Digital Commons Network^™

Metabolism Of Jq1, An Inhibitor Of Bromodomain And Extra Terminal Bromodomain Proteins, In Human And Mouse Liver Microsomes†, Feng Li, Kevin R Mackenzie, Prashi Jain, Conrad Santini, Damian W Young, Martin M Matzuk

Faculty, Staff and Students Publications

JQ1 is a small-molecule inhibitor of the bromodomain and extra terminal (BET) protein family that potently inhibits the bromodomain testis-specific protein (BRDT), which is essential for spermatogenesis. JQ1 treatment produces a reversible contraceptive effect by targeting the activity of BRDT in mouse male germ cells, validating BRDT as a male contraceptive target. Although JQ1 possesses favourable physical properties, it exhibits a short half-life. Because the details of xenobiotic metabolism play important roles in the optimization of drug candidates and in determining the role of metabolism in drug efficacy, we investigated the metabolism of JQ1 in human and mouse liver microsomes. …

Proteolysis-Targeting Chimera (Protac) For Targeted Protein Degradation And Cancer Therapy, Xin Li, Yongcheng Song

Faculty, Staff and Students Publications

Proteolysis-targeting chimera (PROTAC) has been developed to be a useful technology for targeted protein degradation. A bifunctional PROTAC molecule consists of a ligand (mostly small-molecule inhibitor) of the protein of interest (POI) and a covalently linked ligand of an E3 ubiquitin ligase (E3). Upon binding to the POI, the PROTAC can recruit E3 for POI ubiquitination, which is subjected to proteasome-mediated degradation. PROTAC complements nucleic acid-based gene knockdown/out technologies for targeted protein reduction and could mimic pharmacological protein inhibition. To date, PROTACs targeting ~ 50 proteins, many of which are clinically validated drug targets, have been successfully developed with several …

Metabolic Dysregulation In The Atp7b-/- Wilson's Disease Mouse Model, Clavia Ruth Wooton-Kee, Matthew Robertson, Ying Zhou, Bingning Dong, Zhen Sun, Kang Ho Kim, Hailan Liu, Yong Xu, Nagireddy Putluri, Pradip Saha, Cristian Coarfa, David D Moore, Alli M Nuotio-Antar

Faculty, Staff and Students Publications

Inactivating mutations in the copper transporter Atp7b result in Wilson’s disease. The Atp7b−/− mouse develops hallmarks of Wilson’s disease. The activity of several nuclear receptors decreased in Atp7b−/− mice, and nuclear receptors are critical for maintaining metabolic homeostasis. Therefore, we anticipated that Atp7b−/− mice would exhibit altered progression of diet-induced obesity, fatty liver, and insulin resistance. Following 10 wk on a chow or Western-type diet (40% kcal fat), parameters of glucose and lipid homeostasis were measured. Hepatic metabolites were measured by liquid chromatography–mass spectrometry and correlated with transcriptomic data. Atp7b−/− mice fed a chow diet presented …

Non-Uniformity Of Projection Distributions Attenuates Resolution In Cryo-Em, Philip R Baldwin, Dmitry Lyumkis

Faculty, Staff and Students Publications

Virtually all single-particle cryo-EM experiments currently suffer from specimen adherence to the air-water interface, leading to a non-uniform distribution in the set of projection views. Whereas it is well accepted that uniform projection distributions can lead to high-resolution reconstructions, non-uniform (anisotropic) distributions can negatively affect map quality, elongate structural features, and in some cases, prohibit interpretation altogether. Although some consequences of non-uniform sampling have been described qualitatively, we know little about how sampling quantitatively affects resolution in cryo-EM. Here, we show how inhomogeneity in any projection distribution scheme attenuates the global Fourier Shell Correlation (FSC) in relation to the number …

Abcb1 Snp Predicts Outcome In Patients With Acute Myeloid Leukemia Treated With Gemtuzumab Ozogamicin: A Report From Children's Oncology Group Aaml0531 Trial., Roya Rafiee, Lata Chauhan, Todd A. Alonzo, Yi-Cheng Wang, Ahlam Elmasry, Michael R. Loken, Jessica Pollard, Richard Aplenc, Susana Raimondi, Betsy A. Hirsch, Irwin D. Bernstein, A S. Gamis, Soheil Meshinchi, Jatinder K. Lamba

Manuscripts, Articles, Book Chapters and Other Papers

Gemtuzumab-ozogamicin (GO), a humanized-anti-CD33 antibody linked with the toxin-calicheamicin-γ is a reemerging and promising drug for AML. Calicheamicin a key element of GO, induces DNA-damage and cell-death once the linked CD33-antibody facilitates its uptake. Calicheamicin efflux by the drug-transporter PgP-1 have been implicated in GO response thus in this study, we evaluated impact of ABCB1-SNPs on GO response. Genomic-DNA samples from 942 patients randomized to receive standard therapy with or without addition of GO (COG-AAML0531) were genotyped for ABCB1-SNPs. Our most interesting results show that for rs1045642, patients with minor-T-allele (CT/TT) had better outcome as compared to patients with CC …

Progress On Identifying And Characterizing The Human Proteome: 2018 Metrics From The Hupo Human Proteome Project., Gilbert S Omenn, Lydie Lane, Christopher M Overall, Fernando J Corrales, Jochen M Schwenk, Young-Ki Paik, Jennifer E Van Eyk, Siqi Liu, Michael Snyder, Mark S Baker, Eric W Deutsch

Articles, Abstracts, and Reports

The Human Proteome Project (HPP) annually reports on progress throughout the field in credibly identifying and characterizing the human protein parts list and making proteomics an integral part of multiomics studies in medicine and the life sciences. NeXtProt release 2018-01-17, the baseline for this sixth annual HPP special issue of the Journal of Proteome Research, contains 17 470 PE1 proteins, 89% of all neXtProt predicted PE1-4 proteins, up from 17 008 in release 2017-01-23 and 13 975 in release 2012-02-24. Conversely, the number of neXtProt PE2,3,4 missing proteins has been reduced from 2949 to 2579 to 2186 over the past …

Opportunities And Obstacles For Deep Learning In Biology And Medicine, Travers Ching, S Joshua Swamidass, Et Al

2010-2019 OA Pubs

Deep learning describes a class of machine learning algorithms that are capable of combining raw inputs into layers of intermediate features. These algorithms have recently shown impressive results across a variety of domains. Biology and medicine are data-rich disciplines, but the data are complex and often ill-understood. Hence, deep learning techniques may be particularly well suited to solve problems of these fields. We examine applications of deep learning to a variety of biomedical problems-patient classification, fundamental biological processes and treatment of patients-and discuss whether deep learning will be able to transform these tasks or if the biomedical sphere poses unique …

Diverse Amide Analogs Of Sulindac For Cancer Treatment And Prevention, Bini Mathew, Judith V. Hobrath, Michele C. Connelly, R. Kiplin Guy, Robert C. Reynolds

Pharmaceutical Sciences Faculty Publications

Sulindac is a non-steroidal anti-inflammatory drug (NSAID) that has shown significant anticancer activity. Sulindac sulfide amide (1) possessing greatly reduced COX-related inhibition relative to sulindac displayed in vivoantitumor activity that was comparable to sulindac in a human colon tumorxenograft model. Inspired by these observations, a panel of diverse sulindac amide derivatives have been synthesized and their activity probed against three cancer cell lines (prostate, colon and breast). A neutral analog, compound 79 was identified with comparable potency relative to lead 1 and activity against a panel of lymphoblastic leukemia cell lines. Several new series also show good …

Insights Into Onchocerca Volvulus Population Biology Through Multilocus Immunophenotyping, Carmelle T Norice-Tra, José Ribeiro, Sasisekhar Bennuru, Michael P Fay, Rahul Tyagi, Makedonka Mitreva, Thomas B Nutman

2010-2019 OA Pubs

We have developed a serologically based immunophenotyping approach to study Onchocerca volvulus (Ov) population diversity. Using genomic sequence data and polymerase chain reaction-based genotyping, we identified nonsynonymous single-nucleotide polymorphisms (SNPs) in the genes of 16 major immunogenic Ov proteins: Ov-CHI-1/Ov-CHI-2, Ov16, Ov-FAR-1, Ov-CPI-1, Ov-B20, Ov-ASP-1, Ov-TMY-1, OvSOD1, OvGST1, Ov-CAL-1, M3/M4, Ov-RAL-1, Ov-RAL-2, Ov-ALT-1, Ov-FBA-1, and Ov-B8. We assessed the immunoreactivity of onchocerciasis patient sera (n = 152) from the Americas, West Africa, Central Africa, and East Africa against peptides derived from 10 of these proteins containing SNPs. Statistically significant variation in immunoreactivity among the regions was seen in SNP-containing peptides …

Rare Coding Variants In Plcg2, Abi3, And Trem2 Implicate Microglial-Mediated Innate Immunity In Alzheimer's Disease., Rebecca Sims, Sven J Van Der Lee, Adam C Naj, Céline Bellenguez, Nandini Badarinarayan, Johanna Jakobsdottir, Brian W Kunkle, Anne Boland, Rachel Raybould, Joshua C Bis, Eden R Martin, Benjamin Grenier-Boley, Stefanie Heilmann-Heimbach, Vincent Chouraki, Amanda B Kuzma, Kristel Sleegers, Maria Vronskaya, Agustin Ruiz, Robert R Graham, Robert Olaso, Per Hoffmann, Megan L Grove, Badri N Vardarajan, Mikko Hiltunen, Markus M Nöthen, Charles C White, Kara L Hamilton-Nelson, Jacques Epelbaum, Wolfgang Maier, Seung-Hoan Choi, Gary W Beecham, Cécile Dulary, Stefan Herms, Albert V Smith, Cory C Funk, Céline Derbois, Andreas J Forstner, Shahzad Ahmad, Hongdong Li, Delphine Bacq, Denise Harold, Claudia L Satizabal, Otto Valladares, Alessio Squassina, Rhodri Thomas, Jennifer A Brody, Liming Qu, Pascual Sánchez-Juan, Taniesha Morgan, Frank J Wolters, Yi Zhao, Florentino Sanchez Garcia, Nicola Denning, Myriam Fornage, John Malamon, Maria Candida Deniz Naranjo, Elisa Majounie, Thomas H Mosley, Beth Dombroski, David Wallon, Michelle K Lupton, Josée Dupuis, Patrice Whitehead, Laura Fratiglioni, Christopher Medway, Xueqiu Jian, Shubhabrata Mukherjee, Lina Keller, Kristelle Brown, Honghuang Lin, Laura B Cantwell, Francesco Panza, Bernadette Mcguinness, Sonia Moreno-Grau, Jeremy D Burgess, Vincenzo Solfrizzi, Petra Proitsi, Hieab H Adams, Mariet Allen, Davide Seripa, Pau Pastor, L Adrienne Cupples, Nathan D Price, Didier Hannequin, Ana Frank-García, Daniel Levy, Paramita Chakrabarty, Paolo Caffarra, Ina Giegling, Alexa S Beiser, Vilmantas Giedraitis, Harald Hampel, Melissa E Garcia, Xue Wang, Lars Lannfelt, Patrizia Mecocci, Gudny Eiriksdottir, Paul K Crane, Florence Pasquier, Virginia Boccardi, Isabel Henández, Robert C Barber, Martin Scherer, Lluis Tarraga, Perrie M Adams, Markus Leber, Yuning Chen, Marilyn S Albert, Steffi Riedel-Heller, Valur Emilsson, Duane Beekly, Anne Braae, Reinhold Schmidt, Deborah Blacker, Carlo Masullo, Helena Schmidt, Rachelle S Doody, Gianfranco Spalletta, W T Longstreth, Thomas J Fairchild, Paola Bossù, Oscar L Lopez, Matthew P Frosch, Eleonora Sacchinelli, Bernardino Ghetti, Qiong Yang, Ryan M Huebinger, Frank Jessen, Shuo Li, M Ilyas Kamboh, John Morris, Oscar Sotolongo-Grau, Mindy J Katz, Chris Corcoran, Melanie Dunstan, Amy Braddel, Charlene Thomas, Alun Meggy, Rachel Marshall, Amy Gerrish, Jade Chapman, Miquel Aguilar, Sarah Taylor, Matt Hill, Mònica Díez Fairén, Angela Hodges, Bruno Vellas, Hilkka Soininen, Iwona Kloszewska, Makrina Daniilidou, James Uphill, Yogen Patel, Joseph T Hughes, Jenny Lord, James Turton, Annette M Hartmann, Roberta Cecchetti, Chiara Fenoglio, Maria Serpente, Marina Arcaro, Carlo Caltagirone, Maria Donata Orfei, Antonio Ciaramella, Sabrina Pichler, Manuel Mayhaus, Wei Gu, Alberto Lleó, Juan Fortea, Rafael Blesa, Imelda S Barber, Keeley Brookes, Chiara Cupidi, Raffaele Giovanni Maletta, David Carrell, Sandro Sorbi, Susanne Moebus, Maria Urbano, Alberto Pilotto, Johannes Kornhuber, Paolo Bosco, Stephen Todd, David Craig, Janet Johnston, Michael Gill, Brian Lawlor, Aoibhinn Lynch, Nick C Fox, John Hardy, Roger L Albin, Liana G Apostolova, Steven E Arnold, Sanjay Asthana, Craig S Atwood, Clinton T Baldwin, Lisa L Barnes, Sandra Barral, Thomas G Beach, James T Becker, Eileen H Bigio, Thomas D Bird, Bradley F Boeve, James D Bowen, Adam Boxer, James R Burke, Jeffrey M Burns, Joseph D Buxbaum, Nigel J Cairns, Chuanhai Cao, Chris S Carlson, Cynthia M Carlsson, Regina M Carney, Minerva M Carrasquillo, Steven L Carroll, Carolina Ceballos Diaz, Helena C Chui, David G Clark, David H Cribbs, Elizabeth A Crocco, Charles Decarli, Malcolm Dick, Ranjan Duara, Denis A Evans, Kelley M Faber, Kenneth B Fallon, David W Fardo, Martin R Farlow, Steven Ferris, Tatiana M Foroud, Douglas R Galasko, Marla Gearing, Daniel H Geschwind, John R Gilbert, Neill R Graff-Radford, Robert C Green, John H Growdon, Ronald L Hamilton, Lindy E Harrell, Lawrence S Honig, Matthew J Huentelman, Christine M Hulette, Bradley T Hyman, Gail P Jarvik, Erin Abner, Lee-Way Jin, Gyungah Jun, Anna Karydas, Jeffrey A Kaye, Ronald Kim, Neil W Kowall, Joel H Kramer, Frank M Laferla, James J Lah, James B Leverenz, Allan I Levey, Ge Li, Andrew P Lieberman, Kathryn L Lunetta, Constantine G Lyketsos, Daniel C Marson, Frank Martiniuk, Deborah C Mash, Eliezer Masliah, Wayne C Mccormick, Susan M Mccurry, Andrew N Mcdavid, Ann C Mckee, Marsel Mesulam, Bruce L Miller, Carol A Miller, Joshua W Miller, John C Morris, Jill R Murrell, Amanda J Myers, Sid O'Bryant, John M Olichney, Vernon S Pankratz, Joseph E Parisi, Henry L Paulson, William Perry, Elaine Peskind, Aimee Pierce, Wayne W Poon, Huntington Potter, Joseph F Quinn, Ashok Raj, Murray Raskind, Barry Reisberg, Christiane Reitz, John M Ringman, Erik D Roberson, Ekaterina Rogaeva, Howard J Rosen, Roger N Rosenberg, Mark A Sager, Andrew J Saykin, Julie A Schneider, Lon S Schneider, William W Seeley, Amanda G Smith, Joshua A Sonnen, Salvatore Spina, Robert A Stern, Russell H Swerdlow, Rudolph E Tanzi, Tricia A Thornton-Wells, John Q Trojanowski, Juan C Troncoso, Vivianna M Van Deerlin, Linda J Van Eldik, Harry V Vinters, Jean Paul Vonsattel, Sandra Weintraub, Kathleen A Welsh-Bohmer, Kirk C Wilhelmsen, Jennifer Williamson, Thomas S Wingo, Randall L Woltjer, Clinton B Wright, Chang-En Yu, Lei Yu, Fabienne Garzia, Feroze Golamaully, Gislain Septier, Sebastien Engelborghs, Rik Vandenberghe, Peter P De Deyn, Carmen Muñoz Fernadez, Yoland Aladro Benito, Hakan Thonberg, Charlotte Forsell, Lena Lilius, Anne Kinhult-Stählbom, Lena Kilander, Rosemarie Brundin, Letizia Concari, Seppo Helisalmi, Anne Maria Koivisto, Annakaisa Haapasalo, Vincent Dermecourt, Nathalie Fievet, Olivier Hanon, Carole Dufouil, Alexis Brice, Karen Ritchie, Bruno Dubois, Jayanadra J Himali, C Dirk Keene, Joann Tschanz, Annette L Fitzpatrick, Walter A Kukull, Maria Norton, Thor Aspelund, Eric B Larson, Ron Munger, Jerome I Rotter, Richard B Lipton, María J Bullido, Albert Hofman, Thomas J Montine, Eliecer Coto, Eric Boerwinkle, Ronald C Petersen, Victoria Alvarez, Fernando Rivadeneira, Eric M Reiman, Maura Gallo, Christopher J O'Donnell, Joan S Reisch, Amalia Cecilia Bruni, Donald R Royall, Martin Dichgans, Mary Sano, Daniela Galimberti, Peter St George-Hyslop, Elio Scarpini, Debby W Tsuang, Michelangelo Mancuso, Ubaldo Bonuccelli, Ashley R Winslow, Antonio Daniele, Chuang-Kuo Wu, Oliver Peters, Benedetta Nacmias, Matthias Riemenschneider, Reinhard Heun, Carol Brayne, David C Rubinsztein, Jose Bras, Rita Guerreiro, Ammar Al-Chalabi, Christopher E Shaw, John Collinge, David Mann, Magda Tsolaki, Jordi Clarimón, Rebecca Sussams, Simon Lovestone, Michael C O'Donovan, Michael J Owen, Timothy W Behrens, Simon Mead, Alison M Goate, Andre G Uitterlinden, Clive Holmes, Carlos Cruchaga, Martin Ingelsson, David A Bennett, John Powell, Todd E Golde, Caroline Graff, Philip L De Jager, Kevin Morgan, Nilufer Ertekin-Taner, Onofre Combarros, Bruce M Psaty, Peter Passmore, Steven G Younkin, Claudine Berr, Vilmundur Gudnason, Dan Rujescu, Dennis W Dickson, Jean-François Dartigues, Anita L Destefano, Sara Ortega-Cubero, Hakon Hakonarson, Dominique Campion, Merce Boada, John Keoni Kauwe, Lindsay A Farrer, Christine Van Broeckhoven, M Arfan Ikram, Lesley Jones, Jonathan L Haines, Christophe Tzourio, Lenore J Launer, Valentina Escott-Price, Richard Mayeux, Jean-François Deleuze, Najaf Amin, Peter A Holmans, Margaret A Pericak-Vance, Philippe Amouyel, Cornelia M Van Duijn, Alfredo Ramirez, Li-San Wang, Jean-Charles Lambert, Sudha Seshadri, Julie Williams, Gerard D Schellenberg

Articles, Abstracts, and Reports

We identified rare coding variants associated with Alzheimer's disease in a three-stage case-control study of 85,133 subjects. In stage 1, we genotyped 34,174 samples using a whole-exome microarray. In stage 2, we tested associated variants (P < 1 × 10

Shorter Remission Telomere Length Predicts Delayed Neutrophil Recovery After Acute Myeloid Leukemia Therapy: A Report From The Children's Oncology Group., Robert B. Gerbing, Todd A. Alonzo, Lillian Sung, Alan S. Gamis, Soheil Meshinchi, Sharon E. Plon, Alison A. Bertuch, Maria M. Gramatges

Manuscripts, Articles, Book Chapters and Other Papers

Purpose Suboptimal outcomes for children with acute myeloid leukemia (AML) necessitate maximally intensive therapy. Consequently, serious adverse events, such as prolonged periods of profound myelosuppression, contribute to AML treatment-related mortality. Telomeres, the repetitive DNA-protein structures at chromosome ends, influence cellular replicative capacity in that critically short telomeres can induce cell senescence or apoptosis. Our objective was to evaluate the impact of telomere length on duration of post-therapy neutropenia in a pediatric AML cohort. Patients and Methods Patients were diagnosed with de novo AML, enrolled in Children's Oncology Group study AAML0531, and included those with (n = 53) and without (n …

Incidence And Duration Of Type-Specific Human Papillomavirus Infection In High-Risk Hpv-Naïve Women: Results From The Control Arm Of A Phase Ii Hpv-16/18 Vaccine Trial, Agnihotram V. Ramanakumar, Paulo Naud, Cecilia M. Roteli-Martins, Newton S. De Carvalho, Paola C. De Borba, Julio C. Teixeira, Mark Blatter, Anna-Barbara Moscicki, Diane M. Harper, Barbara Romanowski, Stephen K. Tyring, Brian Ramjattan, Anne Schuind, Gary Dubin, Eduardo L. Franco

Dartmouth Scholarship

OBJECTIVES:

Persistence of human papillomaviruses (HPVs) is necessary for cervical carcinogenesis. We evaluated incidence and duration of type-specific HPV infections and the influence of age and number of sexual partners.

METHODS:

Data were obtained from 553 women (15-25 years), who were seronegative and DNA-negative for high-risk HPV (HR-HPV) types and were enrolled in the placebo arm of a randomised trial of the HPV-16/18 vaccine (NCT00689741/NCT00120848). They were followed for 6.3 years. Cervicovaginal samples were self-collected at 3-month intervals for up to 27 months, and cervical samples were collected by clinicians at 6-month intervals until study end. …

Cd33 Expression And Its Association With Gemtuzumab Ozogamicin Response: Results From The Randomized Phase Iii Children's Oncology Group Trial Aaml0531., Jessica A. Pollard, Michael Loken, Robert B. Gerbing, Susana C. Raimondi, Betsy A. Hirsch, Richard Aplenc, Irwin D. Bernstein, Alan S. Gamis, Todd A. Alonzo, Soheil Meshinchi

Manuscripts, Articles, Book Chapters and Other Papers

PURPOSE: CD33 is variably expressed on acute myeloid leukemia (AML) blasts and is targeted by gemtuzumab ozogamicin (GO). GO has shown benefit in both adult and pediatric AML trials, yet limited data exist about whether GO response correlates with CD33 expression level.

PATIENTS AND METHODS: CD33 expression levels were prospectively quantified by multidimensional flow cytometry in 825 patients enrolled in Children's Oncology Group AAML0531 and correlated with response to GO.

RESULTS: Patients with low CD33 expression (lowest quartile of expression [Q1]) had no benefit with the addition of GO to conventional chemotherapy (relapse risk [RR]: GO 36% v No-GO 34%, …

Antagonism Of Triazolam Self-Administration In Rhesus Monkeys Responding Under A Progressive-Ratio Schedule: In Vivo Apparent Pa2 Analysis., Bradford D Fischer, Donna M Platt, Sundari K Rallapalli, Ojas A Namjoshi, James M Cook, James K Rowlett

Cooper Medical School of Rowan University Departmental Research

BACKGROUND: Conventional benzodiazepines bind non-selectively to GABAA receptors containing α1, α2, α3, and α5 subunits (α1GABAA, α2GABAA, α3GABAA, and α5GABAA receptors, respectively), and the role of these different GABAA receptor subtypes in the reinforcing effects of benzodiazepines has not been characterized fully. We used a pharmacological antagonist approach with available subtype-selective ligands to evaluate the role of GABAA receptor subtypes in the reinforcing effects of the non-selective conventional benzodiazepine, triazolam.

METHODS: Rhesus monkeys (n=4) were trained under a progressive-ratio schedule of intravenous midazolam delivery and dose-response functions were determined for triazolam, in the absence and presence of flumazenil (non-selective antagonist), …

Targeting Human Central Nervous System Protein Kinases: An Isoform Selective P38Αmapk Inhibitor That Attenuates Disease Progression In Alzheimer's Disease Mouse Models, Saktimayee M. Roy, Valerie L. Grum-Tokars, James P. Schavocky, Faisal Saeed, Agnieszka Staniszewski, Andrew F. Teich, Ottavio Arancio, Adam D. Bachstetter, Scott J. Webster, Linda J. Van Eldik, George Minasov, Wayne F. Anderson, Jeffrey C. Pelletier, D. Martin Watterson

Spinal Cord and Brain Injury Research Center Faculty Publications

The first kinase inhibitor drug approval in 2001 initiated a remarkable decade of tyrosine kinase inhibitor drugs for oncology indications, but a void exists for serine/threonine protein kinase inhibitor drugs and central nervous system indications. Stress kinases are of special interest in neurological and neuropsychiatric disorders due to their involvement in synaptic dysfunction and complex disease susceptibility. Clinical and preclinical evidence implicates the stress related kinase p38αMAPK as a potential neurotherapeutic target, but isoform selective p38αMAPK inhibitor candidates are lacking and the mixed kinase inhibitor drugs that are promising in peripheral tissue disease indications have limitations for neurologic indications. Therefore, …

Belief About Nicotine Selectively Modulates Value And Reward Prediction Error Signals In Smokers, Xiaosi Gu, Terry Lohrenz, Ramiro Salas, Philip R. Baldwin, Alireza Soltani

Dartmouth Scholarship

Little is known about how prior beliefs impact biophysically described processes in the presence of neuroactive drugs, which presents a profound challenge to the understanding of the mechanisms and treatments of addiction. We engineered smokers' prior beliefs about the presence of nicotine in a cigarette smoked before a functional magnetic resonance imaging session where subjects carried out a sequential choice task. Using a model-based approach, we show that smokers' beliefs about nicotine specifically modulated learning signals (value and reward prediction error) defined by a computational model of mesolimbic dopamine systems. Belief of "no nicotine in cigarette" (compared with "nicotine in …

Bdnf In The Dentate Gyrus Is Required For Consolidation Of "Pattern-Separated" Memories., Pedro Bekinschtein, Brianne A Kent, Charlotte A Oomen, Gregory D Clemenson, Fred H Gage, Lisa M Saksida, Timothy J Bussey

Brain and Mind Institute Researchers' Publications

Successful memory involves not only remembering information over time, but also keeping memories distinct and less confusable. The computational process for making representations for similar input patterns more distinct from each other has been referred to as "pattern separation." In this work, we developed a set of behavioral conditions that allowed us to manipulate the load for pattern separation at different stages of memory. Thus, we provide experimental evidence that a brain-derived neurotrophic factor (BDNF)-dependent pattern separation process occurs during the encoding/storage/consolidation, but not the retrieval stage of memory processing. We also found that a spontaneous increase in BDNF in …

Force Generation By Kinesin And Myosin Cytoskeletal Motor Proteins, F. Jon Kull, Sharyn A. Endow

Dartmouth Scholarship

Kinesins and myosins hydrolyze ATP, producing force that drives spindle assembly, vesicle transport and muscle contraction. How do motors do this? Here we discuss mechanisms of motor force transduction, based on their mechanochemical cycles and conformational changes observed in crystal structures. Distortion or twisting of the central β-sheet - proposed to trigger actin-induced Pi and ADP release by myosin, and microtubule-induced ADP release by kinesins - is shown in a movie depicting the transition between myosin ATP-like and nucleotide-free states. Structural changes in the switch I region form a tube that governs ATP hydrolysis and Pi release by the motors, …

The Complex Transcriptional Landscape Of The Anucleate Human Platelet., Paul F. Bray, Steven E. Mckenzie, Leonard Edelstein, Srikanth Nagalla, Kathleen Delgrosso, Adam Ertel, Joan Kupper, Yi Jing, Eric R. Londin, Phillipe Loher, Huang-Wen Chen, Paolo Fortina, Isidore Rigoutsos

Cardeza Foundation for Hematologic Research

BACKGROUND: Human blood platelets are essential to maintaining normal hemostasis, and platelet dysfunction often causes bleeding or thrombosis. Estimates of genome-wide platelet RNA expression using microarrays have provided insights to the platelet transcriptome but were limited by the number of known transcripts. The goal of this effort was to deep-sequence RNA from leukocyte-depleted platelets to capture the complex profile of all expressed transcripts.

RESULTS: From each of four healthy individuals we generated long RNA (≥40 nucleotides) profiles from total and ribosomal-RNA depleted RNA preparations, as well as short RNA (<40 >nucleotides) profiles. Analysis of ~1 billion reads revealed that coding …

The Proteomics Of Lipid Droplets: Structure, Dynamics, And Functions Of The Organelle Conserved From Bacteria To Humans., Li Yang, Yunfeng Ding, Yong Chen, Shuyan Zhang, Chaoxing Huo, Yang Wang, Jinhai Yu, Peng Zhang, Huimin Na, Huina Zhang, Yanbin Ma, Pingsheng Liu

College of Science & Mathematics Departmental Research

Lipid droplets are cellular organelles that consists of a neutral lipid core covered by a monolayer of phospholipids and many proteins. They are thought to function in the storage, transport, and metabolism of lipids, in signaling, and as a specialized microenvironment for metabolism in most types of cells from prokaryotic to eukaryotic organisms. Lipid droplets have received a lot of attention in the last 10 years as they are linked to the progression of many metabolic diseases and hold great potential for the development of neutral lipid-derived products, such as biofuels, food supplements, hormones, and medicines. Proteomic analysis of lipid …

Microarray-Based Cancer Prediction Using Single Genes., Xiaosheng Wang, Richard Simon

Journal Articles: Genetics, Cell Biology & Anatomy

BACKGROUND: Although numerous methods of using microarray data analysis for cancer classification have been proposed, most utilize many genes to achieve accurate classification. This can hamper interpretability of the models and ease of translation to other assay platforms. We explored the use of single genes to construct classification models. We first identified the genes with the most powerful univariate class discrimination ability and then constructed simple classification rules for class prediction using the single genes.

RESULTS: We applied our model development algorithm to eleven cancer gene expression datasets and compared classification accuracy to that for standard methods including Diagonal Linear …

Effect Of Variable Transmission Rate On The Dynamics Of Hiv In Sub-Saharan Africa, Diego F. Cuadros, Phillip H. Crowley, Ben Augustine, Sarah L. Stewart, Gisela García-Ramos

Biology Faculty Publications

BACKGROUND: The cause of the high HIV prevalence in sub-Saharan Africa is incompletely understood, with heterosexual penile-vaginal transmission proposed as the main mechanism. Heterosexual HIV transmission has been estimated to have a very low probability; but effects of cofactors that vary in space and time may substantially alter this pattern.

METHODS: To test the effect of individual variation in the HIV infectiousness generated by co-infection, we developed and analyzed a mathematical sexual network model that simulates the behavioral components of a population from Malawi, as well as the dynamics of HIV and the co-infection effect caused by other infectious diseases, …

The Marine Sponge Metabolite Mycothiazole: A Novel Prototype Mitochondrial Complex I Inhibitor., J Brian Morgan, Fakhri Mahdi, Yang Liu, Veena Coothankandaswamy, Mika B. Jekabsons, Tyler A. Johnson, Koneni V. Sashidhara, Phillip Crews, Dale G. Nagle, Yu-Dong Zhou

Natural Sciences and Mathematics | Faculty Scholarship

A natural product chemistry-based approach was applied to discover small-molecule inhibitors of hypoxia-inducible factor-1 (HIF-1). A Petrosaspongia mycofijiensis marine sponge extract yielded mycothiazole (1), a solid tumor selective compound with no known mechanism for its cell line-dependent cytotoxic activity. Compound 1 inhibited hypoxic HIF-1 signaling in tumor cells (IC(50) 1nM) that correlated with the suppression of hypoxia-stimulated tumor angiogenesis in vitro. However, 1 exhibited pronounced neurotoxicity in vitro. Mechanistic studies revealed that 1 selectively suppresses mitochondrial respiration at complex I (NADH-ubiquinone oxidoreductase). Unlike rotenone, MPP(+), annonaceous acetogenins, piericidin A, and other complex I inhibitors, mycothiazole is a mixed polyketide/peptide-derived compound …

Genic Regions Of A Large Salamander Genome Contain Long Introns And Novel Genes, Jeramiah J. Smith, Srikrishna Putta, Wei Zhu, Gerald M. Pao, Inder M. Verma, Tony Hunter, Susan V. Bryant, David M. Gardiner, Timothy T. Harkins, S. Randal Voss

Biology Faculty Publications

BACKGROUND: The basis of genome size variation remains an outstanding question because DNA sequence data are lacking for organisms with large genomes. Sixteen BAC clones from the Mexican axolotl (Ambystoma mexicanum: c-value = 32 x 10(9) bp) were isolated and sequenced to characterize the structure of genic regions.

RESULTS: Annotation of genes within BACs showed that axolotl introns are on average 10x longer than orthologous vertebrate introns and they are predicted to contain more functional elements, including miRNAs and snoRNAs. Loci were discovered within BACs for two novel EST transcripts that are differentially expressed during spinal cord regeneration and skin …

Transcriptional Regulatory Network Analysis During Epithelial-Mesenchymal Transformation Of Retinal Pigment Epithelium., Craig H Pratt, Rajanikanth Vadigepalli, Praveen Chakravarthula, Gregory E Gonye, Nancy J Philp, Gerald B Grunwald

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

PURPOSE: Phenotypic transformation of retinal pigment epithelial (RPE) cells contributes to the onset and progression of ocular proliferative disorders such as proliferative vitreoretinopathy (PVR). The formation of epiretinal membranes in PVR may involve an epithelial-mesenchymal transformation (EMT) of RPE cells as part of an aberrant wound healing response. While the underlying mechanism remains unclear, this likely involves changes in RPE cell gene expression under the control of specific transcription factors (TFs). Thus, the purpose of the present study was to identify TFs that may play a role in this process.

METHODS: Regulatory regions of genes that are differentially regulated during …

Energizing Mirna Research: A Review Of The Role Of Mirnas In Lipid Metabolism, With A Prediction That Mir-103/107 Regulates Human Metabolic Pathways, Bernard R. Wilfred, Wang-Xia Wang, Peter T. Nelson

Sanders-Brown Center on Aging Faculty Publications

MicroRNAs (miRNAs) are powerful regulators of gene expression. Although first discovered in worm larvae, miRNAs play fundamental biological roles-including in humans-well beyond development. MiRNAs participate in the regulation of metabolism (including lipid metabolism) for all animal species studied. A review of the fascinating and fast-growing literature on miRNA regulation of metabolism can be parsed into three main categories: (1) adipocyte biochemistry and cell fate determination; (2) regulation of metabolic biochemistry in invertebrates; and (3) regulation of metabolic biochemistry in mammals. Most research into the 'function' of a given miRNA in metabolic pathways has concentrated on a given miRNA acting upon …

Spontaneous Intracranial Arterial Dissection In The Young: Diagnosis By Ct Angiography, William C. Robertson, Curtis A. Given

Neurology Faculty Publications

BACKGROUND: Spontaneous carotid artery dissections have been rarely reported in children. Diagnosis has traditionally been confirmed by catheter arteriography. More recently diagnosis has been made by magnetic resonance imaging and magnetic resonance angiography; however the sensitivity of these techniques has yet to be determined. The authors are unaware of reports of carotid dissection confirmed by dynamic computed tomography (computerized tomographic arteriography) in the young.

CASE PRESENTATION: We recently evaluated a fourteen year-old male following the development of transient neurologic symptoms. There was no antecedent illness or trauma. Dynamic computed tomography revealed an intracranial dissection involving the supraclinoid segment of the …

Embryonic Stem Cell-Derived Hematopoietic Stem Cells, Yuan Wang, Frank Yates, Olaia Naveiras, Patricia Ernst, George Q. Daley

Dartmouth Scholarship

Despite two decades of studies documenting the in vitro blood-forming potential of murine embryonic stem cells (ESCs), achieving stable long-term blood engraftment of ESC-derived hematopoietic stem cells in irradiated mice has proven difficult. We have exploited the Cdx-Hox pathway, a genetic program important for blood development, to enhance the differentiation of ESCs along the hematopoietic lineage. Using an embryonic stem cell line engineered with tetracycline-inducible Cdx4 , we demonstrate that ectopic Cdx4 expression promotes hematopoietic mesoderm specification, increases hematopoietic progenitor formation, and, together with HoxB4, enhances multilineage hematopoietic engraftment of lethally irradiated adult mice. Clonal analysis of retroviral integration sites …

Differences In Peripheral Noradrenergic Function Among Actively Drinking And Abstinent Alcohol-Dependent Individuals., Ashwin A. Patkar, Charles A. Marsden, Prakash C. Naik, David A. Kendall, Raman Gopalakrishnan, Michael J. Vergare, Stephen P. Weinstein

Department of Psychiatry and Human Behavior Faculty Papers

We examined whether excessive alcohol consumption was related to changes in plasma levels of noradrenaline (NA) and whether these changes recover following abstinence. We also explored whether there were differences in NA levels between Type I and Type II alcoholics and controls during active drinking and abstinence. Plasma concentrations of NA were determined in (1) 27 Caucasian men with alcohol dependence who were regularly drinking (active drinkers) within 24 hours of hospitalization, (2) 29 Caucasian alcohol-dependent men who were in remission (abstinent for a minimum of three months), and (3) 28 race- and gender-matched healthy controls. NA concentrations were significantly …

Proteolytic Release Of Cd44 Intracellular Domain And Its Role In The Cd44 Signaling Pathway., I Okamoto, Y Kawano, D Murakami, T Sasayama, N Araki, T Miki, A J Wong, H Saya

Department of Microbiology and Immunology Faculty Papers

CD44 is a widely distributed cell surface adhesion molecule and is implicated in diverse biological processes. However, the nature of intracellular signaling triggered by CD44 remains to be elucidated. Here, we show that CD44 undergoes sequential proteolytic cleavage in the ectodomain and intracellular domain, resulting in the release of a CD44 intracellular domain (ICD) fragment. Consequently, CD44ICD acts as a signal transduction molecule, where it translocates to the nucleus and activates transcription mediated through the 12-O-tetradecanoylphorbol 13-acetate-responsive element, which is found in numerous genes involved in diverse cellular processes. Expression of an uncleavable CD44 mutant as well as metalloprotease inhibitor …