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Armstrong EJ, Krueger JG
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Lipoprotein Metabolism and Inflammation in Patients With Psoriasis
AMERICAN JOURNAL OF CARDIOLOGY 2016 AUG 15; 118(4):603-609
Psoriasis is a chronic inflammatory disease associated with a variety of co-morbid conditions, including cardiovascular disease. Advancements in our understanding of the cellular and molecular mechanisms of psoriasis have led to a better understanding regarding its pathogenesis, which in turn has stimulated ongoing research to identify the underlying pathophysiology responsible for the increased risk of cardiovascular events associated with psoriasis. Although not yet fully elucidated, emerging evidence points to immune-mediated inflammation as a process that contributes to endothelial cell dysfunction, dyslipidemia, and atherosclerosis as key processes influencing cardiovascular disease in psoriasis. In particular, the dyslipidemia present in psoriasis may be associated with altered lipoprotein function and increased atherogenicity. Here, we review how the cytokine networks involved in lipoprotein metabolism and inflammation could impact on the cardiovascular disease risk for patients with psoriasis. Published by Elsevier Inc.
Damez-Werno DM, Sun HS, Scobie KN, Shao NY, Rabkin J, Dias C, Calipari ES, Maze I, Pena CJ, Walker DM, Cahill ME, Chandra R, Gancarz A, Mouzon E, Landry JA, Cates H, Lobo MK, Dietz D, Allis CD, Guccione E, Turecki G, Defilippi P, Neve RL, Hurd YL, Shen L, Nestler EJ
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Histone arginine methylation in cocaine action in the nucleus accumbens
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 2016 AUG 23; 113(34):9623-9628
Repeated cocaine exposure regulates transcriptional regulation within the nucleus accumbens (NAc), and epigenetic mechanisms-such as histone acetylation and methylation on Lys residues-have been linked to these lasting actions of cocaine. In contrast to Lysmethylation, the role of histone Arg (R) methylation remains underexplored in addictionmodels. Here we show that protein-R-methyltransferase-6 (PRMT6) and its associated histone mark, asymmetric dimethylation of R2 on histone H3 (H3R2me2a), are decreased in the NAc of mice and rats after repeated cocaine exposure, including self-administration, and in the NAc of cocaine-addicted humans. Such PRMT6 down-regulation occurs selectively in NAc medium spiny neurons (MSNs) expressing dopamine D2 receptors (D2-MSNs), with opposite regulation occurring in D1-MSNs, and serves to protect against cocaine-induced addictive-like behavioral abnormalities. Using ChIP-seq, we identified Src kinase signaling inhibitor 1 (Srcin1; also referred to as p140Cap) as a key gene target for reduced H3R2me2a binding, and found that consequent Srcin1 induction in the NAc decreases Src signaling, cocaine reward, and the motivation to self-administer cocaine. Taken together, these findings suggest that suppression of Src signaling in NAc D2-MSNs, via PRMT6 and H3R2me2a down-regulation, functions as a homeostatic brake to restrain cocaine action, and provide novel candidates for the development of treatments for cocaine addiction.
Khachatryan V, Sirunyan AM, Tumasyan A, Adam W, Asilar E, Bergauer T, Brandstetter J, Brondolin E, Dragicevic M, Ero J, Flechl M, Friedl M, Fruhwirth R, Ghete VM, Hartl C, Hormann N, Hrubec J, Jeitler M, Knunz V, Konig A, Krammer M, Kratschmer I, Liko D, Matsushita T, Mikulec I, Rabady D, Rahbaran B, Rohringer H, Schieck J, Schofbeck R, Strauss J, Treberer-Treberspurg W, Waltenberger W, Wulz CE, Mossolov V, Shumeiko N, Gonzalez JS, Alderweireldt S, Cornelis T, De Wolf EA, Janssen X, Knutsson A, Lauwers J, Luyckx S, Ochesanu S, Rougny R, Van De Klundert MV, Van Haevermaet H, Van Mechelen P, Van Remortel N, Van Spilbeeck A, Abu Zeid S, Blekman F, D'Hondt J, Daci N, De Bruyn I, Deroover K, Heracleous N, Keaveney J, Lowette S, Moreels L, Olbrechts A, Python Q, Strom D, Tavernier S, Van Doninck W, Van Mulders P, Van Onsem GP, Van Parijs I, Barria P, Caillol C, Clerbaux B, De Lentdecker G, Delannoy H, Fasanella G, Favart L, Gay APR, Grebenyuk A, Karapostoli G, Lenzi T, Leonard A, Maerschalk T, Marinov A, Pernie L, Randle-Conde A, Reis T, Seva T, Vander Velde C, Vanlaer P, Yonamine R, Zenoni F, Zhang F, Beernaert K, Benucci L, Cimmino A, Crucy S, Dobur D, Fagot A, Garcia G, Gul M, Mccartin J, Rios AAO, Poyraz D, Ryckbosch D, Salva S, Sigamani M, Strobbe N, Tytgat M, Van Driessche W, Yazgan E, Zaganidis N, Basegmez S, Beluffi C, Bondu O, Brochet S, Bruno G, Castello R, Caudron A, Ceard L, Da Silveira GG, Delaere C, Favart D, Forthomme L, Giammanco A, Hollar J, Jafari A, Jez P, Komm M, Lemaitre V, Mertens A, Nuttens C, Perrini L, Pin A, Piotrzkowski K, Popov A, Quertenmont L, Selvaggi M, Marono MV, Beliy N, Hammad GH, Alda WL, Alves GA, Brito L, Martins MCM, Hamer M, Hensel C, Herrera CM, Moraes A, Pol ME, Teles PR, Das Chagas EBB, Carvalho W, Chinellato J, Custodio A, Da Costa EM, Damiao DD, Martins CD, De Souza SF, Guativa LMH, Malbouisson H, Figueiredo DM, Mundim L, Nogima H, Da Silva WLP, Santoro A, Sznajder A, Manganote EJ, Pereira AV, Ahuja S, Bernardes CA, Santos AD, Dogra S, Tomei TRFP, Gregores EM, Mercadante PG, Moon CS, Novaes SF, Padula SS, Abad DR, Vargas JCR, Aleksandrov A, Hadjiiska R, Iaydjiev P, Rodozov M, Stoykova S, Sultanov G, Vu-Tova M, Dimitrov A, Glushkov I, Litov L, Pavlov B, Petkov P, Ahmad M, Bian JG, Chen GM, Chen HS, Chen M, Cheng T, Du R, Jiang CH, Plestina R, Romeo F, Shaheen SM, Tao J, Wang C, Wang Z, Zhang H, Asawatangtrakuldee C, Ban Y, Li Q, Liu S, Mao Y, Qian SJ, Wang D, Xu Z, Zou W, Avila C, Cabrera A, Sierra LFC, Florez C, Gomez JP, Moreno BG, Sanabria JC, Godinovic N, Lelas D, Puljak I, Cipriano PMR, Antunovic Z, Kovac M, Brigljevic V, Kadija K, Luetic J, Micanovic S, Sudic L, Attikis A, Mavromanolakis G, Mousa J, Nicolaou C, Ptochos F, Razis PA, Rykaczewski H, Bodlak M, Finger M, Finger M, El-Khateeb E, Elkafrawy T, Mohamed A, Radi A, Salama E, Calpas B, Kadastik M, Murumaa M, Raidal M, Tiko A, Veelken C, Eerola P, Pekkanen J, Voutilainen M, Harkonen J, Karimaki V, Kinnunen R, Lampen T, Lassila-Perini K, Lehti S, Linden T, Luukka P, Maenpaa T, Peltola T, Tuominen E, Tuominiemi J, Tuovinen E, Wend-Land L, Talvitie J, Tuuva T, Besancon M, Couderc F, Dejardin M, Denegri D, Fabbro B, Faure JL, Favaro C, Ferri F, Ganjour S, Givernaud A, Gras P, de Monchenault GH, Jarry P, Locci E, Machet M, Malcles J, Rander J, Rosowsky A, Titov M, Zghiche A, Antropov I, Baffioni S, Beaudette F, Busson P, Cadamuro L, Chapon E, Charlot C, Dahms T, Davignon O, Filipovic N, Florent A, de Cassagnac RG, Lisniak S, Mastrolorenzo L, Mine P, Naranjo IN, Nguyen M, Ochando C, Ortona G, Paganini P, Pigard P, Regnard S, Salerno R, Sauvan JB, Sirois Y, Strebler T, Yilmaz Y, Zabi A, Agram JL, Andrea J, Aubin A, Bloch D, Brom JM, Buttignol M, Chabert EC, Chanon N, Collard C, Conte E, Coubez X, Fontaine JC, Gele D, Goerlach U, Goetzmann C, Le Bihan AC, Merlin JA, Skovpen K, Van Hove P, Gadrat S, Beauceron S, Bernet C, Boudoul G, Bouvier E, Montoya CAC, Chierici R, Contardo D, Courbon B, Depasse P, El Mamouni H, Fan J, Fay J, Gascon S, Gouze-vitch M, Ille B, Lagarde F, Laktineh IB, Lethuillier M, Mirabito L, Pequegnot AL, Perries S, Alvarez JDR, Sabes D, Sgandurra L, Sordini V, Vander Donckt M, Verdier P, Viret S, Xiao H, Toriashvili T, Tsamalaidze Z, Autermann C, Beranek S, Edelhoff M, Feld L, Heister A, Kiesel MK, Klein K, Lipinski M, Ostapchuk A, Preuten M, Raupach F, Schael S, Schulte JF, Verlage T, Weber H, Wittmer B, Zhukov V, Ata M, Brodski M, Dietz-Laursonn E, Duchardt D, Endres M, Erdmann M, Erdweg S, Esch T, Fischer R, Guth A, Hebbeker T, Heidemann C, Hoepfner K, Klingebiel D, Knutzen S, Kreuzer P, Merschmeyer M, Meyer A, Millet P, Olschewski M, Padeken K, Papacz P, Pook T, Radziej M, Reithler H, Rieger M, Scheuch F, Sonnenschein L, Teyssier D, Thuer S, Cherepanov V, Erdogan Y, Flugge G, Geenen H, Geisler M, Hoehle F, Kargoll B, Kress T, Kuessel Y, Kunsken A, Lingemann J, Nehrkorn A, Nowack A, Nugent IM, Pistone C, Pooth O, Stahl A, Martin MA, Asin I, Bartosik N, Behnke O, Behrens U, Bell AJ, Borras K, Burgmeier A, Cakir A, Calligaris L, Campbell A, Choudhury S, Costanza F, Pardos CD, Dolinska G, Dooling S, Dorland T, Eckerlin G, Eckstein D, Eichhorn T, Flucke G, Gallo E, Garcia JG, Geiser A, Gizhko A, Gunnellini P, Hauk J, Hempel M, Jung H, Kalogeropoulos A, Karacheban O, Kasemann M, Katsas P, Kieseler J, Kleinwort C, Korol I, Lange W, Leonard J, Lipka K, Lobanov A, Lohmann W, Mankel R, Marfin I, Melzer-Pellmann IA, Meyer AB, Mittag G, Mnich J, Mussgiller A, Naumann-Emme S, Nayak A, Ntomari E, Perrey H, Pitzl D, Placakyte R, Raspereza A, Roland B, Sahin MO, Saxena P, Schoerner-Sadenius T, Schroder M, Seitz C, Spannagel S, Trippkewitz KD, Walsh R, Wissing C, Blobel V, Vignali MC, Draeger AR, Erfle J, Garutti E, Goebel K, Gonzalez D, Gorner M, Haller J, Hoffmann M, Hoing RS, Junkes A, Klanner R, Kogler R, Lapsien T, Lenz T, Marchesini I, Marconi D, Meyer M, Nowatschin D, Ott J, Pantaleo F, Peiffer T, Perieanu A, Pietsch N, Poehlsen J, Rathjens D, Sander C, Schettler H, Schleper P, Schlieckau E, Schmidt A, Schwandt J, Seidel M, Sola V, Stadie H, Steinbruck G, Tholen H, Troendle D, Usai E, Vanelderen L, Vanhoefer A, Vormwald B, Akbiyik M, Barth C, Baus C, Berger J, Boser C, Butz E, Chwalek T, Colombo F, De Boer W, Descroix A, Dierlamm A, Fink S, Frensch F, Giffels M, Gilbert A, Hartmann F, Heindl SM, Husemann U, Katkov I, Kornmayer A, Pardo PL, Maier B, Mildner H, Mozer MU, Muller T, Muller T, Plagge M, Quast G, Rabbertz K, Rocker S, Roscher F, Simonis HJ, Stober FM, Ulrich R, Wagner-Kuhr J, Wayand S, Weber M, Weiler T, Wohrmann C, Wolf R, Anagnostou G, Daskalakis G, Geralis T, Giakoumopoulou VA, Kyriakis A, Loukas D, Psallidas A, Topsis-Giotis I, Agapitos A, Kesisoglou S, Panagiotou A, Saoulidou N, Tziaferi E, Evangelou I, Flouris G, Foudas C, Kokkas P, Loukas N, Manthos N, Papadopoulos I, Paradas E, Strologas J, Bencze G, Hajdu C, Hazi A, Hidas P, Horvath D, Sikler F, Veszpremi V, Vesztergombi G, Zsigmond AJ, Beni N, Czellar S, Karancsi J, Molnar J, Szillasi Z, Bartok M, Makovec A, Raics P, Trocsanyi ZL, Ujvari B, Mal P, Mandal K, Sahoo N, Swain SK, Bansal S, Beri SB, Bhatnagar V, Chawla R, Gupta R, Bhawandeep U, Kalsi AK, Kaur A, Kaur M, Kumar R, Mehta A, Mittal M, Singh JB, Walia G, Kumar A, Bhardwaj A, Choudhary BC, Garg RB, Kumar A, Malhotra S, Naimuddin M, Nishu N, Ranjan K, Sharma R, Sharma V, Banerjee S, Bhattacharya S, Chatterjee K, Dey S, Dutta S, Jain S, Majumdar N, Modak A, Mondal K, Mukherjee S, Mukhopadhyay S, Roy A, Roy D, Chowdhury SR, Sarkar S, Sharan M, Abdulsalam A, Chudasama R, Dutta D, Jha V, Kumar V, Mohanty AK, Pant LM, Shukla P, Topkar A, Aziz T, Banerjee S, Bhowmik S, Chatterjee RM, Dewanjee RK, Dugad S, Gan-guly S, Ghosh S, Guchait M, Gurtu A, Kole G, Kumar S, Mahakud B, Maity M, Majumder G, Mazumdar K, Mitra S, Mohanty GB, Parida B, Sarkar T, Sudhakar K, Sur N, Sutar B, Wickramage N, Chauhan S, Dube S, Sharma S, Bakhshiansohi H, Behnamian H, Etesami SM, Fahim A, Goldouzian R, Khakzad M, Najafabadi MM, Naseri M, Mehdiabadi SP, Hosseinabadi FR, Safarzadeh B, Zeinali M, Felcini M, Grunewald M, Abbrescia M, Calabria C, Caputo C, Colaleo A, Creanza D, Cristella L, De Filippis N, De Palma M, Fiore L, Iaselli G, Maggi G, Maggi M, Miniello G, My S, Nuzzo S, Pompili A, Pugliese G, Radogna R, Ranieri A, Selvaggi G, Silvestris L, Venditti R, Verwilligen P, Abbiendi G, Battilana C, Benvenuti AC, Bonacorsi D, Braibant-Giacomelli S, Brigliadori L, Campanini R, Capiluppi P, Castro A, Cavallo FR, Chhibra SS, Codispoti G, Cuffiani M, Dallavalle GM, Fabbri F, Fanfani A, Fasanella D, Giacomelli P, Grandi C, Guiducci L, Marcellini S, Masetti G, Montanari A, Navarria FL, Perrotta A, Rossi AM, Rovelli T, Siroli GP, Tosi N, Travaglini R, Cappello G, Chiorboli M, Costa S, Giordano F, Potenza R, Tricomi A, Tuve C, Barbagli G, Ciulli V, Civinini C, D'Alessandro R, Focardi E, Gonzi S, Gori V, Lenzi P, Meschini M, Paoletti S, Sguazzoni G, Tropiano A, Viliani L, Benussi L, Bianco S, Fabbri F, Piccolo D, Primavera F, Calvelli V, Ferro F, Lo Vetere M, Monge MR, Robutti E, Tosi S, Brianza L, Dinardo ME, Fiorendi S, Gennai S, Gerosa R, Ghezzi A, Govoni P, Malvezzi S, Manzoni RA, Marzocchi B, Menasce D, Moroni L, Paganoni M, Pedrini D, Ragazzi S, Redaelli N, de Fatis TT, Buontempo S, Cavallo N, Di Guida S, Esposito M, Fabozzi F, Iorio AOM, Lanza G, Lista L, Meola S, Merola M, Paolucci P, Sciacca C, Thyssen F, Azzi P, Bacchetta N, Benato L, Bisello D, Boletti A, Carlin R, Checchia P, Dall'Osso M, Dorigo T, Fanzago F, Gasparini F, Gasparini U, Gozzelino A, Lacaprara S, Margoni M, Maron G, Meneguzzo AT, Montecassiano F, Pazzini J, Pozzobon N, Ronchese P, Simonetto F, Torassa E, Tosi M, Ventura S, Zanetti M, Zotto P, Zucchetta A, Zumerle G, Braghieri A, Magnani A, Montagna P, Ratti SP, Re V, Riccardi C, Salvini P, Vai I, Vitulo P, Solestizi LA, Biasini M, Bilei GM, Ciangottini D, Fano L, Lariccia P, Mantovani G, Menichelli M, Saha A, Santocchia A, Spiezia A, Androsov K, Azzurri P, Bagliesi G, Bernardini J, Boccali T, Broccolo G, Castaldi R, Ciocci MA, Dell'Orso R, Donato S, Fedi G, Foa L, Giassi A, Grippo MT, Ligabue F, Lomtadze T, Martini L, Messineo A, Palla F, Rizzi A, Savoy-Navarro A, Serban AT, Spagnolo P, Squillacioti P, Tenchini R, Tonelli G, Venturi A, Verdini PG, Barone L, Cavallari F, D'imperio G, Del Re D, Diemoz M, Gelli S, Jorda C, Longo E, Margaroli F, Meridiani P, Organtini G, Paramatti R, Preiato F, Rahatlou S, Rovelli C, Santanastasio F, Traczyk P, Amapane N, Arcidiacono R, Argiro S, Arneodo M, Bellan R, Biino C, Cartiglia N, Costa M, Covarelli R, Degano A, Demaria N, Finco L, Mariotti C, Maselli S, Mazza G, Migliore E, Monaco V, Monteil E, Musich M, Obertino MM, Pacher L, Pastrone N, Pelliccioni M, Angioni GLP, Ravera F, Romero A, Ruspa M, Sacchi R, Solano A, Staiano A, Tamponi U, Belforte S, Candelise V, Casarsa M, Cossutti F, Della Ricca G, Gobbo B, La Licata C, Marone M, Schizzi A, Zanetti A, Kropivnitskaya A, Nam SK, Kim DH, Kim GN, Kim MS, Kong DJ, Lee S, Oh YD, Sakharov A, Son DC, Cifuentes JAB, Kim H, Kim TJ, Ryu MS, Song S, Choi S, Go Y, Gyun D, Hong B, Jo M, Kim H, Kim Y, Lee B, Lee K, Lee KS, Lee S, Park SK, Roh Y, Yoo HD, Choi M, Kim H, Kim JH, Lee JSH, Park IC, Ryu G, Choi Y, Choi YK, Goh J, Kim D, Kwon E, Lee J, Yu I, Juodagalvis A, Vaitkus J, Ahmed I, Ibrahim ZA, Komaragiri JR, Ali MABM, Idris FM, Abdullah WATW, Yusli MN, Linares EC, Castilla-Valdez H, De La Cruz-Burelo E, Heredia-de La Cruz I, Hernandez-Almada A, Lopez-Fernandez R, Sanchez-Hernandez A, Moreno SC, Valencia FV, Pedraza I, Ibarguen HAS, Pineda AM, Krofcheck D, Butler PH, Ahmad A, Ahmad M, Hassan Q, Hoorani HR, Khan WA, Khurshid T, Shoaib M, Bialkowska H, Bluj M, Boimska B, Frueboes T, Gorski M, Kazana M, Nawrocki K, Romanowska-Rybinska K, Szleper M, Zalewski P, Brona G, Bunkowski K, Doroba K, Kalinowski A, Konecki M, Krolikowski J, Mis-iura M, Olszewski M, Walczak M, Bargassa P, Silva CBDE, Di Francesco A, Faccioli P, Parracho PGF, Gallinaro M, Leonardo N, Iglesias LL, Nguyen F, Antunes JR, Seixas J, Toldaiev O, Vadruccio D, Varela J, Vischia P, Afanasiev S, Bunin P, Gavrilenko M, Golutvin I, Gorbunov I, Kamenev A, Karjavin V, Konoplyanikov V, Lanev A, Malakhov A, Matveev V, Moisenz P, Palichik V, Perelygin V, Shmatov S, Shulha S, Skatchkov N, Smirnov V, Zarubin A, Golovtsov V, Ivanov Y, Kim V, Kuznetsova E, Levchenko P, Murzin V, Oreshkin V, Smirnov I, Sulimov V, Uvarov L, Vavilov S, Vorobyev A, Andreev Y, Dermenev A, Gninenko S, Golubev N, Karneyeu A, Kirsanov M, Krasnikov N, Pashenkov A, Tlisov D, Toropin A, Epshteyn V, Gavrilov V, Lychkovskaya N, Popov V, Pozdnyakov I, Safronov G, Spiridonov A, Vlasov E, Zhokin A, Bylinkin A, Andreev V, Azarkin M, Dremin I, Kirakosyan M, Leonidov A, Mesyats G, Rusakov SV, Vinogradov A, Baskakov A, Belyaev A, Boos E, Ershov A, Gribushin A, Khein L, Klyukhin V, Kodolova O, Lokhtin I, Lukina O, Myagkov I, Obraztsov S, Petrushanko S, Savrin V, Snigirev A, Azhgirey I, Bayshev I, Bitioukov S, Kachanov V, Kalinin A, Konstantinov D, Krychkine V, Petrov V, Ryutin R, Sobol A, Tourtchanovitch L, Troshin S, Tyurin N, Uzunian A, Volkov A, Adzic P, Ekmedzic M, Milosevic J, Rekovic V, Maestre JA, Calvo E, Cerrada M, Llatas MC, Colino N, De La Cruz B, Peris AD, Vazquez DD, Del Valle AE, Bedoya CF, Ramos JPF, Flix J, Fouz MC, Garcia-Abia P, Lopez OG, Lopez SG, Hernandez JM, Josa MI, De Martino EN, Yzquierdo APC, Pelayo JP, Olmeda AQ, Redondo I, Romero L, Soares MS, Albajar C, de Troconiz JF, Missiroli M, Moran D, Brun H, Cuevas J, Menendez JF, Folgueras S, Caballero IG, Cortezon EP, Garcia JMV, Cabrillo IJ, Calderon A, De Saa JRC, Manzano PD, Campderros JD, Fernandez M, Garcia-Ferrero J, Gomez G, Virto AL, Marco J, Marco R, Rivero CM, Matorras F, Sanchez FJM, Gomez JP, Rodrigo T, Rodriguez-Marrero AY, Ruiz-Jimeno A, Scodellaro L, Vila I, Cortabitarte RV, Abbaneo D, Auffray E, Auzinger G, Bachtis M, Baillon P, Ball AH, Barney D, Benaglia A, Bendavid J, Benhabib L, Benitez JF, Berruti GM, Bloch P, Bocci A, Bonato A, Botta C, Breuker H, Camporesi T, Cerminara G, Colafranceschi S, D'Alfonso M, d'Enterria D, Dabrowski A, Daponte V, David A, De Gruttola M, De Guio F, De Roeck A, De Visscher S, Di Marco E, Dobson M, Dordevic M, Dorney B, du Pree T, Dunser M, Dupont N, Elliott-Peisert A, Franzoni G, Funk W, Gigi D, Gill K, Giordano D, Girone M, Glege F, Guida R, Gundacker S, Guthoff M, Hammer J, Harris P, Hegeman J, Innocente V, Janot P, Kirschenmann H, Kortelainen MJ, Kousouris K, Krajczar K, Lecoq P, Lourenco C, Lucchini MT, Magini N, Malgeri L, Mannelli M, Martelli A, Masetti L, Meijers F, Mersi S, Meschi E, Moortgat F, Morovic S, Mulders M, Nemallapudi MV, Neugebauer H, Orfanelli S, Orsini L, Pape L, Perez E, Peruzzi M, Petrilli A, Petrucciani G, Pfeiffer A, Piparo D, Racz A, Rolandi G, Rovere M, Ruan M, Sakulin H, Schafer C, Schwick C, Sharma A, Silva P, Simon M, Sphicas P, Spiga D, Steggemann J, Stieger B, Stoye M, Takahashi Y, Treille D, Triossi A, Tsirou A, Veres GI, Wardle N, Wohri HK, Zagozdzinska A, Zeuner WD, Bertl W, Deiters K, Erdmann W, Horisberger R, Ingram Q, Kaestli HC, Kotlinski D, Langenegger U, Renker D, Rohe T, Bachmair F, Bani L, Bianchini L, Buchmann MA, Casal B, Dissertori G, Dittmar M, Donega M, Eller P, Grab C, Heidegger C, Hits D, Hoss J, Kasieczka G, Lustermann W, Mangano B, Marionneau M, del Arbol PMR, Masciovecchio M, Meister D, Micheli F, Musella P, Nessi-Tedaldi F, Pandolfi F, Pata J, Pauss F, Perrozzi L, Quittnat M, Rossini M, Starodumov A, Takahashi M, Tavolaro VR, Theofilatos K, Wallny R, Aarrestad TK, Amsler C, Caminada L, Canelli MF, Chiochia V, De Cosa A, Galloni C, Hinzmann A, Hreus T, Kilminster B, Lange C, Ngadiuba J, Pinna D, Robmann P, Ronga FJ, Salerno D, Yang Y, Cardaci M, Chen KH, Doan TH, Jain S, Khurana R, Konyushikhin M, Kuo CM, Lin W, Lu YJ, Yu SS, Kumar A, Bartek R, Chang P, Chang YH, Chang YW, Chao Y, Chen KF, Chen PH, Dietz C, Fiori F, Grundler U, Hou WS, Hsiung Y, Liu YF, Lu RS, Moya MM, Petrakou E, Tsai JF, Tzeng YM, Asavapibhop B, Kovitanggoon K, Singh G, Srimanobhas N, Suwonjandee N, Adiguzel A, Cerci S, Demiroglu ZS, Dozen C, Dumanoglu I, Girgis S, Gok-Bulut G, Guler Y, Gurpinar E, Hos I, Kangal EE, Topaksu AK, Onengut G, Ozdemir K, Ozturk S, Cerci DS, Topakli H, Vergili M, Zorbilmez C, Akin IV, Bilin B, Bilmis S, Isildak B, Karapinar G, Yalvac M, Zeyrek M, Albayrak EA, Gulmez E, Kaya M, Kaya O, Yetkin T, Cankocak K, Sen S, Vardarli FI, Grynyov B, Levchuk L, Sorokin P, Aggleton R, Ball F, Beck L, Brooke JJ, Clement E, Cussans D, Flacher H, Gold-stein J, Grimes M, Heath GP, Heath HF, Jacob J, Kreczko L, Lucas C, Meng Z, Newbold DM, Paramesvaran S, Poll A, Sakuma T, El Nasr-storey SS, Senkin S, Smith D, Smith VJ, Bell KW, Belyaev A, Brew C, Brown RM, Cieri D, Cockerill DJA, Coughlan JA, Harder K, Harper S, Olaiya E, Petyt D, Shepherd-Themistocleous CH, Thea A, Thomas L, Tomalin IR, Williams T, Womersley WJ, Worm SD, Baber M, Bainbridge R, Buchmuller O, Bundock A, Burton D, Casasso S, Citron M, Colling D, Corpe L, Cripps N, Dauncey P, Davies G, De Wit A, Della Negra M, Dunne P, Elwood A, Ferguson W, Fulcher J, Futyan D, Hall G, Iles G, Kenzie M, Lane R, Lucas R, Lyons L, Magnan AM, Malik S, Nash J, Nikitenko A, Pela J, Pesaresi M, Petridis K, Raymond DM, Richards A, Rose A, Seez C, Tapper A, Uchida K, Acosta MV, Virdee T, Zenz SC, Cole JE, Hobson PR, Khan A, Kyberd P, Leggat D, Leslie D, Reid ID, Symonds P, Teodorescu L, Turner M, Borzou A, Call K, Dittmann J, Hatakeyama K, Kasmi A, Liu H, Pastika N, Charaf O, Cooper SI, Henderson C, Rumerio P, Avetisyan A, Bose T, Fantasia C, Gastler D, Lawson P, Rankin D, Richardson C, Rohlf J, John JS, Sulak L, Zou D, Alimena J, Berry E, Bhattacharya S, Cutts D, Dhingra N, Ferapontov A, Garabe-Dian A, Hakala J, Heintz U, Laird E, Landsberg G, Mao Z, Narain M, Piperov S, Sagir S, Sinthuprasith T, Syarif R, Breedon R, Breto G, Sanchez MCD, Chauhan S, Chertok M, Con-way J, Conway R, Cox PT, Erbacher R, Gardner M, Ko W, Lander R, Mulhearn M, Pellett D, Pilot J, Ricci-Tam F, Shalhout S, Smith J, Squires M, Stolp D, Tripathi M, Wilbur S, Yohay R, Cousins R, Everaerts P, Farrell C, Hauser J, Ignatenko M, Saltzberg D, Takasugi E, Valuev V, Weber M, Burt K, Clare R, Ellison J, Gary JW, Hanson G, Heilman J, Paneva MI, Jandir P, Kennedy E, Lacroix F, Long OR, Luthra A, Malberti M, Negrete MO, Shrinivas A, Wei H, Wimpenny S, Branson JG, Cerati GB, Cittolin S, D'Agnolo RT, Holzner A, Kelley R, Klein D, Letts J, Macneill I, Olivito D, Padhi S, Pieri M, Sani M, Sharma V, Simon S, Tadel M, Vartak A, Wasserbaech S, Welke C, Wurthwein F, Yagil A, Della Porta GZ, Barge D, Bradmiller-Feld J, Campagnari C, Dishaw A, Dutta V, Flowers K, Sevilla MF, Geffert P, George C, Golf F, Gouskos L, Gran J, Incandela J, Justus C, Mccoll N, Mullin SD, Richman J, Stuart D, Suarez I, To W, West C, Yoo J, Anderson D, Apresyan A, Bornheim A, Bunn J, Chen Y, Duarte J, Mott A, Newman HB, Pena C, Pierini M, Spiropulu M, Vlimant JR, Xie S, Zhu RY, Azzolini V, Calamba A, Carlson B, Ferguson T, Paulini M, Russ J, Sun M, Vogel H, Vorobiev I, Cumalat JP, Ford WT, Gaz A, Jensen F, Johnson A, Krohn M, Mulholland T, Nauenberg U, Stenson K, Wagner SR, Alexander J, Chatterjee A, Chaves J, Chu J, Dittmer S, Eggert N, Mirman N, Kaufman GN, Patterson JR, Rinkevicius A, Ryd A, Skinnari L, Soffi L, Sun W, Tan SM, Teo WD, Thom J, Thompson J, Tucker J, Weng Y, Wittich P, Abdullin S, Albrow M, Anderson J, Apollinari G, Bauerdick LAT, Beretvas A, Berryhill J, Bhat PC, Bolla G, Burkett K, Butler JN, Cheung HWK, Chle-bana F, Cihangir S, Elvira VD, Fisk I, Freeman J, Gottschalk E, Gray L, Green D, Grunendahl S, Gutsche O, Hanlon J, Hare D, Harris RM, Hirschauer J, Hooberman B, Hu Z, Jindariani S, Johnson M, Joshi U, Jung AW, Klima B, Kreis B, Kwan S, Lammel S, Linacre J, Lincoln D, Lipton R, Liu T, De Sa RL, Lykken J, Maeshima K, Marraffino JM, Outschoorn VIM, Maruyama S, Mason D, McBride P, Merkel P, Mishra K, Mrenna S, Nahn S, Newman-Holmes C, O'Dell V, Pedro K, Prokofyev O, Rakness G, Sexton-Kennedy E, Soha A, Spalding WJ, Spiegel L, Taylor L, Tkaczyk S, Tran NV, Uplegger L, Vaandering EW, Vernieri C, Verzocchi M, Vidal R, Weber HA, Whitbeck A, Yang F, Acosta D, Avery P, Bortignon P, Bourilkov D, Carnes A, Carver M, Curry D, Das S, Di Giovanni GP, Field RD, Furic IK, Hugon J, Konigsberg J, Korytov A, Low JF, Ma P, Matchev K, Mei H, Milenovic P, Mitselmakher G, Rank D, Rossin R, Shchutska L, Snowball M, Sperka D, Wang J, Wang S, Yelton J, Hewamanage S, Linn S, Markowitz P, Martinez G, Rodriguez JL, Ackert A, Adams JR, Adams T, Askew A, Bochenek J, Diamond B, Haas J, Hagopian S, Hagopian V, Johnson KF, Khatiwada A, Prosper H, Veeraraghavan V, Weinberg M, Baarmand MM, Bhopatkar V, Hohlmann M, Kalakhety H, Noonan D, Roy T, Yumiceva F, Adams MR, Apanasevich L, Berry D, Betts RR, Bucinskaite I, Cavanaugh R, Evdokimov O, Gauthier L, Gerber CE, Hofman DJ, Kurt P, O'Brien C, Gonzalez IDS, Silkworth C, Turner P, Varelas N, Wu Z, Zakaria M, Bilki B, Clarida W, Dilsiz K, Durgut S, Gandrajula RP, Haytmyradov M, Khris-tenko V, Merlo JP, Mermerkaya H, Mestvirishvili A, Moeller A, Nachtman J, Ogul H, Onel Y, Ozok F, Penzo A, Snyder C, Tan P, Tiras E, Wetzel J, Yi K, Anderson I, Barnett BA, Blumenfeld B, Fehling D, Feng L, Gritsan AV, Maksi-Movic P, Martin C, Osherson M, Swartz M, Xiao M, Xin Y, You C, Baringer P, Bean A, Benelli G, Bruner C, Kenny RP, Majumder D, Malek M, Murray M, Sanders S, Stringer R, Wang Q, Wood JS, Ivanov A, Kaadze K, Khalil S, Makouski M, Maravin Y, Mohammadi A, Saini LK, Skhirtladze N, Toda S, Lange D, Rebassoo F, Wright D, Anelli C, Baden A, Baron O, Belloni A, Calvert B, Eno SC, Ferraioli C, Gomez JA, Hadley NJ, Jabeen S, Kellogg RG, Kolberg T, Kunkle J, Lu Y, Mignerey AC, Shin YH, Skuja A, Tonjes MB, Tonwar SC, Apyan A, Barbieri R, Baty A, Bierwagen K, Brandt S, Busza W, Cali IA, Demiragli Z, Di Matteo L, Ceballos GG, Goncharov M, Gulhan D, Iiyama Y, Innocenti GM, Klute M, Kovalskyi D, Lai YS, Lee YJ, Levin A, Luckey PD, Marini AC, Mcginn C, Mironov C, Niu X, Paus C, Ralph D, Roland C, Roland G, Salfeld-Nebgen J, Stephans GSF, Sumorok K, Varma M, Velicanu D, Veverka J, Wang J, Wang TW, Wyslouch B, Yang M, Zhukova V, Dahmes B, Finkel A, Gude A, Hansen P, Kalafut S, Kao SC, Klapoetke K, Kubota Y, Lesko Z, Mans J, Nourbakhsh S, Ruckstuhl N, Rusack R, Tambe N, Turkewitz J, Acosta JG, Oliveros S, Avdeeva E, Bloom K, Bose S, Claes DR, Dominguez A, Fangmeier C, Suarez RG, Kamalieddin R, Keller J, Knowlton D, Kravchenko I, Lazo-Flores J, Meier F, Monroy J, Ratnikov F, Siado JE, Snow GR, Alyari M, Dolen J, George J, Godshalk A, Harrington C, Iashvili I, Kaisen J, Kharchilava A, Kumar A, Rappoccio S, Alverson G, Barberis E, Baumgartel D, Chasco M, Hortiangtham A, Massironi A, Morse DM, Nash D, Orimoto T, De Lima RT, Trocino D, Wang RJ, Wood D, Zhang J, Hahn KA, Kubik A, Mucia N, Odell N, Pollack B, Pozdnyakov A, Schmitt M, Stoynev S, Sung K, Trovato M, Velasco M, Brinkerhoff A, Dev N, Hildreth M, Jessop C, Karmgard DJ, Kellams N, Lannon K, Lynch S, Marinelli N, Meng F, Mueller C, Musienko Y, Pearson T, Planer M, Reinsvold A, Ruchti R, Smith G, Taroni S, Valls N, Wayne M, Wolf M, Woodard A, Antonelli L, Brinson J, Bylsma B, Durkin LS, Flowers S, Hart A, Hill C, Hughes R, Ji W, Kotov K, Ling TY, Liu B, Luo W, Puigh D, Rodenburg M, Winer BL, Wulsin HW, Driga O, Elmer P, Hardenbrook J, Hebda P, Koay SA, Lujan P, Marlow D, Medvedeva T, Mooney M, Olsen J, Palmer C, Piroue P, Quan X, Saka H, Stickland D, Tully C, Werner JS, Zuranski A, Malik S, Barnes VE, Benedetti D, Bortoletto D, Gutay L, Jha MK, Jones M, Jung K, Kress M, Miller DH, Neumeister N, Radburn-Smith BC, Shi X, Shipsey I, Silvers D, Sun J, Svyatkovskiy A, Wang F, Xie W, Xu L, Parashar N, Stupak J, Adair A, Akgun B, Chen Z, Ecklund KM, Geurts FJM, Guilbaud M, Li W, Michlin B, Northup M, Padley BP, Redjimi R, Roberts J, Rorie J, Tu Z, Zabel J, Betchart B, Bodek A, de Barbaro P, Demina R, Eshaq Y, Ferbel T, Galanti M, Garcia-Bellido A, Goldenzweig P, Han J, Harel A, Hindrichs O, Khukhunaishvili A, Petrillo G, Verzetti M, Demortier L, Arora S, Barker A, Chou JP, Contreras-Campana C, Contreras-Campana E, Dug-Gan D, Ferencek D, Gershtein Y, Gray R, Halkiadakis E, Hidas D, Hughes E, Kaplan S, Elayavalli RK, Lath A, Nash K, Panwalkar S, Park M, Salur S, Schnet-zer S, Sheffield D, Somalwar S, Stone R, Thomas S, Thomassen P, Walker M, Foerster M, Riley G, Rose K, Spanier S, York A, Bouhali O, Hernandez AC, Dalchenko M, De Mattia M, Delgado A, Dildick S, Eusebi R, Flanagan W, Gilmore J, Kamon T, Krutelyov V, Montalvo R, Mueller R, Osipenkov I, Pakhotin Y, Patel R, Ff AP, Roe J, Rose A, Safonov A, Tatarinov A, Ulmer KA, Akchurin N, Cowden C, Damgov J, Dragoiu C, Dudero PR, Faulkner J, Kunori S, Lamichhane K, Lee SW, Libeiro T, Undleeb S, Volobouev I, Appelt E, Delannoy AG, Greene S, Gurrola A, Janjam R, Johns W, Maguire C, Mao Y, Melo A, Ni H, Sheldon P, Snook B, Tuo S, Velkovska J, Xu Q, Arenton MW, Boutle S, Cox B, Francis B, Goodell J, Hirosky R, Ledovskoy A, Li H, Lin C, Neu C, Wolfe E, Wood J, Xia F, Clarke C, Harr R, Karchin PE, Don CKK, Lamichhane P, Sturdy J, Belknap DA, Carlsmith D, Cepeda M, Christian A, Dasu S, Dodd L, Duric S, Friis E, Gomber B, Grothe M, Hall-Wilton R, Herndon M, Herve A, Klabbers P, Lanaro A, Levine A, Long K, Loveless R, Mohapatra A, Ojalvo I, Perry T, Pierro GA, Polese G, Ross I, Ruggles T, Sarangi T, Savin A, Sharma A, Smith N, Smith WH, Taylor D, Woods N
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Azimuthal decorrelation of jets widely separated in rapidity in pp collisions at root s=7 TeV
JOURNAL OF HIGH ENERGY PHYSICS 2016 AUG 24; ?(8):? Article 139
The decorrelation in the azimuthal angle between the most forward and the most backward jets (Mueller-Navelet jets) is measured in data collected in pp collisions with the CMS detector at the LHC at root s = 7 TeV. The measurement is presented in the form of distributions of azimuthal-angle differences, Delta phi, between the Mueller-Navelet jets, the average cosines of (pi - Delta phi), 2(pi - Delta phi), and 3(pi - Delta phi), and ratios of these cosines. The jets are required to have transverse momenta, p(T), in excess of 35 GeV and rapidities, |y|, of less than 4.7. The results are presented as a function of the rapidity separation, Delta y, between the Mueller-Navelet jets, reaching Delta y up to 9.4 for the first time. The results are compared to predictions of various Monte Carlo event generators and to analytical predictions based on the DGLAP and BFKL parton evolution schemes.
Ha JY, Chou HT, Ungar D, Yip CK, Walz T, Hughson FM
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Molecular architecture of the complete COG tethering complex
NATURE STRUCTURAL & MOLECULAR BIOLOGY 2016 AUG; 23(8):758-760
The conserved oligomeric Golgi (COG) complex orchestrates vesicular trafficking to and within the Golgi apparatus. Here, we use negative-stain electron microscopy to elucidate the architecture of the hetero-octameric COG complex from Saccharomyces cerevisiae. Intact COG has an intricate shape, with four (or possibly five) flexible legs, that differs strikingly from that of the exocyst complex and appears to be well suited for vesicle capture and fusion.
Kessl JJ, Kutluay SB, Townsend D, Rebensburg S, Slaughter A, Larue RC, Shkriabai N, Bakouche N, Fuchs JR, Bieniasz PD, Kvaratskhelia M
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HIV-1 Integrase Binds the Viral RNA Genome and Is Essential during Virion Morphogenesis
CELL 2016 AUG 25; 166(5):1257-1268
While an essential role of HIV-1 integrase (IN) for integration of viral cDNA into human chromosome is established, studies with IN mutants and allosteric IN inhibitors (ALLINIs) have suggested that IN can also influence viral particle maturation. However, it has remained enigmatic as to how IN contributes to virion morphogenesis. Here, we demonstrate that IN directly binds the viral RNA genome in virions. These interactions have specificity, as IN exhibits distinct preference for select viral RNA structural elements. We show that IN substitutions that selectively impair its binding to viral RNA result in eccentric, non-infectious virions without affecting nucleocapsid-RNA interactions. Likewise, ALLINIs impair IN binding to viral RNA in virions of wildtype, but not escape mutant, virus. These results reveal an unexpected biological role of IN binding to the viral RNA genome during virion morphogenesis and elucidate the mode of action of ALLINIs.
Kung A, Chen YC, Schimpl M, Ni F, Zhu JF, Turner M, Molina H, Overman R, Zhang C
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Development of Specific, Irreversible Inhibitors for a Receptor Tyrosine Kinase EphB3
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY 2016 AUG 24; 138(33):10554-10560
Erythropoietin-producing human hepatocellular carcinoma (Eph) receptor tyrosine kinases (RTKs) regulate a variety of dynamic cellular events, including cell protrusion, migration, proliferation, and cell fate determination. Small-molecule inhibitors of Eph kinases are valuable tools for dissecting the physiological and pathological roles of Eph. However, there is a lack of small-molecule inhibitors that are selective for individual Eph isoforms due to the high homology within the family. Herein, we report the development of the first potent and specific inhibitors of a single Eph isoform, EphB3. Through structural bioinformatic analysis, we identified a cysteine in the hinge region of the EphB3 kinase domain, a feature that is not shared with any other human kinases. We synthesized and characterized a series of electrophilic quinazolines to target this unique, reactive feature in EphB3. Some of the electrophilic quinazolines selectively and potently inhibited EphB3 both in vitro and in cells. Cocrystal structures of EphB3 in complex with two quinazolines confirmed the covalent linkage between the protein and the inhibitors. A "clickable" version of an optimized inhibitor was created and employed to verify specific target engagement in the whole proteome and to probe the extent and kinetics of target engagement of existing EphB3 inhibitors. Furthermore, we demonstrate that the autophosphorylation of EphB3 within the juxtamembrane region occurs in trans using a specific inhibitor. These exquisitely specific inhibitors will facilitate the dissection of EphB3's role in various biological processes and disease contribution.
Marsch LA, Moore SK, Borodovsky JT, Solhkhah R, Badger GJ, Semino S, Jarrett K, Condon KD, Rossettie K, Vincent P, Hajizadeh N, Ducat E
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A randomized controlled trial of buprenorphine taper duration among opioid-dependent adolescents and young adults
ADDICTION 2016 AUG; 111(8):1406-1415
Background and AimsFew randomized controlled trials have evaluated buprenorphine treatment interventions for opioid-dependent youth. Consequently, optimal administration strategies for this cohort are unclear. Our aim was to evaluate the relative efficacy of two different buprenorphine taper lengths in promoting abstinence from illicit opioids and treatment retention among opioid-dependent youth. DesignA double-blind, placebo controlled, multicenter randomized controlled trial. SettingTwo hospital-based research clinics (Manhattan and Brooklyn) in New York City, USA from 2005 to 2010. ParticipantsVolunteer sample of 53 primarily Caucasian participants between the ages of 16 and 24 (n=11 under age 18) who met DSM-IV opioid dependence criteria. InterventionParticipants were assigned randomly to either a 28-day buprenorphine taper (n=28) or 56-day buprenorphine taper (n=25) via a parallel-groups design during a 63-day period. Both groups received behavioral counseling and opioid abstinence incentives. Both taper conditions had a minimum of 1week of placebo dosing at the end of the taper. MeasurementsThe primary outcome was opioid abstinence measured as a percentage of scheduled urine toxicology tests documented to be negative for opioids. The secondary outcome was treatment retention, measured as number of days attended scheduled visits. FindingsIntent-to-treat analyses revealed that participants who received a 56-day buprenorphine taper had a significantly higher percentage of opioid-negative scheduled urine tests compared with participants who received a 28-day buprenorphine taper [35 versus 17%, P=0.039; Cohen's d=0.57, 95% confidence interval (CI)=0.02, 1.13]. Participants who received a 56-day buprenorphine taper were retained in treatment significantly longer than participants who received a 28-day buprenorphine taper (37.5 versus 26.4days, P=0.027; Cohen's d=0.63, 95% CI=0.06, 1.19). Daily attendance requirement was associated with decreased abstinence and shorter retention compared with a two to three times weekly attendance requirement, independent of taper duration. Follow-up data were insufficient to report. ConclusionLonger (56-day) buprenorphine taper produces better opioid abstinence and retention outcomes than shorter (28-day) buprenorphine taper for opioid-dependent youth.
Eckwahl MJ, Arnion H, Kharytonchyk S, Zang T, Bieniasz PD, Telesnitsky A, Wolin SL
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Analysis of the human immunodeficiency virus-1 RNA packageome
RNA 2016 AUG; 22(8):1228-1238
All retroviruses package cellular RNAs into virions. Studies of murine leukemia virus (MLV) revealed that the major host cell RNAs encapsidated by this simple retrovirus were LTR retrotransposons and noncoding RNAs (ncRNAs). Several classes of ncRNAs appeared to be packaged by MLV shortly after synthesis, as precursors to tRNAs, small nuclear RNAs, and small nucleolar RNAs were all enriched in virions. To determine the extent to which the human immunodeficiency virus (HIV-1) packages similar RNAs, we used high-throughput sequencing to characterize the RNAs within infectious HIV-1 virions produced in CEM-SS T lymphoblastoid cells. We report that the most abundant cellular RNAs in HIV-1 virions are 7SL RNA and transcripts from numerous divergent and truncated members of the long interspersed element (LINE) and short interspersed element (SINE) families of retrotransposons. We also detected precursors to several tRNAs and small nuclear RNAs as well as transcripts derived from the ribosomal DNA (rDNA) intergenic spacers. We show that packaging of a pre-tRNA requires the nuclear export receptor Exportin 5, indicating that HIV-1 recruits at least some newly made ncRNAs in the cytoplasm. Together, our work identifies the set of RNAs packaged by HIV-1 and reveals that early steps in HIV-1 assembly intersect with host cell ncRNA biogenesis pathways.
Salvi JD, Maoileidigh DO, Hudspeth AJ
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Identification of Bifurcations from Observations of Noisy Biological Oscillators
BIOPHYSICAL JOURNAL 2016 AUG 23; 111(4):798-812
Hair bundles are biological oscillators that actively transduce mechanical stimuli into electrical signals in the auditory, vestibular, and lateral-line systems of vertebrates. A bundle's function can be explained in part by its operation near a particular type of bifurcation, a qualitative change in behavior. By operating near different varieties of bifurcation, the bundle responds best to disparate classes of stimuli. We show how to determine the identity of and proximity to distinct bifurcations despite the presence of substantial environmental noise. Using an improved mechanical-load clamp to coerce a hair bundle to traverse different bifurcations, we find that a bundle operates within at least two functional regimes. When coupled to a high-stiffness load, a bundle functions near a supercritical Hopf bifurcation, in which case it responds best to sinusoidal stimuli such as those detected by an auditory organ. When the load stiffness is low, a bundle instead resides close to a subcritical Hopf bifurcation and achieves a graded frequency response-a continuous change in the rate, but not the amplitude, of spiking in response to changes in the offset force-a behavior that is useful in a vestibular organ. The mechanical load in vivo might therefore control a hair bundle's responsiveness for effective operation in a particular receptor organ. Our results provide direct experimental evidence for the existence of distinct bifurcations associated with a noisy biological oscillator, and demonstrate a general strategy for bifurcation analysis based on observations of any noisy system.
Van Kempen TA, Narayan A, Waters EM, Marques-Lopes J, Iadecola C, Glass MJ, Pickel VM, Milner TA
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Alterations in the Subcellular Distribution of NADPH Oxidase p47(phox) in Hypothalamic Paraventricular Neurons Following Slow-Pressor Angiotensin II Hypertension in Female Mice With Accelerated Ovarian Failure
JOURNAL OF COMPARATIVE NEUROLOGY 2016 AUG 1; 524(11):2251-2265
At younger ages, women have a lower risk for hypertension than men, but this sexual dimorphism declines with the onset of menopause. These differences are paralleled in rodents following "slow-pressor" angiotensin II (AngII) administration: young male and aged female mice, but not young females, develop hypertension. There is also an established sexual dimorphism both in the cardiovascular response to the neurohypophyseal hormone arginine vasopressin (AVP) and in the expression of oxidative stress. We examined the relationship between AngII-mediated hypertension and the cellular distribution of the superoxide generating NADPH oxidase (NOX) in AVP-expressing hypothalamic paraventricular nucleus (PVN) neurons in "menopausal" female mice. Dual-labeling immunoelectron microscopy was used to determine whether the subcellular distribution of the organizer/adapter NOX p47(phox) subunit is altered in PVN dendrites following AngII administered (14 days) during the "postmenopausal" stage of accelerated ovarian failure (AOF) in young female mice treated with 4-vinylcyclohexene diepoxide. Slow-pressor AngII elevated blood pressure in AOF females and induced a significant increase in near plasmalemmal p47(phox) and a decrease in cytoplasmic p47(phox) in PVN AVP dendrites. These changes are the opposite of those observed in AngII-induced hypertensive male mice (Coleman et al. [2013] J. Neurosci. 33:4308-4316) and may be ascribed in part to baseline differences between young females and males in the near plasmalemmal p47(phox) on AVP dendrites seen in the present study. These findings highlight fundamental differences in the neural substrates of oxidative stress in the PVN associated with AngII hypertension in postmenopausal females compared with males. (C) 2015 Wiley Periodicals, Inc.