cannizzaro, Gerard Joberty, Aoife Ward, Meike Wiese, Chun Yew Fong, Sarah Ftouni, Dean Tyler, Kym Stanley, Laura MacPherson, Chen-Fang Weng, Yih-Chih Chan, Margherita Ghisi, David Smil, Christopher Carpenter, Peter Brown, Neil Garton, Marnie E Blewitt, Andrew J Bannister, Tony Kouzarides, Brian J P Huntly, Ricky W Johnstone, Gerard Drewes, Sarah-Jane Dawson, Cheryl H Arrowsmith, Paola Grandi, Rab K Prinjha, Mark A Dawson
Targeted therapies against disruptor of telomeric silencing 1-like (DOT1L) and bromodomain-containing protein 4 (BRD4) are currently being evaluated in clinical trials. However, the mechanisms by which BRD4 and DOT1L regulate leukemogenic transcription programs remain unclear. Using quantitative proteomics, chemoproteomics and biochemical fractionation, we found that native BRD4 and DOT1L exist in separate protein complexes. Genetic disruption or small-molecule inhibition of BRD4 and DOT1L showed marked synergistic activity against MLL leukemia cell lines, primary human leukemia cells and mouse leukemia models...
July 2016: Nature Structural & Molecular Biology
https://www.readbyqxmd.com/read/26934220/therapeutic-efficacy-of-the-small-molecule-gs-5734-against-ebola-virus-in-rhesus-monkeys
#16
Travis K Warren, Robert Jordan, Michael K Lo, Adrian S Ray, Richard L Mackman, Veronica Soloveva, Dustin Siegel, Michel Perron, Roy Bannister, Hon C Hui, Nate Larson, Robert Strickley, Jay Wells, Kelly S Stuthman, Sean A Van Tongeren, Nicole L Garza, Ginger Donnelly, Amy C Shurtleff, Cary J Retterer, Dima Gharaibeh, Rouzbeh Zamani, Tara Kenny, Brett P Eaton, Elizabeth Grimes, Lisa S Welch, Laura Gomba, Catherine L Wilhelmsen, Donald K Nichols, Jonathan E Nuss, Elyse R Nagle, Jeffrey R Kugelman, Gustavo Palacios, Edward Doerffler, Sean Neville, Ernest Carra, Michael O Clarke, Lijun Zhang, Willard Lew, Bruce Ross, Queenie Wang, Kwon Chun, Lydia Wolfe, Darius Babusis, Yeojin Park, Kirsten M Stray, Iva Trancheva, Joy Y Feng, Ona Barauskas, Yili Xu, Pamela Wong, Molly R Braun, Mike Flint, Laura K McMullan, Shan-Shan Chen, Rachel Fearns, Swami Swaminathan, Douglas L Mayers, Christina F Spiropoulou, William A Lee, Stuart T Nichol, Tomas Cihlar, Sina Bavari
The most recent Ebola virus outbreak in West Africa, which was unprecedented in the number of cases and fatalities, geographic distribution, and number of nations affected, highlights the need for safe, effective, and readily available antiviral agents for treatment and prevention of acute Ebola virus (EBOV) disease (EVD) or sequelae. No antiviral therapeutics have yet received regulatory approval or demonstrated clinical efficacy. Here we report the discovery of a novel small molecule GS-5734, a monophosphoramidate prodrug of an adenosine analogue, with antiviral activity against EBOV...
March 17, 2016: Nature
https://www.readbyqxmd.com/read/26798008/real-time-detection-of-an-extreme-scattering-event-constraints-on-galactic-plasma-lenses
#17
Keith W Bannister, Jamie Stevens, Artem V Tuntsov, Mark A Walker, Simon Johnston, Cormac Reynolds, Hayley Bignall
Extreme scattering events (ESEs) are distinctive fluctuations in the brightness of astronomical radio sources caused by occulting plasma lenses in the interstellar medium. The inferred plasma pressures of the lenses are ~10(3) times the ambient pressure, challenging our understanding of gas conditions in the Milky Way. Using a new survey technique, we discovered an ESE while it was in progress. Here we report radio and optical follow-up observations. Modeling of the radio data demonstrates that the lensing structure is a density enhancement and the lens is diverging, ruling out one of two competing physical models...
January 22, 2016: Science
https://www.readbyqxmd.com/read/26621868/ml264-a-novel-small-molecule-compound-that-potently-inhibits-growth-of-colorectal-cancer
#18
Ainara Ruiz de Sabando, Chao Wang, Yuanjun He, Mónica García-Barros, Julie Kim, Kenneth R Shroyer, Thomas D Bannister, Vincent W Yang, Agnieszka B Bialkowska
Colorectal cancer is one of the leading causes of cancer mortality in Western civilization. Studies have shown that colorectal cancer arises as a consequence of the modification of genes that regulate important cellular functions. Deregulation of the WNT and RAS/MAPK/PI3K signaling pathways has been shown to be important in the early stages of colorectal cancer development and progression. Krüppel-like factor 5 (KLF5) is a transcription factor that is highly expressed in the proliferating intestinal crypt epithelial cells...
January 2016: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/26537024/tuning-helical-chirality-in-polycyclic-ladder-systems
#19
Michel Rickhaus, Oliver T Unke, Rajesh Mannancherry, Linda M Bannwart, Markus Neuburger, Daniel Häussinger, Marcel Mayor
Conceptually and experimentally, a new set of helical model compounds is presented herein that allow correlations between structural features and their expression in the secondary structure to be investigated. A cross-linked oligomer with two strands of mismatching lengths connected in a ladder-type fashion serves as a model system. Compensation for the dimensional mismatch leads to the adoption of a helical arrangement. A strategically placed relay ensures the continuity and uniformity of the helix. Upon exchanging the heteroatomic linkage, the helix responds by increasing or decreasing the torsion of the backbone...
December 7, 2015: Chemistry: a European Journal
https://www.readbyqxmd.com/read/26516549/cancer-pain-physiology
#20
Sarah Falk, Kirsty Bannister, Anthony H Dickenson
Mechanisms of inflammatory and neuropathic pains have been elucidated and translated to patient care by the use of animal models of these pain states. Cancer pain has lagged behind since early animal models of cancer-induced bone pain were based on the systemic injection of carcinoma cells. This precluded systematic investigation of specific neuronal and pharmacological alterations that occur in cancer-induced bone pain. In 1999, Schwei et al. described a murine model of cancer-induced bone pain that paralleled the clinical condition in terms of pain development and bone destruction, confined to the mouse femur...
November 2014: British Journal of Pain
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