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Sahin G, Palanduz A, Aydogan G, Cassar O, Ertem AU, Telhan L, Canpolat N, Jouanguy E, Picard C, Gessain A, Abel L, Casanova JL, Plancoulaine S
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Classic Kaposi Sarcoma in 3 Unrelated Turkish Children Born to Consanguineous Kindreds

PEDIATRICS 2010 MAR; 125(3):E704-E708
Infection by human herpesvirus 8 (HHV-8) in childhood is common in the Mediterranean basin; however, classic Kaposi sarcoma (KS) is exceedingly rare in children not infected with HIV and not receiving immunosuppression, with only 30 cases having been reported since 1960. We recently reported 2 children with autosomal and X-linked recessive primary immunodeficiencies underlying KS in a context of multiple clinical manifestations. These reports suggested that classic KS in otherwise healthy children might also result from inborn errors of immunity more specific to HHV-8. In this article, we describe 3 unrelated Turkish children with classic KS born to first-cousin parents. The first patient, a girl, developed KS at 2 years of age with disseminated cutaneous and mucosal lesions. The clinical course progressed rapidly, and the patient died within 3 months despite treatment with vincristine. The other 2 children developed a milder form of KS at the age of 9 years, with multiple cutaneous lesions. A boy treated with interferon alpha therapy for 12 months is now in full remission at the age of 14, 2 years after treatment. The second girl is currently stabilized with etoposide, which was begun 4 months ago. None of the 3 children had any relevant familial history or other clinical features. The occurrence of classic KS in 3 unrelated Turkish children, each born to consanguineous parents, strongly suggests that autosomal recessive predisposition may drive the rare occurrence of HHV-8-associated classic KS in children. Pediatrics 2010; 125: e704-e708
Bekker V, Chanock SJ, Yeager M, Hutchinson AA, von Hahn T, Chen S, Xiao N, Dotrang M, Brown M, Busch MP, Edlin BR, Rice CM, O'Brien TR
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Genetic variation in CLDN1 and susceptibility to hepatitis C virus infection

JOURNAL OF VIRAL HEPATITIS 2010 MAR; 17(3):192-200
Claudin-1 is a recently discovered co-receptor for hepatitis C virus (HCV) that is required for late-stage binding of the virus. Because variants in the gene that encodes claudin-1 (CLDN1) could play a role in HCV infection, we conducted a 'whole gene association study' among injection drug users (IDUs) to examine whether CLDN1 genetic variants were associated with the risk of HCV infection or with viral clearance. In a cross sectional study, we examined genotype results for 50 single nucleotide polymorphisms (SNPs) across the CLDN1 gene region, comparing genotypes among participants with chronic HCV (n = 658) to those in IDUs who had cleared HCV (n = 199) or remained HCV-uninfected (n = 68). Analyses were controlled for racial ancestry (African-American or European-American) by stratification and logistic regression modeling. We found that participants who remained uninfected more often carried CLDN1 promoter region SNPs -15312C [odds ratio (OR), 1.72; 95% confidence interval (CI) 1.00-2.94; P = 0.048], -7153A (OR, 2.13; 95% CI, 1.25-3.62; P = 0.006) and -5414C (OR, 1.78; 95% CI, 1.06-3.00; P = 0.03). HCV-uninfected participants less often carried CLDN1 IVS1-2983C (OR, 0.55; 95% CI, 0.31-0.97; P = 0.04), which lies in intron 1. CLDN1 -15312C, -7153A and -5414C formed a haplotype in both the African-American and European-American participants and a haplotype analysis supported the association of CLDN1 -7153A in the HCV-uninfected participants. The analyses of HCV clearance revealed no associations with any SNP. These results indicate that genetic variants in regulatory regions of CLDN1 may alter susceptibility to HCV infection.
Craig JW, Chang FY, Kim JH, Obiajulu SC, Brady SF
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Expanding Small-Molecule Functional Metagenomics through Parallel Screening of Broad-Host-Range Cosmid Environmental DNA Libraries in Diverse Proteobacteria

APPLIED AND ENVIRONMENTAL MICROBIOLOGY 2010 MAR; 76(5):1633-1641
The small-molecule biosynthetic diversity encoded within the genomes of uncultured bacteria is an attractive target for the discovery of natural products using functional metagenomics. Phenotypes commonly associated with the production of small molecules, such as antibiosis, altered pigmentation, or altered colony morphology, are easily identified from screens of arrayed metagenomic library clones. However, functional metagenomic screening methods are limited by their intrinsic dependence on a heterologous expression host. Toward the goal of increasing the small-molecule biosynthetic diversity found in functional metagenomic studies, we report the phenotypic screening of broad-host-range environmental DNA libraries in six different proteobacteria: Agrobacterium tumefaciens, Burkholderia graminis, Caulobacter vibrioides, Escherichia coli, Pseudomonas putida, and Ralstonia metallidurans. Clone-specific small molecules found in culture broth extracts from pigmented and antibacterially active clones, as well as the genetic elements responsible for the biosynthesis of these metabolites, are described. The host strains used in this investigation provided access to unique sets of clones showing minimal overlap, thus demonstrating the potential advantage conferred on functional metagenomics through the use of multiple diverse host species.
Sfeir A, Kabir S, van Overbeek M, Celli GB, de Lange T
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Loss of Rap1 Induces Telomere Recombination in the Absence of NHEJ or a DNA Damage Signal

SCIENCE 2010 MAR 26; 327(5973):1657-1661
Shelterin is an essential telomeric protein complex that prevents DNA damage signaling and DNA repair at mammalian chromosome ends. Here we report on the role of the TRF2-interacting factor Rap1, a conserved shelterin subunit of unknown function. We removed Rap1 from mouse telomeres either through gene deletion or by replacing TRF2 with a mutant that does not bind Rap1. Rap1 was dispensable for the essential functions of TRF2-repression of ATM kinase signaling and nonhomologous end joining (NHEJ)-and mice lacking telomeric Rap1 were viable and fertile. However, Rap1 was critical for the repression of homology-directed repair (HDR), which can alter telomere length. The data reveal that HDR at telomeres can take place in the absence of DNA damage foci and underscore the functional compartmentalization within shelterin.
Bonnen PE, Lowe JK, Altshuler DM, Breslow JL, Stoffel M, Friedman JM, Pe'er I
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European admixture on the Micronesian island of Kosrae: lessons from complete genetic information

EUROPEAN JOURNAL OF HUMAN GENETICS 2010 MAR; 18(3):309-316
The architecture of natural variation present in a contemporary population is a result of multiple population genetic forces, including population bottleneck and expansion, selection, drift, and admixture. We seek to untangle the contribution of admixture to genetic diversity on the Micronesian island of Kosrae. Toward this goal, we used a complete genetic approach by combining a dense genome-wide map of 100 000 single-nucleotide polymorphisms (SNPs) with data from uniparental markers from the mitochondrial genome and the nonrecombining portion of the Y chromosome. These markers were typed in similar to 3200 individuals from Kosrae, representing 80% of the adult population of the island. We developed novel software that uses SNP data to delineate ancestry for individual segments of the genome. Through this analysis, we determined that 39% of Kosraens have some European ancestry. However, the vast majority of admixed individuals (77%) have European alleles spanning less than 10% of their genomes. Data from uniparental markers show most of this admixture to be male, introduced in the late nineteenth century. Furthermore, pedigree analysis shows that the majority of European admixture on Kosrae is because of the contribution of one individual. This approach shows the benefit of combining information from autosomal and uniparental polymorphisms and provides new methodology for determining ancestry in a population. European Journal of Human Genetics (2010) 18, 309-316; doi: 10.1038/ejhg.2009.180; published online 21 October 2009
de Jong YP, Rice CM, Ploss A
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New horizons for studying human hepatotropic infections

JOURNAL OF CLINICAL INVESTIGATION 2010 MAR; 120(3):650-653
The liver serves as a target organ for several important pathogens, including hepatitis B and C viruses (HBV and HCV, respectively) and the human malaria parasites, all of which represent serious global health problems. Because these pathogens are restricted to human hepatocytes, research in small animals has been compromised by the frailty of the current mouse xenotransplantation models. In this issue of the JCI, Bissig et al. demonstrate robust HBV and HCV infection in a novel xenotransplantation model in which large numbers of immunodeficient mice with liver injury were engrafted with significant quantities of human hepatocytes. This technical advance paves the way for more widespread use of human liver chimeric mice and forms the basis for creating increasingly complex humanized mouse models that could prove useful for studying immunopathogenesis and vaccine development against hepatotropic pathogens.
Chatrchyan S, Khachatryan V, Sirunyan AM, Adam W, Arnold B, Bergauer H, Bergauer T, Dragicevic M, Eichberger M, Ero J, Friedl M, Fruhwirth R, Ghete VM, Hammer J, Hansel S, Hoch M, Hormann N, Hrubec J, Jeitler M, Kasieczka G, Kastner K, Krammer M, Liko D, de Abril IM, Mikulec I, Mittermayr F, Neuherz B, Oberegger M, Padrta M, Pernicka M, Rohringer H, Schmid S, Schofbeck R, Schreiner T, Stark R, Steininger H, Strauss J, Taurok A, Teischinger F, Themel T, Uhl D, Wagner P, Waltenberger W, Walzel G, Widl E, Wulz CE, Chekhovsky V, Dvornikov O, Emeliantchik I, Litomin A, Makarenko V, Marfin I, Mossolov V, Shumeiko N, Solin A, Stefanovitch R, Gonzalez JS, Tikhonov A, Fedorov A, Karneyeu A, Korzhik M, Panov V, Zuyeuski R, Kuchinsky P, Beaumont W, Benucci L, Cardaci M, De Wolf EA, Delmeire E, Druzhkin D, Hashemi M, Janssen X, Maes T, Mucibello L, Ochesanu S, Rougny R, Selvaggi M, Van Haevermaet H, Van Mechelen P, Van Remortel N, Adler V, Beauceron S, Blyweert S, D'Hondt J, De Weirdt S, Devroede O, Heyninck J, Kalogeropoulos A, Maes J, Maes M, Mozer MU, Tavernier S, Van Doninck W, Van Mulders P, Villella I, Bouhali O, Chabert EC, Charaf O, Clerbaux B, De Lentdecker G, Dero V, Elgammal S, Gay APR, Hammad GH, Marage PE, Rugovac S, Vander Velde C, Vanlaer P, Wickens J, Grunewald M, Klein B, Marinov A, Ryckbosch D, Thyssen F, Tytgat M, Vanelderen L, Verwilligen P, Basegmez S, Bruno G, Caudron J, Delaere C, Demin P, Favart D, Giammanco A, Gregoire G, Lemaitre V, Militaru O, Ovyn S, Piotrzkowski K, Quertenmont L, Schul N, Beliy N, Daubie E, Alves GA, Pol ME, Souza MHG, Carvalho W, Damiao DD, Martins CD, De Souza SF, Mundim L, Oguri V, Santoro A, Do Amaral SMS, Sznajder A, Tomei TRFP, Dias MAF, Gregores EM, Novaes SF, Abadjiev K, Anguelov T, Damgov J, Darmenov N, Dimitrov L, Genchev V, Iaydjiev P, Piperov S, Stoykova S, Sultanov G, Trayanov R, Vankov I, Dimitrov A, Dyulendarova M, Kozhuharov V, Litov L, Marinova E, Mateev M, Pavlov B, Petkov P, Toteva Z, Chen GM, Chen HS, Guan W, Jiang CH, Liang D, Liu B, Meng X, Tao J, Wang J, Wang Z, Xue Z, Zhang Z, Ban Y, Cai J, Ge Y, Guo S, Hu Z, Mao Y, Qian SJ, Teng H, Zhu B, Avila C, Ruiz MB, Montoya CAC, Gomez A, Moreno BG, Rios AAO, Oliveros AFO, Romero DR, Sanabria JC, Godinovic N, Lelas K, Plestina R, Polic D, Puljak I, Antunovic Z, Dzelalija M, Brigljevic V, Duric S, Kadija K, Morovic S, Fereos R, Galanti M, Mousa J, Papadakis A, Ptochos F, Razis PA, Tsiakkouri D, Zinonos Z, Hektor A, Kadastik M, Kannike K, Muntel M, Raidal M, Rebane L, Anttila E, Czellar S, Harkonen J, Heikkinen A, Karimaki V, Kinnunen R, Klem J, Kortelainen MJ, Lampen T, Lassila-Perini K, Lehti S, Linden T, Luukka P, Maenpaa T, Nysten J, Tuominen E, Tuominiemi J, Ungaro D, Wendland L, Banzuzi K, Korpela A, Tuuva T, Nedelec P, Sillou D, Besancon M, Chipaux R, Dejardin M, Denegri D, Descamps J, Fabbro B, Faure JL, Ferri F, Ganjour S, Gentit FX, Givernaud A, Gras P, de Monchenault GH, Jarry P, Lemaire MC, Locci E, Malcles J, Marionneau M, Millischer L, Rander J, Rosowsky A, Rousseau D, Titov M, Verrecchia P, Baffioni S, Bianchini L, Bluj M, Busson P, Charlot C, Dobrzynski L, de Cassagnac RG, Haguenauer M, Mine P, Paganini P, Sirois Y, Thiebaux C, Zabi A, Agram JL, Besson A, Bloch D, Bodin D, Brom JM, Conte E, Drouhin F, Fontaine JC, Gele D, Goerlach U, Gross L, Juillot P, Le Bihan AC, Patois Y, Speck J, Van Hove P, Baty C, Bedjidian M, Blaha J, Boudoul G, Brun H, Chanon N, Chierici R, Contardo D, Depasse P, Dupasquier T, El Mamouni H, Fassi F, Fay J, Gascon S, Ille B, Kurca T, Le Grand T, Lethuillier M, Lumb N, Mirabito L, Perries S, Vander Donckt M, Verdier P, Djaoshvili N, Roinishvili N, Roinishvili V, Amaglobeli N, Adolphi R, Anagnostou G, Brauer R, Braunschweig W, Edelhoff M, Esser H, Feld L, Karpinski W, Khomich A, Klein K, Mohr N, Ostaptchouk A, Pandoulas D, Pierschel G, Raupach F, Schael S, von Dratzig AS, Schwering G, Sprenger D, Thomas M, Weber M, Wittmer B, Wlochal M, Actis O, Altenhofer G, Bender W, Biallass P, Erdmann M, Fetchenhauer G, Frangenheim J, Hebbeker T, Hilgers G, Hinzmann A, Hoepfner K, Hof C, Kirsch M, Klimkovich T, Kreuzer P, Lanske D, Merschmeyer M, Meyer A, Philipps B, Pieta H, Reithler H, Schmitz SA, Sonnenschein L, Sowa M, Steggemann J, Szczesny H, Teyssier D, Zeidler C, Bontenackels M, Davids M, Duda M, Flugge G, Geenen H, Giffels M, Ahmad WH, Hermanns T, Heydhausen D, Kalinin S, Kress T, Linn A, Nowack A, Perchalla L, Poettgens M, Pooth O, Sauerland P, Stahl A, Tornier D, Zoeller MH, Martin MA, Behrens U, Borras K, Campbell A, Castro E, Dammann D, Eckerlin G, Flossdorf A, Flucke G, Geiser A, Hatton D, Hauk J, Jung H, Kasemann M, Katkov I, Kleinwort C, Kluge H, Knutsson A, Kuznetsova E, Lange W, Lohmann W, Mankel R, Marienfeld M, Meyer AB, Miglioranzi S, Mnich J, Ohlerich M, Olzem J, Parenti A, Rosemann C, Schmidt R, Schoerner-Sadenius T, Volyanskyy D, Wissing C, Zeuner WD, Autermann C, Bechtel F, Draeger J, Eckstein D, Gebbert U, Kaschube K, Kaussen G, Klanner R, Mura B, Naumann-Emme S, Nowak F, Pein U, Sander C, Schleper P, Schum T, Stadie H, Steinbruck G, Thomsen J, Wolf R, Bauer J, Blum P, Buege V, Cakir A, Chwalek T, De Boer W, Dierlamm A, Dirkes G, Feindt M, Felzmann U, Frey M, Furgeri A, Gruschke J, Hackstein C, Hartmann F, Heier S, Heinrich M, Held H, Hirschbuehl D, Hoffmann KH, Honc S, Jung C, Kuhr T, Liamsuwan T, Martschei D, Mueller S, Muller T, Neuland MB, Niegel M, Oberst O, Oehler A, Ott J, Peiffer T, Piparo D, Quast G, Rabbertz K, Ratnikov F, Ratnikova N, Renz M, Saout C, Sartisohn G, Scheurer A, Schieferdecker P, Schilling FP, Schott G, Simonis HJ, Stober FM, Sturm P, Troendle D, Trunov A, Wagner W, Wagner-Kuhr J, Zeise M, Zhukov V, Ziebarth EB, Daskalakis G, Geralis T, Karafasoulis K, Kyriakis A, Loukas D, Markou A, Markou C, Mavrommatis C, Petrakou E, Zachariadou A, Gouskos L, Katsas P, Panagiotou A, Evangelou I, Kokkas P, Manthos N, Papadopoulos I, Patras V, Triantis FA, Bencze G, Boldizsar L, Debreczeni G, Hajdu C, Hernath S, Hidas P, Horvath D, Krajczar K, Laszlo A, Patay G, Sikler F, Toth N, Vesztergombi G, Beni N, Christian G, Imrek J, Molnar J, Novak D, Palinkas J, Szekely G, Szillasi Z, Tokesi K, Veszpremi V, Kapusi A, Marian G, Raics P, Szabo Z, Trocsanyi ZL, Ujvari B, Zilizi G, Bansal S, Bawa HS, Beri SB, Bhatnagar V, Jindal M, Kaur M, Kaur R, Kohli JM, Mehta MZ, Nishu N, Saini LK, Sharma A, Singh A, Singh JB, Singh SP, Ahuja S, Arora S, Bhattacharya S, Chauhan S, Choudhary BC, Gupta P, Jain S, Jain S, Jha M, Kumar A, Ranjan K, Shivpuri RK, Srivastava AK, Choudhury RK, Dutta D, Kailas S, Kataria SK, Mohanty AK, Pant LM, Shukla P, Topkar A, Aziz T, Guchait M, Gurtu A, Maity M, Majumder D, Majumder G, Mazumdar K, Nayak A, Saha A, Sudhakar K, Banerjee S, Dugad S, Mondal NK, Arfaei H, Bakhshiansohi H, Fahim A, Jafari A, Najafabadi MM, Moshaii A, Mehdiabadi SP, Rouhani S, Safarzadeh B, Zeinali M, Felcini M, Abbrescia M, Barbone L, Chiumarulo F, Clemente A, Colaleo A, Creanza D, Cuscela G, De Filippis N, De Palma M, De Robertis G, Donvito G, Fedele F, Fiore L, Franco M, Iaselli G, Lacalamita N, Loddo F, Lusito L, Maggi G, Maggi M, Manna N, Marangelli B, My S, Natali S, Nuzzo S, Papagni G, Piccolomo S, Pierro GA, Pinto C, Pompili A, Pugliese G, Rajan R, Ranieri A, Romano F, Roselli G, Selvaggi G, Shinde Y, Silvestris L, Tupputi S, Zito G, Abbiendi G, Bacchi W, Benvenuti AC, Boldini M, Bonacorsia D, Braibant-Giacomelli S, Cafaro VD, Caiazza SS, Capiluppi P, Castro A, Cavallo FR, Codispoti G, Cuffiani M, D'Antone I, Dallavalle GM, Fabbri F, Fanfani A, Fasanella D, Giacomelli P, Giordano V, Giunta M, Grandi C, Guerzoni M, Marcellini S, Masetti G, Montanari A, Navarria FL, Odorici F, Pellegrini G, Perrotta A, Rossi AM, Rovelli T, Siroli G, Torromeo G, Travaglini R, Albergo S, Costa S, Potenza R, Tricomi A, Tuve C, Barbagli G, Broccolo G, Ciulli V, Civinini C, D'Alessandro R, Focardi E, Frosali S, Gallo E, Genta C, Landi G, Lenzi P, Meschini M, Paoletti S, Sguazzoni G, Tropiano A, Benussi L, Bertani M, Bianco S, Colafranceschi S, Colonna D, Fabbri F, Giardoni M, Passamonti L, Piccolo D, Pierluigi D, Ponzio B, Russo A, Fabbricatore P, Musenich R, Benaglia A, Calloni M, Cerati GB, D'Angelo P, De Guio F, Farina FM, Ghezzi A, Govoni P, Malberti M, Malvezzi S, Martelli A, Menasce D, Miccio V, Moroni L, Negri P, Paganoni M, Pedrini D, Pullia A, Ragazzi S, Redaelli N, Sala S, Salerno R, De Fatis TT, Tancini V, Taroni S, Buontempo S, Cavallo N, Cimmino A, De Gruttola M, Fabozzi F, Iorio AOM, Lista L, Lomidze D, Noli P, Paolucci P, Sciacca C, Azzi P, Bacchetta N, Barcellan L, Bellan P, Bellato M, Benettoni M, Biasotto M, Bisello D, Borsato E, Branca A, Carlin R, Castellani L, Checchia P, Conti E, Dal Corso F, De Mattia M, Dorigo T, Dosselli U, Fanzago F, Gasparini F, Gasparini U, Giubilato P, Gonella F, Gresele A, Gulmini M, Kaminskiy A, Lacaprara S, Lazzizzera I, Margoni M, Maron G, Mattiazzo S, Mazzucato M, Meneghelli M, Meneguzzo AT, Michelotto M, Montecassiano F, Nespolo M, Passaseo M, Pegoraro M, Perrozzi L, Pozzobon N, Ronchese P, Simonetto F, Toniolo N, Torassa E, Tosi M, Triossi A, Vanini S, Ventura S, Zotto P, Zumerle G, Baesso P, Berzano U, Bricola S, Necchi MM, Pagano D, Ratti SP, Riccardi C, Torre P, Vicini A, Vitulo P, Viviani C, Aisa D, Aisa S, Babucci E, Biasini M, Bilei GM, Caponeri B, Checcucci B, Dinu N, Fano L, Farnesini L, Lariccia P, Lucaroni A, Mantovani G, Nappi A, Piluso A, Postolache V, Santocchia A, Servoli L, Tonoiu D, Vedaee A, Volpe R, Azzurri P, Bagliesi G, Bernardini J, Berretta L, Boccali T, Bocci A, Borrello L, Bosi F, Calzolari F, Castaldi R, Dell'Orso R, Fiori F, Foa L, Gennai S, Giassi A, Kraan A, Ligabue F, Lomtadze T, Mariani F, Martini L, Massa M, Messineo A, Moggi A, Palla F, Palmonari F, Petragnani G, Petrucciani G, Raffaelli F, Sarkar S, Segneri G, Serban AT, Spagnolo P, Tenchini R, Tolaini S, Tonelli G, Venturi A, Verdini PG, Baccaro S, Barone L, Bartoloni A, Cavallari F, Dafinei I, Del Re D, Di Marco E, Diemoz M, Franci D, Longo E, Organtini G, Palma A, Pandolfi F, Paramatti R, Pellegrino F, Rahatlou S, Rovelli C, Alampi G, Amapane N, Arcidiacono R, Argiro S, Arneodo M, Biino C, Borgia MA, Botta C, Cartiglia N, Castello R, Cerminara G, Costa M, Dattola D, Dellacasa G, Demaria N, Dughera G, Dumitrache F, Graziano A, Mariotti C, Marone M, Maselli S, Migliore E, Mila G, Monaco V, Musich M, Nervo M, Obertino MM, Oggero S, Panero R, Pastrone N, Pelliccioni M, Romero A, Ruspa M, Sacchi R, Solano A, Staiano A, Trapani PP, Trocino D, Pereira AV, Visca L, Zampieri A, Ambroglini F, Belforte S, Cossutti F, Della Ricca G, Gobbo B, Penzo A, Chang S, Chung J, Kim DH, Kim GN, Kong DJ, Park H, Son DC, Bahk SY, Song S, Jung SY, Hong B, Kim H, Kim JH, Lee KS, Moon DH, Park SK, Rhee HB, Sim KS, Kim J, Choi M, Hahn G, Park IC, Choi S, Choi Y, Goh J, Jeong H, Kim TJ, Lee J, Lee S, Janulis M, Martisiute D, Petrov P, Sabonis T, Valdez HC, Hernandez AS, Moreno SC, Pineda AM, Allfrey P, Gray RNC, Krofcheck D, Rodrigues NB, Butler PH, Signal T, Williams JC, Ahmad M, Ahmed I, Ahmed W, Asghar MI, Awan MIM, Hoorani HR, Hussain I, Khan WA, Khurshid T, Muhammad S, Qazi S, Shahzad H, Cwiok M, Dabrowski R, Dominik W, Doroba K, Konecki M, Krolikowski J, Pozniak K, Romaniuk R, Zabolotny W, Zych P, Frueboes T, Gokieli R, Goscilo L, Gorski M, Kazana M, Nawrocki K, Szleper M, Wrochna G, Zalewski P, Almeida N, Pedro LA, Bargassa P, David A, Faccioli P, Parracho PGF, Ferreira MF, Gallinaro M, Jordao MG, Martins P, Mini G, Musella P, Pela J, Raposo L, Ribeiro PQ, Sampaio S, Seixas J, Silva J, Silva P, Soares D, Sousa M, Varela J, Wohri HK, Altsybeev I, Belotelov I, Bunin P, Ershov Y, Filozova I, Finger M, Finger M, Golunov A, Golutvin I, Gorbounov N, Kalagin V, Kamenev A, Karjavin V, Konoplyanikov V, Korenkov V, Kozlov G, Kurenkov A, Lanev A, Makankin A, Mitsyn VV, Moisenz P, Nikonov E, Oleynik D, Palichik V, Perelygin V, Petrosyan A, Semenov R, Shmatov S, Smirnov V, Smolin D, Tikho-Nenko E, Vasil'ev S, Vishnevskiy A, Volodko A, Zarubin A, Zhiltsov V, Bondar N, Chtchipounov L, Denisov A, Gavrikov Y, Gavrilov G, Golovtsov V, Ivanov Y, Kim V, Kozlov V, Levchenko P, Obrant G, Orishchin E, Petrunin A, Shcheglov Y, Shchetkovskiy A, Sknar V, Smirnov I, Sulimov V, Tarakanov V, Uvarov L, Vavilov S, Velichko G, Volkov S, Vorobyev A, Andreev Y, Anisimov A, Antipov P, Dermenev A, Gninenko S, Golubev N, Kirsanov M, Krasnikov N, Matveev V, Pashenkov A, Postoev VE, Solovey A, Solovey A, Toropin A, Troitsky S, Baud A, Epshteyn V, Gavrilov V, Ilina N, Kaftanov V, Kolosov V, Kossov M, Krokhotin A, Kuleshov S, Oulianov A, Safronov G, Semenov S, Shreyber I, Stolin V, Vlasov E, Zhokin A, Boos E, Dubinin M, Dudko L, Ershov A, Gribushin A, Klyukhin V, Kodolova O, Lokhtin I, Petrushanko S, Sarycheva L, Savrin V, Snigirev A, Vardanyan I, Dremin I, Kirakosyan M, Konovalova N, Rusakov SV, Vinogradov A, Akimenko S, Artamonov A, Azhgirey I, Bitioukov S, Burtovoy V, Grishin V, Kachanov V, Konstantinov D, Krychkine V, Levine 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Fine synchronization of the CMS muon drift-tube local trigger using cosmic rays

JOURNAL OF INSTRUMENTATION 2010 MAR; 5(?):? Article T03004
The CMS experiment uses self-triggering arrays of drift tubes in the barrel muon trigger to perform the identification of the correct bunch crossing. The identification is unique only if the trigger chain is correctly synchronized. In this paper, the synchronization performed during an extended cosmic ray run is described and the results are reported. The random arrival time of cosmic ray muons allowed several synchronization aspects to be studied and a simple method for the fine synchronization of the Drift Tube Local Trigger at LHC to be developed.
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Mattson M, Sakharov A, Anderson M, Bachtis M, Bellinger JN, Carlsmith D, Crotty I, Dasu S, Dutta S, Efron J, Feyzi F, Flood K, Gray L, Grogg KS, Grothe M, Hall-Wilton R, Jaworski M, Klabbers P, Klukas J, Lanaro A, Lazaridis C, Leonard J, Loveless R, de Abril MM, Mohapatra A, Ott G, Polese G, Reeder D, Savin A, Smith WH, Sourkov A, Swanson J, Weinberg M, Wenman D, Wensveen M, White A
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Alignment of the CMS muon system with cosmic-ray and beam-halo muons

JOURNAL OF INSTRUMENTATION 2010 MAR; 5(?):? Article T03020
The CMS muon system has been aligned using cosmic-ray muons collected in 2008 and beam-halo muons from the 2008 LHC circulating beam tests. After alignment, the resolution of the most sensitive coordinate is 80 microns for the relative positions of superlayers in the same barrel chamber and 270 microns for the relative positions of endcap chambers in the same ring structure. The resolution on the position of the central barrel chambers relative to the tracker is comprised between two extreme estimates, 200 and 700 microns, provided by two complementary studies. With minor modifications, the alignment procedures can be applied using muons from LHC collisions, leading to additional significant improvements.
Prasad PV, Bashir M, Sitruk-Ware R, Kumar N
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Single-dose Pharmacokinetics of Nestorone (R), a potential female-contraceptive

STEROIDS 2010 MAR; 75(3):252-264
A synthetic progestin Nestorone (R) is being developed for female-contraception. This Study was conducted to determine the distribution, metabolism, and excretion of tritium-labeled Nestorone ((3)H Nestorone) in adult female rats. Rats were injected subcutaneously (S.C.) with a single dose of 400 mu Ci (3)H Nestorone/kg BW. Its distribution and concentrations in blood. plasma and other tissues were determined at defined times. The excreta were examined for elimination of (3)H Nestorone. Radioactivity in all samples was analyzed by liquid scintillation counter. Metabolite profiling was performed by HPLC and LC/MS analysis of the plasma. urine, and feces samples. Following subcutaneous injection of (3)H Nestorone, the mean peak concentrations of radioactivity (C(max)) in the blood and plasma were 58.1 and 95.5 ng equiv. (3)H Nestorone/g, respectively, at 2-h postdose (T(max)). Thereafter, the concentration of drug steadily declined through 96-h postdose with a terminal elimination half-life (t(1/2)) of 15.6h. (3)H Nestorone-derived radioactivity was widely distributed in most tissues by 0.5 h and attained a mean maximal concentration by 2-h postdose. Approximately, 81.4% and 7.62% of the administered dose was excreted via feces and urine, respectively. In vivo metabolism of (3)H Nestorone resulted into a total of 19 metabolites. Among them, two metabolites viz., 17 alpha-deacetyl-Nestorone (M9) and 4,5-dihydro-17 alpha-deacetyl-Nestorone (M 19) were identified by HPLC and LC/MS analysis. Metabolite profiling of plasma samples showed that most of the circulating radioactivity was associated with unchanged parent drug, and M19. The M19 was a major metabolite in the profiled urine and feces samples. Presence of large proportion of drug/drug-related material in feces suggested that the biliary excretion is a main elimination route of (3)H Nestorone. The distribution, metabolism, and excretion profiles of (3)H Nestorone obtained in this study provide a fairly good insight about its fate in women. (C) 2010 Elsevier Inc. All rights reserved.
Lee JI, O'Halloran DM, Eastham-Anderson J, Juang BT, Kaye JA, Hamilton OS, Lesch B, Goga A, L'Etoile ND
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Nuclear entry of a cGMP-dependent kinase converts transient into long-lasting olfactory adaptation

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 2010 MAR 30; 107(13):6016-6021
To navigate a complex and changing environment, an animal's sensory neurons must continually adapt to persistent cues while remaining responsive to novel stimuli. Long-termexposure to an inherently attractive odor causes Caenorhabditis elegans to ignore that odor, a process termed odor adaptation. Odor adaptation is likely to begin within the sensory neuron, because it requires factors that act within these cells at the time of odor exposure. The process by which an olfactory sensory neuron makes a decisive shift over time from a receptive state to a lasting unresponsive one remains obscure. In C. elegans, adaptation to odors sensed by the AWC pair of olfactory neurons requires the cGMP-dependent protein kinase EGL-4. Using a fully functional, GFP-tagged EGL-4, we show here that prolonged odor exposure sends EGL-4 into the nucleus of the stimulated AWC neuron. This odor-induced nuclear translocation correlates temporally with the stable dampening of chemotaxis that is indicative of long-term adaptation. Long-term adaptation requires cGMP binding residues as well as an active EGL-4 kinase. We show here that EGL-4 nuclear accumulation is both necessary and sufficient to induce long-lasting odor adaptation. After it is in the AWC nucleus, EGL-4 decreases the animal's responsiveness to AWC-sensed odors by acting downstream of the primary sensory transduction. Thus, the EGL-4 protein kinase acts as a sensor that integrates odor signaling over time, and its nuclear translocation is an instructive switch that allows the animal to ignore persistent odors.