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Lewis DR, Kholodovych V, Tomasini MD, Abdelhamid D, Petersen LK, Welsh WJ, Uhrich KE, Moghe PV
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In silico design of anti-atherogenic biomaterials
BIOMATERIALS 2013 OCT; 34(32):7950-7959
Atherogenesis, the uncontrolled deposition of modified lipoproteins in inflamed arteries, serves as a focal trigger of cardiovascular disease (CVD). Polymeric biomaterials have been envisioned to counteract atherogenesis based on their ability to repress scavenger mediated uptake of oxidized lipoprotein (oxLDL) in macrophages. Following the conceptualization in our laboratories of a new library of amphiphilic macromolecules (AMs), assembled from sugar backbones, aliphatic chains and poly(-ethylene glycol) tails, a more rational approach is necessary to parse the diverse features such as charge, hydrophobicity, sugar composition and stereochemistry. In this study, we advance a computational biomaterials design approach to screen and elucidate anti-atherogenic biomaterials with high efficacy. AMs were quantified in terms of not only 1D (molecular formula) and 2D (molecular connectivity) descriptors, but also new 3D (molecular geometry) descriptors of AMs modeled by coarse-grained molecular dynamics (MD) followed by all-atom MD simulations. Quantitative structure-activity relationship (QSAR) models for anti-atherogenic activity were then constructed by screening a total of 1164 descriptors against the corresponding, experimentally measured potency of AM inhibition of oxLDL uptake in human monocyte-derived macrophages. Five key descriptors were identified to provide a strong linear correlation between the predicted and observed anti-atherogenic activity values, and were then used to correctly forecast the efficacy of three newly designed AMs. Thus, a new ligand-based drug design framework was successfully adapted to computationally screen and design biomaterials with cardiovascular therapeutic properties. (C) 2013 Elsevier Ltd. All rights reserved.
Rodriguez JM, Wolfrum S, Robblee M, Chen KY, Gilbert ZN, Choi JH, Teupser D, Breslow JL
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Altered Expression of Raet1e, a Major Histocompatibility Complex Class 1-Like Molecule, Underlies the Atherosclerosis Modifier Locus Ath11 10b
CIRCULATION RESEARCH 2013 OCT 12; 113(9):1054-1064
Rationale: Quantitative trait locus mapping of an intercross between C57.Apoe(-/-) and FVB.Apoe(-/-) mice revealed an atherosclerosis locus controlling aortic root lesion area on proximal chromosome 10, Ath11. In a previous work, subcongenic analysis showed Ath11 to be complex with proximal (10a) and distal (10b) regions. Objective: To identify the causative genetic variation underlying the atherosclerosis modifier locus Ath11 10b. Methods and Results: We now report subcongenic J, which narrows the 10b region to 5 genes, Myb, Hbs1L, Aldh8a1, Sgk1, and Raet1e. Sequence analysis of these genes revealed no amino acid coding differences between the parental strains. However, comparing aortic expression of these genes between F1.Apoe(-/-) Chr10SubJ((B/F)) and F1.Apoe(-/-) Chr10SubJ((F/F)) uncovered a consistent difference only for Raet1e, with decreased, virtually background, expression associated with increased atherosclerosis in the latter. The key role of Raet1e was confirmed by showing that transgene-induced aortic overexpression of Raet1e in F1.Apoe(-/-) Chr10SubJ((F/F)) mice decreased atherosclerosis. Promoter reporter constructs comparing C57 and FVB sequences identified an FVB mutation in the core of the major aortic transcription start site abrogating activity. Conclusions: This nonbiased approach has revealed Raet1e, a major histocompatibility complex class 1-like molecule expressed in lesional aortic endothelial cells and macrophage-rich regions, as a novel atherosclerosis gene and represents one of the few successes of the quantitative trait locus strategy in complex diseases.
Poon K, Mandava S, Chen K, Barson JR, Buschlen S, Leibowitz SF
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Prenatal Exposure to Dietary Fat Induces Changes in the Transcriptional Factors, TEF and YAP, Which May Stimulate Differentiation of Peptide Neurons in Rat Hypothalamus
PLOS ONE 2013 OCT 11; 8(10):? Article e77668
Gestational exposure to a high-fat diet (HFD) stimulates the differentiation of orexigenic peptide-expressing neurons in the hypothalamus of offspring. To examine possible mechanisms that mediate this phenomenon, this study investigated the transcriptional factor, transcription enhancer factor-1 (TEF), and co-activator, Yes-associated protein (YAP), which when inactivated stimulate neuronal differentiation. In rat embryos and postnatal offspring prenatally exposed to a HFD compared to chow, changes in hypothalamic TEF and YAP and their relationship to the orexigenic peptide, enkephalin (ENK), were measured. The HFD offspring at postnatal day 15 (P15) exhibited in the hypothalamic paraventricular nucleus a significant reduction in YAP mRNA and protein, and increased levels of inactive and total TEF protein, with no change in mRNA. Similarly, HFD-exposed embryos at embryonic day 19 (E19) showed in whole hypothalamus significantly decreased levels of YAP mRNA and protein and TEF mRNA, and increased levels of inactive TEF protein, suggesting that HFD inactivates TEF and YAP. This was accompanied by increased density and fluorescence intensity of ENK neurons. A close relationship between TEF and ENK was suggested by the finding that TEF co-localizes with this peptide in hypothalamic neurons and HFD reduced the density of TEF/ENK co-labeled neurons, even while the number and fluorescence intensity of single-labeled TEF neurons were increased. Increased YAP inactivity by HFD was further evidenced by a decrease in number and fluorescence intensity of YAP-containing neurons, although the density of YAP/ENK co-labeled neurons was unaltered. Genetic knockdown of TEF or YAP stimulated ENK expression in hypothalamic neurons, supporting a close relationship between these transcription factors and neuropeptide. These findings suggest that prenatal HFD exposure inactivates both hypothalamic TEF and YAP, by either decreasing their levels or increasing their inactive form, and that this contributes to the stimulatory effect of HFD on ENK expression and possibly the differentiation of ENK-expressing neurons.
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Marinov A, Mccartin J, Rios AAO, Ryckbosch D, Sigamani M, Strobbe N, Thyssen F, Tytgat M, Walsh S, Yazgan E, Zaganidis N, Basegmez S, Bruno G, Castello R, Ceard L, Delaere C, du Pree T, Favart D, Forthomme L, Giammanco A, Hollar J, Lemaitre V, Liao J, Militaru O, Nuttens C, Pagano D, Pin A, Piotrzkowski K, Popov A, Selvaggi M, Garcia JMV, Beliy N, Caebergs T, Daubie E, Hammad GH, Alves GA, Martins MC, Martins T, Pol ME, Souza MHG, Alda WL, Carvalho W, Chinellato J, Custodio A, Da Costa EM, Damiao DD, Martins CD, De Souza SF, Malbouisson H, Malek M, Figueiredo DM, Mundim L, Nogima H, Da Silva WLP, Santoro A, Jorge LS, Sznajder A, Manganote EJT, Pereira AV, Anjos TS, Bernardes CA, Dias FA, Tomei TRFP, Gregores EM, Lagana C, Marinho F, Mercadante PC, Novaes SF, Padula SS, Genchev V, Iaydjiev P, Piperov S, Rodozov M, Stoykova S, Sultanov G, Tcholakov V, Trayanov R, Vutova M, Dimitrov A, Hadjiiska R, Kozhuharov V, Litov L, Pavlov B, Petkov P, Bian JG, Chen GM, Chen HS, Jiang CH, Liang D, Liang S, Meng X, Tao J, Wang J, Wang X, Wang Z, Xiao H, Xu M, Asawatangtrakuldee C, Ban Y, Guo Y, Li Q, Li W, Liu S, Mao Y, Qian SJ, Wang D, Zhang L, Zou W, Avila C, Montoya CAC, Gomez JP, Moreno BG, Sanabria JC, Godinovic N, Lelas D, Plestina R, Polic D, Puljak I, Antunovic Z, Kovac M, Brigljevic V, Dune S, Kadija K, Luetic J, Mekterovic D, Morovic S, Tikvica L, Attikis A, Mavromanolakis G, Mousa J, Nicolaou C, Ptochos F, Razis PA, Finger M, Finger M, Assran Y, Kamel AE, Mahmoud MA, Mahrous A, Radi A, Kadastik M, Muntel M, Murumaa M, Raidal M, Rebane L, Tiko A, Eerola P, Fedi G, Voutilainen M, Harkonen J, Karimaki V, Kinnunen R, Kortelainen MJ, Lampen T, Lassila-Perini K, Lehti S, Linden T, Luukka P, Maenpaa T, Peltola T, Tuominen E, Tuominiemi J, Tuovinen E, Wendland L, Korpela A, Tuuva T, Besancon M, Choudhury S, Couderc F, Dejardin M, Denegri D, Fabbro B, Faure JL, Ferri F, Ganjour S, Givernaud A, Gras P, de Monchenault GH, Jarry P, Locci E, Malcles J, Millischer L, Nayak A, Rander 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Petrukhin A, Pitzl D, Raspereza A, Cipriano PMR, Riedl C, Ron E, Rosin M, Salfeld-Nebgen J, Schmidt R, Schoerner-Sadenius T, Sen N, Stein M, Walsh R, Wissing C, Blobel V, Enderle H, Erfle J, Gebbert U, Gorner M, Gosselink M, Haller J, Heine K, Hoing RS, Kaschube K, Kaussen G, Kirschenmann H, Klanner R, Lange J, Peiffer T, Pietsch N, Rathjens D, Sander C, Schettler H, Schleper P, Schlieckau E, Schmidt A, Schroder M, Schum T, Seidel M, Sibille J, Sola V, Stadie H, Steinbruck G, Thomsen J, Vanelderen L, Barth C, Baus C, Berger J, Boser C, Chwalek T, De Boer W, Descroix A, Dierlamm A, Feindt M, Guthoff M, Hackstein C, Hartmann F, Hauth T, Heinrich M, Held H, Hoffmann KH, Husemann U, Katkov I, Komaragiri JR, Kornmayer A, Pardo PL, Martschei D, Mueller S, Muller T, Niegel M, Nurnberg A, Oberst O, Ott J, Quast G, Rabbertz K, Ratnikov F, Ratnikova N, Rocker S, Schilling FP, Schott G, Simonis HJ, Stober FM, Troendle D, Ulrich R, Wagner-Kuhr J, Wayand S, Weiler T, Zeise M, Anagnostou G, 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T, Broccolo G, Castaldi R, D'Agnolo RT, Dell'Orso R, Fiori F, Foa L, Giassi A, Kraan A, Ligabue F, Lomtadze T, Martini L, Messineo A, Palla F, Rizzi A, Serban AT, Spagnolo P, Squillacioti P, Tenchini R, Tonelli G, Venturi A, Verdini PG, Vernieri C, Barone L, Cavallari F, Del Re D, Diemoz M, Fanelli C, Grassi M, Longo E, Margaroli F, Meridiani P, Micheli F, Nourbakhsh S, Organtini G, Paramatti R, Rahatlou S, Soffi L, Amapane N, Arcidiacono R, Argiro S, Arneodo M, Biino C, Cartiglia N, Casasso S, Costa M, Demaria N, Mariotti C, Maselli S, Mazza G, Migliore E, Monaco V, Musich M, Obertino MM, Pastrone N, Pelliccioni M, Potenza A, 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, Montanino D, Penzo A, Schizzi A, Zanetti A, Kim TY, Nam SK, Chang S, Kim DH, Kim GN, Kim JE, Kong DJ, Oh YD, Park H, Son DC, Kim JY, Kim ZJ, Song S, Choi S, Gyun D, Hong B, Jo M, Kim H, Kim TJ, Lee KS, Moon 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Visscher S, Di Guida S, Dobson M, Dupont-Sagorin N, Elliott-Peisert A, Eugster J, Funk W, Georgiou G, Giffels M, Gigi D, Gill K, Giordano D, Girone M, Giunta M, Glege F, Garrido RGR, Gowdy S, Guida R, Hammer J, Hansen M, Harris P, Hartl C, Hegner B, Hinzmann A, Innocente V, Janot P, Kaadze K, Karavakis E, Kousouris K, Krajczar K, Lecoq P, Lee YJ, Lourenco C, Magini N, Malberti M, Malgeri L, Mannelli M, Masetti L, Meijers F, Mersi S, Meschi E, Moser R, Mulders M, Musella P, Nesvold E, Orsini L, Cortezon EP, Perez E, Perrozzi L, Petrilli A, Pfeiffer A, Pierini M, Pimia M, Piparo D, Polese G, Quertenmont L, Racz A, Reece W, Antunes JR, Rolandi G, Rovelli C, Rovere M, Sakulin H, Santanastasio F, Schafer C, Schwick C, Segoni I, Sekmen S, Sharma A, Siegrist P, Silva P, Simon M, Sphicas P, Spiga D, Stoye M, Tsirou A, Veres GI, Vlimant JR, Wohri HK, Worm SD, Zeuner WD, Bertl W, Deiters K, Erdmann W, Gabathuler K, Horisberger R, Ingram Q, Kaestli HC, Konig S, Kotlinski D, Langenegger U, Meier F, Renker D, Rohe T, Bachmair F, Bani L, Bortignon P, Buchmann MA, Casal B, Chanon N, Deisher A, Dissertori G, Dittmar M, Donega M, Dunser M, Eller P, Grab C, Hits D, Lecomte P, Lustermann W, Marini AC, del Arbol PMR, Mohr N, Moortgat F, Nageli C, Nef P, Nessi-Tedaldi F, Pandolfi F, Pape L, Pauss F, Peruzzi M, Ronga FJ, Rossini M, Sala L, Sanchez AK, Starodumov A, Stieger B, Takahashi M, Tauscher L, Thea A, Theofilatos K, Treille D, Urscheler C, Wallny R, Weber HA, Amsler C, Chiochia V, Favaro C, Rikova MI, Kilminster B, Mejias BM, Otiougova P, Robmann P, Snoek H, Taroni S, Tupputi S, Verzetti M, Cardaci M, Chen KH, Ferro C, Kuo CM, Li SW, Lin W, Lu YJ, Volpe R, Yu SS, Bartalini P, Chang P, Chang YH, Chang YW, Chao Y, Chen KF, Dietz C, Grundler U, Hou WS, Hsiung Y, Kao KY, Lei YJ, Lu RS, Majumder D, Petrakou E, Shi X, Shiu JG, Tzeng YM, Wang M, Asavapibhop B, Suwonjandee N, Adiguzel A, Bakirci MN, Cerci S, Dozen C, Dumanoglu I, Eskut E, Girgis S, Gokbulut G, Gurpinar E, Hos I, Kangal EE, Topaksu AK, Onengut G, Ozdemir K, Ozturk S, Polatoz A, Sogut K, Cerci DS, Tali B, Topakli H, Vergili M, Akin IV, Aliev T, Bilin B, Bilmis S, Deniz M, Gamsizkan H, Guler AM, Karapinar G, Ocalan K, Ozpineci A, Serin M, Sever R, Surat UE, Yalvac M, Zeyrek M, Gulmez E, Isildak B, Kaya M, Kaya O, Ozkorucuklu S, Sonmez N, Bahtiyar H, Barlas E, Cankocak K, Gunaydin YO, Vardarh FI, Yucel M, Levchuk L, Sorokin P, Brooke JJ, Clement E, Cussans D, Flacher H, Frazier R, Goldstein J, Grimes M, Heath GP, Heath HF, Kreczko L, Metson S, Newbold DM, Nirunpong K, Poll A, Senkin S, Smith VJ, Williams T, Basso L, Bell KW, Belyaev A, Brew C, Brown RM, Cockerill DJA, Coughlan JA, Harder K, Harper S, Jackson J, Olaiya E, Petyt D, Radburn-Smith BC, Shepherd-Themistocleous CH, Tomalin IR, Womersley WJ, Bainbridge R, Ball G, Buchmuller O, Burton D, Colling D, Cripps N, Cutajar M, Dauncey P, Davies G, Della Negra M, Ferguson W, Fulcher J, Futyan D, Gilbert A, Bryer AG, Hall G, Hatherell Z, Hays J, Iles G, Jarvis M, Karapostoli G, Kenzie M, Lane R, Lucas R, Lyons L, Magnan AM, Marrouche J, Mathias B, Nandi R, Nash J, Nikitenko A, Pela J, Pesaresi M, Petridis K, Pioppi M, Raymond DM, Rogerson S, Rose A, Seez C, Sharp P, Sparrow A, Tapper A, Acosta MV, Virdee T, Wakefield S, Wardle N, Whyntie T, Chadwick M, Cole JE, Hobson PR, Khan A, Kyberd P, Leggat D, Leslie D, Martin W, Reid ID, Symonds P, Teodorescu L, Turner M, Dittmann J, Hatakeyama K, Kasmi A, Liu H, Scarborough T, Charaf O, Cooper SI, Henderson C, Rumerio P, Avetisyan A, Bose T, Fantasia C, Heister A, Lawson P, Lazic D, Rohlf J, Sperka D, St John J, Sulak L, Alimena J, Bhattacharya S, Christopher G, Cutts D, Demiragli Z, Ferapontov A, Garabedian A, Heintz U, Kukartsev G, Laird E, Landsberg G, Luk M, Narain M, Segala M, Sinthuprasith T, Speer T, Breedon R, Breto G, Sanchez MCD, Chauhan S, Chertok M, Conway J, Conway R, Cox PT, Erbacher R, Gardner M, Houtz R, Ko W, Kopecky A, Lander R, Mall O, Miceli T, Nelson R, Pellett D, Ricci-Tam F, Rutherford B, Searle M, Smith J, Squires M, Tripathi M, Yohay R, Andreev V, Cline D, Cousins R, Erhan S, Everaerts P, Farrell C, Felcini M, Hauser J, Ignatenko M, Jarvis C, Rakness G, Schlein P, Traczyk P, Valuev V, Weber M, Babb J, Clare R, Dinardo ME, Ellison J, Gary JW, Giordano F, Hanson G, Liu H, Long OR, Luthra A, Nguyen H, Paramesvaran S, Sturdy J, Sumowidagdo S, Wilken R, Wimpenny S, Andrews W, Branson JG, Cerati GB, Cittolin S, Evans D, Holzner A, Kelley R, Lebourgeois M, Letts J, Macneill I, Mangano B, Padhi S, Palmer C, Petrucciani G, Pieri M, Sani M, Sharma V, Simon S, Sudano E, Tadel M, Tu Y, Vartak A, Wasserbaech S, Wurthwein F, Yagil A, Yoo J, Barge D, Bellan R, Campagnari C, D'Alfonso M, Danielson T, Flowers K, Geffert P, George C, Golf F, Incandela J, Justus C, Kalavase P, Kovalskyi D, Krutelyov V, Lowette S, Villalba RM, Mccoll N, Pavlunin V, Ribnik J, Richman J, Rossin R, Stuart D, To W, West C, Apresyan A, Bornheim A, Bunn J, Chen Y, Di Marco E, Duarte J, Kcira D, Ma Y, Mott A, Newman HB, Rogan C, Spiropulu M, Timciuc V, Veverka J, Wilkinson R, Xie S, Yang Y, Zhu RY, Azzolini V, Calamba A, Carroll R, Ferguson T, Iiyama Y, Jang DW, Liu YF, Paulini M, Russ J, Vogel H, Vorobiev I, Cumalat JP, Drell BR, Ford WT, Gaz A, Lopez EL, Nauenberg U, Smith JG, Stenson K, Ulmer KA, Wagner SR, Alexander J, Chatterjee A, Eggert N, Gibbons LK, Hopkins W, Khukhunaishvili A, Kreis B, Mirman N, Kaufman GN, Patterson JR, Ryd A, Salvati E, Sun W, Teo WD, Thom J, Thompson J, Tucker J, Weng Y, Winstrom L, Wittich P, Winn D, Abdullin S, Albrow M, Anderson J, Apollinari G, Bauerdick LAT, Beretvas A, Berryhill J, Bhat PC, Burkett K, Butler JN, Chetluru V, Cheung HWK, Chlebana F, Cihangir S, Elvira VD, Fisk I, Freeman J, Gao Y, Gottschalk E, Gray L, Green D, Gutsche O, Harris RM, Hirschauer J, Hooberman B, Jindariani S, Johnson M, Joshi U, Klima B, Kunori S, Kwan S, Linacre J, Lincoln D, Lipton R, Lykken J, Maeshima K, Marraffino JM, Outschoorn VIM, Maruyama S, Mason D, McBride P, Mishra K, Mrenna S, Musienko Y, Newman-Holmes C, O'Dell V, Prokofyev O, Sexton-Kennedy E, Sharma S, Spalding WJ, Spiegel L, Taylor L, Tkaczyk S, Tran NV, Uplegger L, Vaandering EW, Vidal R, Whitmore J, Wu W, Yang F, Yun JC, Acosta D, Avery P, Bourilkov D, Chen M, Cheng T, Das S, De Gruttola M, Di Giovanni GP, Dobur D, Drozdetskiy A, Field RD, Fisher M, Fu Y, Furic IK, Hugon J, Kim B, Konigsberg J, Korytov A, Kropivnitskaya A, Kypreos T, Low JF, Matchev K, Milenovic P, Mitselmakher G, Muniz L, Remington R, Rinkevicius A, Skhirtladze N, Snowball M, Yelton J, Zakaria M, Gaultney V, Hewamanage S, Lebolo LM, Linn S, Markowitz P, Martinez G, Rodriguez JL, Adams T, Askew A, Bochenek J, Chen J, Diamond B, Gleyzer SV, Haas J, Hagopian S, Hagopian V, Johnson KF, Prosper H, Veeraraghavan V, Weinberg M, Baarmand MM, Dorney B, Hohlmann M, Kalakhety H, Yumiceva F, Adams MR, Apanasevich L, Bazterra VE, Betts RR, Bucinskaite I, Callner J, Cavanaugh R, Evdokimov O, Gauthier L, Gerber CE, Hofman DJ, Khalatyan S, Kurt P, Lacroix F, O'Brien C, Silkworth C, Strom D, Turner P, Varelas N, Akgun U, Albayrak EA, Bilki B, Clarida W, Dilsiz K, Duru F, Griffiths S, Merlo JP, Mermerkaya H, Mestvirishvili A, Moeller A, Nachtman J, Newsom CR, Ogul H, Onel Y, Ozok F, Sen S, Tan P, Tiras E, Wetzel J, Yetkin T, Yi K, Barnett BA, Blumenfeld B, Bolognesi S, Fehling D, Giurgiu G, Gritsan AV, Hu G, Maksimovic P, Swartz M, Whitbeck A, Baringer P, Bean A, Benelli G, Kenny RP, Murray M, Noonan D, Sanders S, Stringer R, Wood JS, Barfuss AF, Chakaberia I, Ivanov A, Khalil S, Makouski M, Maravin Y, Shrestha S, Svintradze I, Gronberg J, Lange D, Rebassoo F, Wright D, Baden A, Calvert B, Eno SC, Gomez JA, Hadley NJ, Kellogg RG, Kolberg T, Lu Y, Marionneau M, Mignerey AC, Pedro K, Peterman A, Skuja A, Temple J, Tonjes MB, Tonwar SC, Apyan A, Bauer G, Busza W, Butz E, Cali IA, Chan M, Dutta V, Ceballos GG, Goncharov M, Kim Y, Klute M, Levin A, Luckey PD, Ma T, Nahn S, Paus C, Ralph D, Roland C, Roland G, Stephans GSF, Stockli F, Sumorok K, Sung K, Velicanu D, Wolf R, Wyslouch B, Yang M, Yilmaz Y, Yoon AS, Zanetti M, Zhukova V, Dahmes B, De Benedetti A, Franzoni G, Gude A, Haupt J, Kao SC, Klapoetke K, Kubota Y, Mans J, Pastika N, Rusack R, Sasseville M, Singovsky A, Tambe N, Turkewitz J, Cremaldi LM, Kroeger R, Perera L, Rahmat R, Sanders DA, Summers D, Avdeeva E, Bloom K, Bose S, Claes DR, Dominguez A, Eads M, Suarez RG, Keller J, Kravchenko I, Lazo-Flores J, Malik S, Snow GR, Dolen J, Godshalk A, Iashvili I, Jain S, Kharchilava A, Kumar A, Rappoccio S, Wan Z, Alverson G, Barberis E, Baumgartel D, Chasco M, Haley J, Nash D, Orimoto T, Trocino D, Wood D, Zhang J, Anastassov A, Hahn KA, Kubik A, Lusito L, Mucia N, Odell N, Pollack B, Pozdnyakov A, Schmitt M, Stoynev S, Velasco M, Won S, Berry D, Brinkerhoff A, Chan KM, Hildreth M, Jessop C, Karmgard DJ, Kolb J, Lannon K, Luo W, Lynch S, Marinelli N, Morse DM, Pearson T, Planer M, Ruchti R, Slaunwhite J, Valls N, Wayne M, Wolf M, Antonelli L, Bylsma B, Durkin LS, Hill C, Hughes R, Kotov K, Ling TY, Puigh D, Rodenburg M, Smith G, Vuosalo C, Williams G, Winer BL, Wolfe H, Berry E, Elmer P, Halyo V, Hebda P, Hegeman J, Hunt A, Jindal P, Koay SA, Pegna DL, Lujan P, Marlow D, Medvedeva T, Mooney M, Olsen J, Piroue P, Quan X, Raval A, Saka H, Stickland D, Tully C, Werner JS, Zenz SC, Zuranski A, Brownson E, Lopez A, Mendez H, Vargas JER, Alagoz E, Benedetti D, Bolla G, Bortoletto D, De Mattia M, Everett A, Hu Z, Jones M, Koybasi O, Kress M, Leonardo N, Maroussov V, Merkel P, Miller DH, Neumeister N, Shipsey I, Silvers D, Svyatkovskiy A, Marono MV, Yoo HD, Zablocki J, Zheng Y, Guragain S, Parashar N, Adair A, Akgun B, Ecklund KM, Geurts FJM, Li W, Padley BP, Redjimi R, Roberts J, Zabel J, Betchart B, Bodek A, Covarelli R, de Barbaro P, Demina R, Eshaq Y, Ferbel T, Garcia-Bellido A, Goldenzweig P, Han J, Harel A, Miner DC, Petrillo G, Vishnevskiy D, Zielinski M, Bhatti A, Ciesielski R, Demortier L, Goulianos K, Lungu G, Malik S, Mesropian C, Arora S, Barker A, Chou JP, Contreras-Campana C, Contreras-Campana E, Duggan D, Ferencek D, Gershtein Y, Gray R, Halkiadakis E, Hidas D, Lath A, Panwalkar S, Park M, Patel R, Rekovic V, Robles J, Rose K, Salur S, Schnetzer S, Seitz C, Somalwar S, Stone R, Thomas S, Walker M, Cerizza G, Hollingsworth M, Spanier S, Yang ZC, York A, Eusebi R, Flanagan W, Gilmore J, Kamon T, Khotilovich V, Montalvo R, Osipenkov I, Pakhotin Y, Perloff A, Roe J, Safonov A, Sakuma T, Suarez I, Tatarinov A, Toback D, Akchurin N, Damgov J, Dragoiu C, Dudero PR, Jeong C, Kovitanggoon K, Lee SW, Libeiro T, Volobouev I, Appelt E, Delannoy AG, Greene S, Gurrola A, Johns W, Maguire C, Mao Y, Melo A, Sharma M, Sheldon P, Snook B, Tuo S, Velkovska J, Arenton MW, Balazs M, Boutle S, Cox B, Francis B, Goodell J, Hirosky R, Ledovskoy A, Lin C, Neu C, Wood J, Gollapinni S, Harr R, Karchin PE, Don CKK, Lamichhane P, Sakharov A, Anderson M, Belknap DA, Borrello L, Carlsmith D, Cepeda M, Dasu S, Friis E, Grogg KS, Grothe M, Hall-Wilton R, Herndon M, Herve A, Klabbers P, Klukas J, Lanaro A, Lazaridis C, Loveless R, Mohapatra A, Mozer MU, Ojalvo I, Pierro GA, Ross I, Savin A, Smith WH, Swanson J
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Measurement of the hadronic activity in events with a Z and two jets and extraction of the cross section for the electroweak production of a Z with two jets in pp collisions at root s=7 TeV
JOURNAL OF HIGH ENERGY PHYSICS 2013 OCT 10; ?(10):? Article 062
The first measurement of the electroweak production cross section of a Z boson with two jets (Zjj) in pp collisions at root s = 7 TeV is presented, based on a data sample recorded by the CMS experiment at the LHC with an integrated luminosity of 5 fb(-1). The cross section is measured for the lljj (l = e, mu) final state in the kinematic region m(ll) > 50 GeV, m(jj) > 120 GeV, transverse momenta p(T)(j) > 25 GeV and pseudorapidity vertical bar eta(j)vertical bar < 4.0. The measurement, combining the muon and electron channels, yields sigma = 154 +/- 24 (stat.) +/- 46 (exp. syst.) +/- 27 (th. syst.) +/- 3 (lum.) fb, in agreement with the theoretical cross section. The hadronic activity, in the rapidity interval between the jets, is also measured. These results establish an important foundation for the more general study of vector boson fusion processes, of relevance for Higgs boson searches and for measurements of electroweak gauge couplings and vector boson scattering.
Fins JJ
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Disorders of Consciousness and Disordered Care: Families, Caregivers, and Narratives of Necessity
ARCHIVES OF PHYSICAL MEDICINE AND REHABILITATION 2013 OCT; 94(10):1934-1939
By their nature, care decisions for patients with severe disorders of consciousness must involve surrogates. Patients, so impaired, have lost their decision-making capacity and the ability to direct their own care. Surrogates-family members, friends, or other intimates-must step in and make decisions about ongoing care or its withdrawal. This article shares the narrative experiences of these surrogate decision makers as they encounter the American health care system and accompany patients from injury through rehabilitation. Through their perspectives, the article considers challenges to ongoing care and rehabilitation that are a function of a prevailing medical infrastructure and reimbursement framework better suited to patients with acute care needs. Specific attention is paid to the ethical challenges posed by reimbursement strategies such as "medical necessity" as well as those proposed for the Affordable Care Act. The argument concludes that when it comes to care for a disorder related to consciousness, its provision is not discretionary, and its receipt is not an entitlement but a civil right. (c) 2013 by the American Congress of Rehabilitation Medicine
Ishino R, Minami K, Tanaka S, Nagai M, Matsui K, Hasegawa N, Roeder RG, Asano S, Ito M
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FGF7 supports hematopoietic stem and progenitor cells and niche-dependent myeloblastoma cells via autocrine action on bone marrow stromal cells in vitro
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 2013 OCT 11; 440(1):125-131
FGF1 and FGF2 support hematopoietic stem and progenitor cells (HSPCs) under stress conditions. In this study, we show that fibroblast growth factor (FGF7) may be a novel niche factor for HSPC support and leukemic growth. FGF7 expression was attenuated in mouse embryonic fibroblasts (MEFs) deficient for the MEDI subunit of the Mediator transcriptional coregulator complex. When normal mouse bone marrow (BM) cells were cocultured with Med1(+/+) MEFs or BM stromal cells in the presence of anti-FGF7 antibody, the growth of BM cells and the number of long-time culture-initiating cells (LTC-ICs) decreased significantly. Anti-FGF7 antibody also attenuated the proliferation and cobblestone formation of MB1 stromal cell-dependent myeloblastoma cells. The addition of recombinant FGF7 to the coculture of BM cells and Med1(-/-) MEFs increased BM cells and LTC-ICs. FGF7 and its cognate receptor, FGFR2IIIb, were undetectable in BM cells, but MEFs and BM stromal cells expressed both. FGF7 activated downstream targets of FGFR2IIIb in Med1(+/+) and Med1(-/-) MEFs and BM stromal cells. Taken together, we propose that FGF7 supports HSPCs and leukemia-initiating cells indirectly via FGFR2IIIb expressed on stromal cells. (C) 2013 Elsevier Inc. All rights reserved.
Banta AB, Chumanov RS, Yuan AH, Lin HL, Campbell EA, Burgess RR, Gourse RL
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Key features of sigma(S) required for specific recognition by Crl, a transcription factor promoting assembly of RNA polymerase holoenzyme
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 2013 OCT 1; 110(40):15955-15960
Bacteria use multiple sigma factors to coordinate gene expression in response to environmental perturbations. In Escherichia coli and other.-proteobacteria, the transcription factor Crl stimulates sigma(s) -dependent transcription during times of cellular stress by promoting the association of sigma(5) with core RNA polymerase. The molecular basis for specific recognition of sigma(5) by Crl, rather than the homologous and more abundant primary sigma factor sigma(70), is unknown. Here we use bacterial two-hybrid analysis in vivo and p-benzoylphenylalanine cross-linking in vitro to define the features in s S responsible for specific recognition by Crl. We identify residues in s S conserved domain 2 (sigma(S) (2)) that are necessary and sufficient to allow recognition of sigma(70) conserved domain 2 by Crl, one near the promoter-melting region and the other at the position where a large nonconserved region interrupts the sequence of sigma(70.) We then use luminescence resonance energy transfer to demonstrate directly that Crl promotes holoenzyme assembly using these specificity determinants on sigma(5). Our results explain how Crl distinguishes between sigma factors that are largely homologous and activates discrete sets of promoters even though it does not bind to promoter DNA.
Zhou Y, Colombo G, Gessa GL, Kreek MJ
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Effects of voluntary alcohol drinking on corticotropin-releasing factor and preprodynorphin mRNA levels in the central amygdala of Sardinian alcohol-preferring rats
NEUROSCIENCE LETTERS 2013 OCT 25; 554(?):110-114
The stress-response corticotropin-releasing factor (CRF) and dynorphin systems are critically involved in alcohol drinking and "anxiety"-related behaviors. Selectively bred Sardinian alcohol-preferring (sP) rats display high inherent "anxiety"-related behaviors, in comparison with their alcohol-nonpreferring counterpart (sNP rats). The present study was undertaken to investigate: (1) if there were genetically determined differences in basal gene expression levels of CRF, CRF-R1, preprodynorphin (ppDyn) and kappa opioid receptor (KOP-r) between sP and sNP rats; specifically, mRNA levels of the above genes were measured in the central amygdala (CeA), hypothalamus and other stress responsive and mesolimbic regions of alcohol-naive sP and sNP rats; and (2) if the above mRNA levels were altered by voluntary alcohol drinking in sP rats exposed to the standard, homecage 2-bottle "alcohol vs. water" choice regimen 24 h/day for 17 days. Higher basal CRF mRNA levels were found only in CeA of alcohol-naive sP rats, compared with sNP rats; these levels were decreased after alcohol consumption. In contrast, ppDyn mRNA levels in CeA of sP rats were increased by alcohol consumption, but with no basal difference from sNP rats. Although higher basal ppDyn mRNA levels were found in hypothalamus of sP rats, compared with sNP rats, there was no alteration after alcohol drinking in sP rats. No difference for the above mRNA levels was observed in other regions, including nucleus accumbens shell or core, caudate-putamen, ventral tegmental area and medial/basolateral amygdala, between the two rat lines before or after alcohol consumption. Our results demonstrate the existence of genetically determined high basal CRF mRNA levels in CeA of sP rats. Alcohol consumption decreased CeA CRF mRNA levels with parallel increases in CeA ppDyn mRNA levels. (C) 2013 Elsevier Ireland Ltd. All rights reserved.
Lanternier F, Pathan S, Vincent QB, Liu LY, Cypowyj S, Prando C, Migaud M, Taibi L, Ammar-Khodja A, Boudghene Stambouli O, Guellil B, Jacobs F, Goffard JC, Schepers K, del Marmol V, Boussofara L, Denguezli M, Larif M, Bachelez H, Michel L, Lefranc G, Hay R, Jouvion G, Chretien F, Fraitag S, Bougnoux ME, Boudia M, Abel L, Lortholary O, Casanova JL, Picard C, Grimbacher B, Puel A
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Deep Dermatophytosis and Inherited CARD9 Deficiency
NEW ENGLAND JOURNAL OF MEDICINE 2013 OCT 31; 369(18):1704-1714
BackgroundDeep dermatophytosis is a severe and sometimes life-threatening fungal infection caused by dermatophytes. It is characterized by extensive dermal and subcutaneous tissue invasion and by frequent dissemination to the lymph nodes and, occasionally, the central nervous system. The condition is different from common superficial dermatophyte infection and has been reported in patients with no known immunodeficiency. Patients are mostly from North African, consanguineous, multiplex families, which strongly suggests a mendelian genetic cause. MethodsWe studied the clinical features of deep dermatophytosis in 17 patients with no known immunodeficiency from eight unrelated Tunisian, Algerian, and Moroccan families. Because CARD9 (caspase recruitment domain-containing protein 9) deficiency has been reported in an Iranian family with invasive fungal infections, we also sequenced CARD9 in the patients. ResultsFour patients died, at 28, 29, 37, and 39 years of age, with clinically active deep dermatophytosis. No other severe infections, fungal or otherwise, were reported in the surviving patients, who ranged in age from 37 to 75 years. The 15 Algerian and Tunisian patients, from seven unrelated families, had a homozygous Q289X CARD9 allele, due to a founder effect. The 2 Moroccan siblings were homozygous for the R101C CARD9 allele. Both alleles are rare deleterious variants. The familial segregation of these alleles was consistent with autosomal recessive inheritance and complete clinical penetrance. ConclusionsAll the patients with deep dermatophytosis had autosomal recessive CARD9 deficiency. Deep dermatophytosis appears to be an important clinical manifestation of CARD9 deficiency. (Funded by Agence Nationale pour la Recherche and others.) Dermatophyte infections are unusual but can cause serious invasive disease. In this report, autosomal recessive CARD9 deficiency indicated a potential genetic susceptibility to deep dermatophytosis, a severe invasive fungal infection. Deep dermatophytosis is a rare, invasive, sometimes life-threatening, fungal infection caused by dermatophytes.(1) These filamentous fungi are ubiquitous and usually cause benign infections that are limited to keratinized tissues and lead to onychomycosis, tinea corporis, tinea cruris, tinea pedis, or tinea capitis.(2) In deep dermatophytosis, dermatophytes invade the dermis and hypodermis and disseminate to the skin, hair, nails, lymph nodes, and brain.(3) Deep dermatophytosis has been reported in patients with the human immunodeficiency virus and patients who are receiving immunosuppressive therapy.(3) It was first described in 1959 in otherwise apparently healthy persons as dermatophytic disease.(1) Forty-five cases have been reported ...
Wu CY, Young L, Young D, Martel J, Young JD
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Bions: A Family of Biomimetic Mineralo-Organic Complexes Derived from Biological Fluids
PLOS ONE 2013 SEP 25; 8(9):? Article e75501
Mineralo-organic nanoparticles form spontaneously in human body fluids when the concentrations of calcium and phosphate ions exceed saturation. We have shown previously that these mineralo-organic nanoparticles possess biomimetic properties and can reproduce the whole phenomenology of the so-called nanobacteria-mineralized entities initially described as the smallest microorganisms on earth. Here, we examine the possibility that various charged elements and ions may form mineral nanoparticles with similar properties in biological fluids. Remarkably, all the elements tested, including sodium, magnesium, aluminum, calcium, manganese, iron, cobalt, nickel, copper, zinc, strontium, and barium form mineralo-organic particles with bacteria-like morphologies and other complex shapes following precipitation with phosphate in body fluids. Upon formation, these mineralo-organic particles, which we term bions, invariably accumulate carbonate apatite during incubation in biological fluids; yet, the particles also incorporate additional elements and thus reflect the ionic milieu in which they form. Bions initially harbor an amorphous mineral phase that gradually converts to crystals in culture. Our results show that serum produces a dual inhibition-seeding effect on bion formation. Using a comprehensive proteomic analysis, we identify a wide range of proteins that bind to these mineral particles during incubation in medium containing serum. The two main binding proteins identified, albumin and fetuin-A, act as both inhibitors and seeders of bions in culture. Notably, bions possess several biomimetic properties, including the possibility to increase in size and number and to be sub-cultured in fresh culture medium. Based on these results, we propose that bions represent biological, mineralo-organic particles that may form in the body under both physiological and pathological homeostasis conditions. These mineralo-organic particles may be part of a physiological cycle that regulates the function, transport and disposal of elements and minerals in the human body.