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https://www.readbyqxmd.com/read/29334375/a-small-molecule-inhibitor-of-the-ubiquitin-activating-enzyme-for-cancer-treatment
#1
Marc L Hyer, Michael A Milhollen, Jeff Ciavarri, Paul Fleming, Tary Traore, Darshan Sappal, Jessica Huck, Judy Shi, James Gavin, Jim Brownell, Yu Yang, Bradley Stringer, Robert Griffin, Frank Bruzzese, Teresa Soucy, Jennifer Duffy, Claudia Rabino, Jessica Riceberg, Kara Hoar, Anya Lublinsky, Saurabh Menon, Michael Sintchak, Nancy Bump, Sai M Pulukuri, Steve Langston, Stephen Tirrell, Mike Kuranda, Petter Veiby, John Newcomb, Ping Li, Jing Tao Wu, Josh Powe, Lawrence R Dick, Paul Greenspan, Katherine Galvin, Mark Manfredi, Chris Claiborne, Benjamin S Amidon, Neil F Bence
The ubiquitin-proteasome system (UPS) comprises a network of enzymes that is responsible for maintaining cellular protein homeostasis. The therapeutic potential of this pathway has been validated by the clinical successes of a number of UPS modulators, including proteasome inhibitors and immunomodulatory imide drugs (IMiDs). Here we identified TAK-243 (formerly known as MLN7243) as a potent, mechanism-based small-molecule inhibitor of the ubiquitin activating enzyme (UAE), the primary mammalian E1 enzyme that regulates the ubiquitin conjugation cascade...
January 15, 2018: Nature Medicine
https://www.readbyqxmd.com/read/29315364/200-years-of-parkinson-s-disease-what-have-we-learnt-from-james-parkinson
#2
Claire McDonald, Gavin Gordon, Annette Hand, Richard W Walker, James M Fisher
2017 marks 200 years since James Parkinson's published his 'Essay on the Shaking Palsy'. Although now most famous for describing the condition that came to bear his name, Parkinson had a wide range of interests and his influence spread beyond medicine. In this review, we provide a biography of James Parkinson's remarkable life.Parkinson's paper not only comprehensively described the symptoms of Parkinson's disease (PD), but challenged his peers to better understand the pathophysiology of the PD. Key observation over the next 2 centuries, included the recognition of the link between the substantia nigra and PD and the discoveries of dopamine deficiency in patients with PD...
January 5, 2018: Age and Ageing
https://www.readbyqxmd.com/read/29260311/body-mass-index-hip-function-and-surgeon-volume-are-independent-predictors-of-dislocation-an-analysis-of-4334-total-hip-replacements
#3
John Annan, Nick Clement, Gavin J Macpherson, Ivan J Brenkel, James A Ballantyne, Edward Dunstan
The aim of this study was to identify pre-operative and intra-operative factors that are predictive of dislocation following primary total hip replacement (THR). Data were prospectively collected for a consecutive series of 4334 THRs undertaken over a 14-year period. Ninety-eight (2.3%) of the 4334 patients had one or more dislocation post-operatively. A body mass index (BMI) of ≥ 35 (p < 0.001), a Harris Hip Score (HHS) of ≤ 41 (p < 0.001) and a low-volume surgeon (p < 0.001), which was defined as performing fewer than 43 THRs per annum, were identified as independent predictors of dislocation using logistic regression analysis...
December 19, 2017: European Journal of Orthopaedic Surgery & Traumatology: Orthopédie Traumatologie
https://www.readbyqxmd.com/read/29225714/incorporating-high-dimensional-exposure-modelling-into-studies-of-air-pollution-and-health
#4
Yi Liu, Gavin Shaddick, James V Zidek
Performing studies on the risks of environmental hazards on human health requires accurate estimates of exposures that might be experienced by the populations at risk. Often there will be missing data and in many epidemiological studies, the locations and times of exposure measurements and health data do not match. To a large extent this will be due to the health and exposure data having arisen from completely different data sources and not as the result of a carefully designed study, leading to problems of both 'change of support' and 'misaligned data'...
2017: Statistics in Biosciences
https://www.readbyqxmd.com/read/29212826/diet-in-multiple-sclerosis-science-takes-a-seat-at-the-table
#5
EDITORIAL
James F Sumowski, Gavin V McDonnell, Dennis Bourdette
No abstract text is available yet for this article.
December 6, 2017: Neurology
https://www.readbyqxmd.com/read/29199020/the-library-of-integrated-network-based-cellular-signatures-nih-program-system-level-cataloging-of-human-cells-response-to-perturbations
#6
REVIEW
Alexandra B Keenan, Sherry L Jenkins, Kathleen M Jagodnik, Simon Koplev, Edward He, Denis Torre, Zichen Wang, Anders B Dohlman, Moshe C Silverstein, Alexander Lachmann, Maxim V Kuleshov, Avi Ma'ayan, Vasileios Stathias, Raymond Terryn, Daniel Cooper, Michele Forlin, Amar Koleti, Dusica Vidovic, Caty Chung, Stephan C Schürer, Jouzas Vasiliauskas, Marcin Pilarczyk, Behrouz Shamsaei, Mehdi Fazel, Yan Ren, Wen Niu, Nicholas A Clark, Shana White, Naim Mahi, Lixia Zhang, Michal Kouril, John F Reichard, Siva Sivaganesan, Mario Medvedovic, Jaroslaw Meller, Rick J Koch, Marc R Birtwistle, Ravi Iyengar, Eric A Sobie, Evren U Azeloglu, Julia Kaye, Jeannette Osterloh, Kelly Haston, Jaslin Kalra, Steve Finkbiener, Jonathan Li, Pamela Milani, Miriam Adam, Renan Escalante-Chong, Karen Sachs, Alex Lenail, Divya Ramamoorthy, Ernest Fraenkel, Gavin Daigle, Uzma Hussain, Alyssa Coye, Jeffrey Rothstein, Dhruv Sareen, Loren Ornelas, Maria Banuelos, Berhan Mandefro, Ritchie Ho, Clive N Svendsen, Ryan G Lim, Jennifer Stocksdale, Malcolm S Casale, Terri G Thompson, Jie Wu, Leslie M Thompson, Victoria Dardov, Vidya Venkatraman, Andrea Matlock, Jennifer E Van Eyk, Jacob D Jaffe, Malvina Papanastasiou, Aravind Subramanian, Todd R Golub, Sean D Erickson, Mohammad Fallahi-Sichani, Marc Hafner, Nathanael S Gray, Jia-Ren Lin, Caitlin E Mills, Jeremy L Muhlich, Mario Niepel, Caroline E Shamu, Elizabeth H Williams, David Wrobel, Peter K Sorger, Laura M Heiser, Joe W Gray, James E Korkola, Gordon B Mills, Mark LaBarge, Heidi S Feiler, Mark A Dane, Elmar Bucher, Michel Nederlof, Damir Sudar, Sean Gross, David F Kilburn, Rebecca Smith, Kaylyn Devlin, Ron Margolis, Leslie Derr, Albert Lee, Ajay Pillai
The Library of Integrated Network-Based Cellular Signatures (LINCS) is an NIH Common Fund program that catalogs how human cells globally respond to chemical, genetic, and disease perturbations. Resources generated by LINCS include experimental and computational methods, visualization tools, molecular and imaging data, and signatures. By assembling an integrated picture of the range of responses of human cells exposed to many perturbations, the LINCS program aims to better understand human disease and to advance the development of new therapies...
November 24, 2017: Cell Systems
https://www.readbyqxmd.com/read/29184385/aflibercept-treatment-for-neovascular-amd-beyond-the-first-year-consensus-recommendations-by-a-uk-expert-roundtable-panel-2017-update
#7
EDITORIAL
Praveen J Patel, Helen Devonport, Sobha Sivaprasad, Adam H Ross, Gavin Walters, Richard P Gale, Andrew J Lotery, Sajjad Mahmood, James S Talks, Jackie Napier
National recommendations on continued administration of aflibercept solution for injection after the first year of treatment for neovascular age-related macular degeneration (nAMD) have been developed by an expert panel of UK retina specialists, based on clinician experience and treatment outcomes seen in year 2. The 2017 update reiterates that the treatment goal is to maintain or improve the macular structural and functional gains achieved in year 1 while attempting to reduce or minimize the treatment burden, recognizing the need for ongoing treatment...
2017: Clinical Ophthalmology
https://www.readbyqxmd.com/read/29170203/identification-of-a-novel-locus-on-chromosome-2q13-which-predisposes-to-clinical-vertebral-fractures-independently-of-bone-density
#8
Nerea Alonso, Karol Estrada, Omar M E Albagha, Lizbeth Herrera, Sjur Reppe, Ole K Olstad, Kaare M Gautvik, Niamh M Ryan, Kathryn L Evans, Carrie M Nielson, Yi-Hsiang Hsu, Douglas P Kiel, George Markozannes, Evangelia E Ntzani, Evangelos Evangelou, Bjarke Feenstra, Xueping Liu, Mads Melbye, Laura Masi, Maria Luisa Brandi, Philip Riches, Anna Daroszewska, José Manuel Olmos, Carmen Valero, Jesús Castillo, José A Riancho, Lise B Husted, Bente L Langdahl, Matthew A Brown, Emma L Duncan, Stephen Kaptoge, Kay-Tee Khaw, Ricardo Usategui-Martín, Javier Del Pino-Montes, Rogelio González-Sarmiento, Joshua R Lewis, Richard L Prince, Patrizia D'Amelio, Natalia García-Giralt, Xavier Nogués, Simona Mencej-Bedrac, Janja Marc, Orit Wolstein, John A Eisman, Ling Oei, Carolina Medina-Gómez, Katharina E Schraut, Pau Navarro, James F Wilson, Gail Davies, John Starr, Ian Deary, Toshiko Tanaka, Luigi Ferrucci, Fernando Gianfrancesco, Luigi Gennari, Gavin Lucas, Roberto Elosua, André G Uitterlinden, Fernando Rivadeneira, Stuart H Ralston
OBJECTIVES: To identify genetic determinants of susceptibility to clinical vertebral fractures, which is an important complication of osteoporosis. METHODS: Here we conduct a genome-wide association study in 1553 postmenopausal women with clinical vertebral fractures and 4340 controls, with a two-stage replication involving 1028 cases and 3762 controls. Potentially causal variants were identified using expression quantitative trait loci (eQTL) data from transiliac bone biopsies and bioinformatic studies...
November 23, 2017: Annals of the Rheumatic Diseases
https://www.readbyqxmd.com/read/29165554/the-effect-of-1-5%C3%A2-t-cardiac-magnetic-resonance-on-human-circulating-leucocytes
#9
William R Critchley, Anna Reid, Julie Morris, Josephine H Naish, John P Stone, Alexandra L Ball, Triin Major, David Clark, Nick Waldron, Christien Fortune, Jakub Lagan, Gavin A Lewis, Mark Ainslie, Erik B Schelbert, Daniel M Davis, Matthias Schmitt, James E Fildes, Christopher A Miller
Aims: Investigators have proposed that cardiovascular magnetic resonance (CMR) should have restrictions similar to those of ionizing imaging techniques. We aimed to investigate the acute effect of 1.5 T CMR on leucocyte DNA integrity, cell counts, and function in vitro, and in a large cohort of patients in vivo. Methods and results: In vitro study: peripheral blood mononuclear cells (PBMCs) were isolated from healthy volunteers, and histone H2AX phosphorylation (γ-H2AX) expression, leucocyte counts, and functional parameters were quantified using flow cytometry under the following conditions: (i) immediately following PBMC isolation, (ii) after standing on the benchside as a temperature and time control, (iii) after a standard CMR scan...
November 18, 2017: European Heart Journal
https://www.readbyqxmd.com/read/29133869/erratum-organocatalyzed-synthesis-of-fluorinated-poly-aryl-thioethers
#10
Nathaniel H Park, Gabriel Dos Passos Gomes, Mareva Fevre, Gavin O Jones, Igor V Alabugin, James L Hedrick
A correction to this article has been published and is linked from the HTML version of this article.
November 13, 2017: Nature Communications
https://www.readbyqxmd.com/read/29093263/human-vaccination-against-rh5-induces-neutralizing-antimalarial-antibodies-that-inhibit-rh5-invasion-complex-interactions
#11
Ruth O Payne, Sarah E Silk, Sean C Elias, Kazutoyo Miura, Ababacar Diouf, Francis Galaway, Hans de Graaf, Nathan J Brendish, Ian D Poulton, Oliver J Griffiths, Nick J Edwards, Jing Jin, Geneviève M Labbé, Daniel Gw Alanine, Loredana Siani, Stefania Di Marco, Rachel Roberts, Nicky Green, Eleanor Berrie, Andrew S Ishizuka, Carolyn M Nielsen, Martino Bardelli, Frederica D Partey, Michael F Ofori, Lea Barfod, Juliana Wambua, Linda M Murungi, Faith H Osier, Sumi Biswas, James S McCarthy, Angela M Minassian, Rebecca Ashfield, Nicola K Viebig, Fay L Nugent, Alexander D Douglas, Johan Vekemans, Gavin J Wright, Saul N Faust, Adrian Vs Hill, Carole A Long, Alison M Lawrie, Simon J Draper
The development of a highly effective vaccine remains a key strategic goal to aid the control and eventual eradication of Plasmodium falciparum malaria. In recent years, the reticulocyte-binding protein homolog 5 (RH5) has emerged as the most promising blood-stage P. falciparum candidate antigen to date, capable of conferring protection against stringent challenge in Aotus monkeys. We report on the first clinical trial to our knowledge to assess the RH5 antigen - a dose-escalation phase Ia study in 24 healthy, malaria-naive adult volunteers...
November 2, 2017: JCI Insight
https://www.readbyqxmd.com/read/29075258/quantitative-characterization-of-the-t-cell-receptor-repertoire-of-na%C3%A3-ve-and-memory-subsets-using-an-integrated-experimental-and-computational-pipeline-which-is-robust-economical-and-versatile
#12
Theres Oakes, James M Heather, Katharine Best, Rachel Byng-Maddick, Connor Husovsky, Mazlina Ismail, Kroopa Joshi, Gavin Maxwell, Mahdad Noursadeghi, Natalie Riddell, Tabea Ruehl, Carolin T Turner, Imran Uddin, Benny Chain
The T cell receptor (TCR) repertoire can provide a personalized biomarker for infectious and non-infectious diseases. We describe a protocol for amplifying, sequencing, and analyzing TCRs which is robust, sensitive, and versatile. The key experimental step is ligation of a single-stranded oligonucleotide to the 3' end of the TCR cDNA. This allows amplification of all possible rearrangements using a single set of primers per locus. It also introduces a unique molecular identifier to label each starting cDNA molecule...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/29068448/color-manipulation-through-microchip-tinting-for-colorimetric-detection-using-hue-image-analysis
#13
Shannon T Krauss, Aeren Q Nauman, Gavin T Garner, James P Landers
Colorimetry with microfluidic devices has been proven to be an advantageous method for in situ analyses where limited resources and rapid response for untrained users are desired. Image analysis using a small camera or cell phone can be easily incorporated for an objective readout, eliminating variations from normal differences in color perception and environmental factors during analysis. The image analysis using the parameter hue, for example, has been utilized as a highly effective, objective analysis method that correlates with the psychological way color is perceived...
November 21, 2017: Lab on a Chip
https://www.readbyqxmd.com/read/29051622/genome-guided-phylo-transcriptomic-methods-and-the-nuclear-phylogentic-tree-of-the-paniceae-grasses
#14
Jacob D Washburn, James C Schnable, Gavin C Conant, Thomas P Brutnell, Ying Shao, Yang Zhang, Martha Ludwig, Gerrit Davidse, J Chris Pires
The past few years have witnessed a paradigm shift in molecular systematics from phylogenetic methods (using one or a few genes) to those that can be described as phylogenomics (phylogenetic inference with entire genomes). One approach that has recently emerged is phylo-transcriptomics (transcriptome-based phylogenetic inference). As in any phylogenetics experiment, accurate orthology inference is critical to phylo-transcriptomics. To date, most analyses have inferred orthology based either on pure sequence similarity or using gene-tree approaches...
October 19, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29028128/diagnostic-accuracy-of-magnetic-resonance-imaging-hepatic-proton-density-fat-fraction-in-pediatric-nonalcoholic-fatty-liver-disease
#15
Michael S Middleton, Mark L Van Natta, Elhamy R Heba, Adina Alazraki, Andrew T Trout, Prakash Masand, Elizabeth M Brunt, David E Kleiner, Edward Doo, James Tonascia, Joel E Lavine, Wei Shen, Gavin Hamilton, Jeffrey B Schwimmer, Claude B Sirlin
We assessed the performance of magnetic resonance imaging (MRI) proton density fat fraction (PDFF) in children to stratify hepatic steatosis grade before and after treatment in the Cysteamine Bitartrate Delayed-Release for the Treatment of Nonalcoholic Fatty Liver Disease in Children (CyNCh) trial, using centrally-scored histology as reference. Participants had multi-echo 1.5T or 3T MRI on scanners from three manufacturers. Of 169 enrolled children, 110 (65%) and 83 (49%) had MRI and liver biopsy at baseline and at end-of-treatment (EOT; 52-weeks), respectively...
October 13, 2017: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
https://www.readbyqxmd.com/read/29020412/emerging-role-of-one-carbon-metabolism-and-dna-methylation-enrichment-on-%C3%AE-containing-gabaa-receptor-expression-in-the-cerebellum-of-subjects-with-alcohol-use-disorders-aud
#16
Eleonora Gatta, James Auta, David P Gavin, Dulal K Bhaumik, Dennis R Grayson, Subhash C Pandey, Alessandro Guidotti
BACKGROUND: Cerebellum is an area of the brain particularly sensitive to the effects of acute and chronic alcohol consumption. Alcohol exposure decreases cerebellar Purkinje cell output by increasing GABA release from Golgi cells onto extrasynaptic α6/δ-containing GABAA receptors located on glutamatergic granule cells. Here, we studied whether chronic alcohol consumption induces changes in GABAA receptor subunit expression and whether these changes are associated with alterations in epigenetic mechanisms via DNA methylation...
August 19, 2017: International Journal of Neuropsychopharmacology
https://www.readbyqxmd.com/read/28991255/patient-derived-xenografts-undergo-mouse-specific-tumor-evolution
#17
Uri Ben-David, Gavin Ha, Yuen-Yi Tseng, Noah F Greenwald, Coyin Oh, Juliann Shih, James M McFarland, Bang Wong, Jesse S Boehm, Rameen Beroukhim, Todd R Golub
Patient-derived xenografts (PDXs) have become a prominent cancer model system, as they are presumed to faithfully represent the genomic features of primary tumors. Here we monitored the dynamics of copy number alterations (CNAs) in 1,110 PDX samples across 24 cancer types. We observed rapid accumulation of CNAs during PDX passaging, often due to selection of preexisting minor clones. CNA acquisition in PDXs was correlated with the tissue-specific levels of aneuploidy and genetic heterogeneity observed in primary tumors...
November 2017: Nature Genetics
https://www.readbyqxmd.com/read/28985562/cohesin-loss-eliminates-all-loop-domains
#18
Suhas S P Rao, Su-Chen Huang, Brian Glenn St Hilaire, Jesse M Engreitz, Elizabeth M Perez, Kyong-Rim Kieffer-Kwon, Adrian L Sanborn, Sarah E Johnstone, Gavin D Bascom, Ivan D Bochkov, Xingfan Huang, Muhammad S Shamim, Jaeweon Shin, Douglass Turner, Ziyi Ye, Arina D Omer, James T Robinson, Tamar Schlick, Bradley E Bernstein, Rafael Casellas, Eric S Lander, Erez Lieberman Aiden
The human genome folds to create thousands of intervals, called "contact domains," that exhibit enhanced contact frequency within themselves. "Loop domains" form because of tethering between two loci-almost always bound by CTCF and cohesin-lying on the same chromosome. "Compartment domains" form when genomic intervals with similar histone marks co-segregate. Here, we explore the effects of degrading cohesin. All loop domains are eliminated, but neither compartment domains nor histone marks are affected. Loss of loop domains does not lead to widespread ectopic gene activation but does affect a significant minority of active genes...
October 5, 2017: Cell
https://www.readbyqxmd.com/read/28945243/germline-bias-dictates-cross-serotype-reactivity-in-a-common-dengue-virus-specific-cd8-t-cell-response
#19
Abigail Culshaw, Kristin Ladell, Stephanie Gras, James E McLaren, Kelly L Miners, Carine Farenc, Heleen van den Heuvel, Emma Gostick, Wanwisa Dejnirattisai, Apirath Wangteeraprasert, Thaneeya Duangchinda, Pojchong Chotiyarnwong, Wannee Limpitikul, Sirijitt Vasanawathana, Prida Malasit, Tao Dong, Jamie Rossjohn, Juthathip Mongkolsapaya, David A Price, Gavin R Screaton
Adaptive immune responses protect against infection with dengue virus (DENV), yet cross-reactivity with distinct serotypes can precipitate life-threatening clinical disease. We found that clonotypes expressing the T cell antigen receptor (TCR) β-chain variable region 11 (TRBV11-2) were 'preferentially' activated and mobilized within immunodominant human-leukocyte-antigen-(HLA)-A*11:01-restricted CD8(+) T cell populations specific for variants of the nonstructural protein epitope NS3133 that characterize the serotypes DENV1, DENV3 and DENV4...
November 2017: Nature Immunology
https://www.readbyqxmd.com/read/28911947/administration-of-albumin-solution-increases-serum-levels-of-albumin-in-patients-with-chronic-liver-failure-in-a-single-arm-feasibility-trial
#20
Louise China, Simon S Skene, Zainib Shabir, Alexander Maini, Yvonne Sylvestre, Kate Bennett, Scott Bevan, James O'Beirne, Ewan Forrest, Jim Portal, Steve Ryder, Gavin Wright, Derek W Gilroy, Alastair O'Brien
BACKGROUND & AIMS: Infections are life-threatening to patients with acute decompensation and acute-on-chronic liver failure (AD/ACLF). Patients with AD/ACLF have prostaglandin E2-mediated immune suppression, which can be reversed by administration of albumin; infusion of 20% human albumin solution (HAS) might improve outcomes of infections. We performed a feasibility study to determine optimal trial design, assess safety, and validate laboratory assessments of immune function to inform design of a phase 3 trial...
September 12, 2017: Clinical Gastroenterology and Hepatology
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