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Govek EE, Hatten ME
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Tag-Team Genetics of Spinocerebellar Ataxia 6

NEURON 2019 MAY 22; 102(4):707-709
In this issue of Neuron, Du et al. (2019) demonstrate that the bicistronic CACNA1A gene encodes a transcription factor alpha 1ACT, mutations in which are associated with SCA6, that controls expression of genes important for cerebellar Purkinje cell development and excitability. Reduction of alpha 1ACT in the adult is well tolerated, suggesting a potential new therapy for SCA6.
Cupido T, Pisa R, Kelley ME, Kapoor TM
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Designing a chemical inhibitor for the AAA protein spastin using active site mutations

Spastin is a microtubule-severing AAA (ATPases associated with diverse cellular activities) protein needed for cell division and intracellular vesicle transport. Currently, we lack chemical inhibitors to probe spastin function in such dynamic cellular processes. To design a chemical inhibitor of spastin, we tested selected heterocyclic scaffolds against wild-type protein and constructs with engineered mutations in the nucleotide-binding site that do not substantially disrupt ATPase activity. These data, along with computational docking, guided improvements in compound potency and selectivity and led to spastazoline, a pyrazolyl-pyrrolopyrimidine-based cell-permeable probe for spastin. These studies also identified spastazoline-resistance-conferring point mutations in spastin. Spastazoline, along with the matched inhibitor-sensitive and inhibitor-resistant cell lines we generated, were used in parallel experiments to dissect spastin-specific phenotypes in dividing cells. Together, our findings suggest how chemical probes for AAA proteins, along with inhibitor resistance-conferring mutations, can be designed and used to dissect dynamic cellular processes.
Maji B, Gangopadhyay SA, Lee M, Shi MC, Wu P, Heler R, Mok B, Lim D, Siriwardena SU, Paul B, Dancik V, Vetere A, Mesleh MF, Marraffini LA, Liu DR, Clemons PA, Wagner BK, Choudhary A
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A High-Throughput Platform to Identify Small-Molecule Inhibitors of CRISPR-Cas9

CELL 2019 MAY 2; 177(4):1067-1079.e19
The precise control of CRISPR-Cas9 activity is required for a number of genome engineering technologies. Here, we report a generalizable platform that provided the first synthetic small-molecule inhibitors of Streptococcus pyogenes Cas9 (SpCas9) that weigh <500 Da and are cell permeable, reversible, and stable under physiological conditions. We developed a suite of high-throughput assays for SpCas9 functions, including a primary screening assay for SpCas9 binding to the protospacer adjacent motif, and used these assays to screen a structurally diverse collection of natural-product-like small molecules to ultimately identify compounds that disrupt the SpCas9-DNA interaction. Using these synthetic anti-CRISPR small molecules, we demonstrated dose and temporal control of SpCas9 and catalytically impaired SpCas9 technologies, including transcription activation, and identified a pharmacophore for SpCas9 inhibition using structure-activity relationships. These studies establish a platform for rapidly identifying synthetic, miniature, cell-permeable, and reversible inhibitors against both SpCas9 and next-generation CRISPR-associated nucleases.
Azevedo EP, Pomeranz L, Cheng J, Schneeberger M, Vaughan R, Stem SA, Tan BW, Doerig K, Greengard P, Friedman JM
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A Role of Drd2 Hippocampal Neurons in Context-Dependent Food Intake

NEURON 2019 MAY 22; 102(4):873-886.e5
Associative learning of food cues that link location in space to food availability guides feeding behavior in mammals. However, the function of specific neurons that are elements of the higher-order, cognitive circuitry controlling feeding behavior is largely unexplored. Here, we report that hippocampal dopamine 2 receptor (hD2R) neurons are specifically activated by food and that both acute and chronic modulation of their activity reduces food intake in mice. Upstream projections from the lateral entorhinal cortex (LEC) to the hippocampus activate hD2R cells and can also decrease food intake. Finally, activation of hD2R neurons interferes with the encoding of a spatial memory linking food to a specific location via projections from the hippocampus to the septal area. Altogether these data describe a previously unidentified LEC > hippocampus > septal higher-order circuit that regulates feeding behavior.
Abt I, Adamczyk L, Aggarwal R, Aushev V, Behnke O, Behrens U, Bertolin A, Bloch I, Brock I, Brook NH, Brugnera R, Bruni A, Bussey PJ, Caldwell A, Capua M, Catterall CD, Chwastowski J, Ciborowski J, Ciesielski R, Cooper-Sarkar AM, Corradi M, Dementiev RK, Dusini S, Ferrando J, Foster B, Gallo E, Gangadharan D, Garfagnini A, Geiser A, Gladilin LK, Golubkov YA, Grzelak G, Gwenlan C, Hochman D, Jomhari NZ, Kadenko I, Kananov S, Karshon U, Kaur P, Klanner R, Klein U, Korzhavina IA, Kovalchuk N, Kowalski H, Kuprash O, Kuze M, Levchenko BB, Levy A, Lohr B, Lohrmann E, Longhin A, Lukina OY, Makarenko I, Malka J, Masciocchi S, Nagano K, Nam JD, Onderwaater J, Onishchuk Y, Paul E, Pidhurskyi I, Polini A, Przybycien M, Quintero A, Ruspa M, Saxon DH, Schneekloth U, Schorner-Sadenius T, Selyuzhenkov I, Shchedrolosiev M, Shcheglova LM, Shkola O, Skillicorn IO, Slominski W, Solano A, Stanco L, Stefaniuk N, Stopa P, Surrow B, Sztuk-Dambietz J, Tassi E, Tokushuku K, Turcato M, Turkot O, Tymieniecka T, Verbytskyi A, Abdullah WATW, Wichmann K, Wing M, Yamada S, Yamazaki Y, Zarnecki AF, Zawiejski L, Zenaiev O
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Charm production in charged current deep inelastic scattering at HERA

JOURNAL OF HIGH ENERGY PHYSICS 2019 MAY 29; ?(5):? Article 201
Charm production in charged current deep inelastic scattering has been measured for the first time in e(+/-)p collisions, using data collected with the ZEUS detector at HERA, corresponding to an integrated luminosity of 358 pb(-1). Results are presented separately for e(+)p and e(-)p scattering at a centre-of-mass energy of root s = 318 GeV within a kinematic phase-space region of 200 GeV2 < Q(2) < 60000 GeV2 and y < 0.9, where Q(2) is the squared four-momentum transfer and y is the inelasticity. The measured cross sections of electroweak charm production are consistent with expectations from the Standard Model within the large statistical uncertainties.
Gurney J, Pleska M, Levin BR
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Why put up with immunity when there is resistance: an excursion into the population and evolutionary dynamics of restriction-modification and CRISPR-Cas

Bacteria can readily generate mutations that prevent bacteriophage (phage) adsorption and thus make bacteria resistant to infections with these viruses. Nevertheless, the majority of bacteria carry complex innate and/or adaptive immune systems: restriction-modification (RM) and CRISPR-Cas, respectively. Both RM and CRISPR-Cas are commonly assumed to have evolved and be maintained to protect bacteria from succumbing to infections with lytic phage. Using mathematical models and computer simulations, we explore the conditions under which selection mediated by lytic phage will favour such complex innate and adaptive immune systems, as opposed to simple envelope resistance. The results of our analysis suggest that when populations of bacteria are confronted with lytic phage: (i) In the absence of immunity, resistance to even multiple bacteriophage species with independent receptors can evolve readily. (ii) RM immunity can benefit bacteria by preventing phage from invading established bacterial populations and particularly so when there are multiple bacteriophage species adsorbing to different receptors. (iii) Whether CRISPR-Cas immunity will prevail over envelope resistance depends critically on the number of steps in the coevolutionary arms race between the bacteria-acquiring spacers and the phage-generating CRISPR-escape mutants. We discuss the implications of these results in the context of the evolution and maintenance of RM and CRISPR-Cas and highlight fundamental questions that remain unanswered. This article is part of a discussion meeting issue 'The ecology and evolution of prokaryotic CRISPR-Cas adaptive immune systems'.
Soliman YS, Hoffman LK, Guzman AK, Patel ZS, Lowes MA, Cohen SR
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African American Patients With Hidradenitis Suppurativa Have Significant Health Care Disparities: A Retrospective Study

Sirunyan AM, Tumasyan A, Adam W, Ambrogi F, Asilar E, Bergauer T, Brandstetter J, Brondolin E, Dragicevic M, Ero J, Del Valle AE, Flechl M, Friedl M, Fruhwirth R, Ghete VM, Grossmann J, Hrubec J, Jeitler M, Konig A, Krammer N, Kratschmer I, Liko D, Madlener T, Mikulec I, Pree E, Rad N, Rohringer H, Schieck J, Schofbeck R, Spanring M, Spitzbart D, Taurok A, Waltenberger W, Wittmann J, Wulz CE, Zarucki M, Chekhovsky V, Mossolov V, Gonzalez JS, De Wolf EA, Di Croce D, Janssen X, Lauwers J, Pieters M, Van de Klundert M, Van Haevermaet H, Van Mechelen P, Van Remortel N, Abu Zeid S, Blekman F, D'Hondt J, De Bruyn I, De Clercq J, Deroover K, Flouris G, Lontkovskyi D, Lowette S, Marchesini I, Moortgat S, Moreels L, Python Q, Skovpen K, Tavernier S, Van Doninck W, Van Mulders P, Van Parijs I, Beghin D, Bilin B, Brun H, Clerbaux B, De Lentdecker G, Delannoy H, Dorney B, Fasanella G, Favart L, Goldouzian R, Grebenyuk A, Kalsi AK, Lenzi T, Luetic J, Maerschalk T, Seva T, Starling E, Vander Velde C, Vanlaer P, Vannerom D, Yonamine R, Zenoni F, Cornelis T, Dobur D, Fagot A, Gul M, Khvastunov I, Poyraz D, Roskas C, Trocino D, Tytgat M, Verbeke W, Vit M, Zaganidis N, Bakhshiansohi H, Bondu O, Brochet S, Bruno G, Caputo C, Caudron A, David P, De Visscher S, Delaere C, Delcourt M, Francois B, Giammanco A, Krintiras G, Lemaitre V, Magitteri A, Mertens A, Musich M, Piotrzkowski K, Quertenmont L, Saggio A, Marono MV, Wertz S, Zobec J, Alda WL, Alves FL, Alves GA, Brito L, Silva GC, Hensel C, Moraes A, Pol ME, Teles PR, Das Chagas EBB, Carvalho W, Chinellato J, Coelho E, Da Costa EM, Da Silveira GG, Damiao DD, De Souza SF, Guativa LMH, Malbouisson H, De Almeida MM, Herrera CM, Mundim L, Nogima H, Rosas LJS, Santoro A, Sznajder A, Thiel M, Manganote EJT, De Araujo FTD, Pereira AV, Ahuja S, Bernardes CA, Tomei TRFP, Gregores EM, Mercadante PG, Novaes SF, Padula SS, Abad DR, Vargas JCR, Aleksandrov A, Hadjiiska R, Iaydjiev P, Marinov A, Misheva M, Rodozov M, Shopova M, Sultanov G, Dimitrov A, Litov L, Pavlov B, Petkov P, Fang W, Gao X, Yuan L, Ahmad M, Bian JG, Chen GM, Chen HS, Chen M, Chen Y, Jiang CH, Leggat D, Liao H, Liu Z, Romeo F, Shaheen SM, Spiezia A, Tao J, Wang C, Wang Z, Yazgan E, Zhang H, Zhao J, Ban Y, Chen G, Li J, Li Q, Liu S, Mao Y, Qian SJ, Wang D, Xu Z, Wang Y, Avila C, Cabrera A, Sierra LFC, Florez C, Hernaandez CFG, Alvarez JDR, Delgado MAS, Courbon B, Godinovic N, Lelas D, Puljak I, Cipriano PMR, Sculac T, Antunovic Z, Kovac M, Brigljevic V, Ferencek D, Kadija K, Mesic B, Starodumov A, Susa T, Ather MW, Attikis A, Mavromanolakis G, Mousa J, Nicolaou C, Ptochos F, Razis PA, Rykaczewski H, Finger M, Finger M, Jarrin EC, Abdelalim AA, Assran Y, Elgammal S, Bhowmik S, Dewanjee RK, Kadastik M, Perrini L, Raidal M, Veelken C, Eerola P, Kirschenmann H, Pekkanen J, Voutilainen M, Havukainen J, Heikkila JK, Jarvinen T, Karimaki V, Kinnunen R, Lampen T, Lassila-Perini K, Laurila S, Lehti S, Linden T, Luukka P, Maenpaa T, Siikonen H, Tuominen E, Tuominiemi J, Tuuva T, Besancon M, Couderc F, Dejardin M, Denegri D, Faure JL, Ferri F, Ganjour S, Ghosh S, Givernaud A, Gras P, de Monchenault GH, Jarry P, Leloup C, Locci E, Machet M, Malcles J, Negro G, Rander J, Rosowsky A, Sahin MO, Titov M, Abdulsalam A, Amendola C, Antropov I, Baffioni S, Beaudette F, Busson P, Cadamuro L, Charlot C, de Cassagnac RG, Jo M, Kucher I, Lisniak S, Lobanov A, Blanco JM, Nguyen M, Ochando C, Ortona G, Paganini P, Pigard P, Salerno R, Sauvan JB, Sirois Y, Leiton AGS, Yilmaz Y, Zabi A, Zghiche A, Agram JL, Andrea J, Bloch D, Brom JM, Buttignol M, Chabert EC, Collard C, Conte E, Coubez X, Drouhin F, Fontaine JC, Gele D, Goerlach U, Jansova M, Juillot P, Le Bihan AC, Tonon N, Van Hove P, Gadrat S, Beauceron S, Bernet C, Boudoul G, Chanon N, Chierici R, Contardo D, Depasse P, El Mamouni H, Fay J, Finco L, Gascon S, Gouzevitch M, Grenier G, Ille B, Lagarde F, Laktineh IB, Lethuillier M, Mirabito L, Pequegnot AL, Perries S, Popov A, Sordini V, Vander Donckt M, Viret S, Zhang S, Khvedelidze A, Lomidze D, Autermann C, Feld L, Kiesel MK, Klein K, Lipinski M, Preuten M, Schomakers C, Schulz J, Teroerde M, Wittmer B, Zhukov V, Albert A, Duchardt D, Endres M, Erdmann M, Erdweg S, Esch T, Fischer R, Guth A, Hebbeker T, Heidemann C, Hoepfner K, Knutzen S, Merschmeyer M, Meyer A, Millet P, Mukherjee S, Pook T, Radziej M, Reithler H, Rieger M, Scheuch F, Teyssier D, Thuer S, Flugge G, Kargoll B, Kress T, Kunsken A, Muller T, Nehrkorn A, Nowack A, Pistone C, Pooth O, Stahl A, Martin MA, Arndt T, Asawatangtrakuldee C, Beernaert K, Behnke O, Behrens U, Martinez AB, Bin Anuar AA, Borras K, Botta V, Campbell A, Connor P, Contreras-Campana C, Costanza F, Pardos CD, Eckerlin G, Eckstein D, Eichhorn T, Eren E, Gallo E, Garcia JG, Geiser A, Luyando JMG, Grohsjean A, Gunnellini P, Guthoff M, Harb A, Hauk J, Hempel M, Jung H, Kasemann M, Keaveney J, Kleinwort C, Korol I, Krucker D, Lange W, Lelek A, Lenz T, Lipka K, Lohmann W, Mankel R, Melzer-Pellmann IA, Meyer AB, Missiroli M, Mittag G, Mnich J, Mussgiller A, Pitzl D, Raspereza A, Savitskyi M, Saxena P, Shevchenko R, Stefaniuk N, Tholen H, Van Onsem GP, Walsh R, Wen Y, Wichmann K, Wissing C, Zenaiev O, Aggleton R, Bein S, Blobel V, Vignali MC, Dreyer T, Garutti E, Gonzalez D, Haller J, Hinzmann A, Hoffmann M, Karavdina A, Kasieczka G, Klanner R, Kogler R, Kovalchuk N, Kurz S, Marconi D, Meyer M, Niedziela M, Nowatschin D, Peiffer T, Perieanu A, Scharf C, Schleper P, Schmidt A, Schumann S, Schwandt J, Sonneveld J, Stadie H, Steinbruck G, Stober FM, Stover M, Troendle D, Usai E, Vanhoefer A, Vormwald B, Akbiyik M, Barth C, Baselga M, Baur S, Butz E, Caspart R, Chwalek T, Colombo F, De Boer W, Dierlamm A, Faltermann N, Freund B, Friese R, Giffels M, Harrendorf MA, Hartmann F, Heindl SM, Husemann U, Kassel F, Kudella S, Mildner H, Mozer MU, Muller T, Plagge M, Quast G, Rabbertz K, Schroder M, Shvetsov I, Sieber G, Simonis HJ, Ulrich R, Wayand S, Weber M, Weiler T, Williamson S, Woehrmann C, Wolf R, Anagnostou G, Daskalakis G, Geralis T, Kyriakis A, Loukas D, Topsis-Giotis I, Karathanasis G, Kesisoglou S, Panagiotou A, Saoulidou N, Tziaferi E, Kousouris K, Evangelou I, Foudas C, Gianneios P, Katsoulis P, Kokkas P, Mallios S, Manthos N, Papadopoulos I, Paradas E, Strologas J, Triantis FA, Tsitsonis D, Csanad M, Filipovic N, Pasztor G, Suranyi O, Veres GI, Bencze G, Hajdu C, Horvath D, Hunyadi A, Sikler F, Veszpremi V, Vesztergombi G, Beni N, Czellar S, Karancsi J, Makovec A, Molnar J, Szillasi Z, Bartok M, Raics P, Trocsanyi ZL, Ujvari B, Choudhury S, Komaragiri JR, Bahinipati S, Mal P, Mandal K, Nayak A, Sahoo DK, Sahoo N, Swain SK, Bansal S, Beri SB, Bhatnagar V, Chawla R, Dhingra N, Kaur A, Kaur M, Kaur S, Kumar R, Kumari P, Mehta A, Singh JB, Walia G, Kumar A, Shah A, Bhardwaj A, Chauhan S, Choudhary BC, Garg RB, Keshri S, Kumar A, Malhotra S, Naimuddin M, Ranjan K, Sharma R, Bhardwaj R, Bhattacharya R, Bhattacharya S, Bhawandeep U, Bhowmik D, Dey S, Dutt S, Dutta S, Ghosh S, Majumdar N, Modak A, Mondal K, Mukhopadhyay S, Nandan S, Purohit A, Rout PK, Roy A, Chowdhury SR, Sarkar S, Sharan M, Singh B, Thakur S, Behera PK, Chudasama R, Dutta D, Jha V, Kumar V, Mohanty AK, Netrakanti PK, Pant LM, Shukla P, Topkar A, Aziz T, Dugad S, Mahakud B, Mitra S, Mohanty GB, Sur N, Sutar B, Banerjee S, Bhattacharya S, Chatterjee S, Das P, Guchait M, Jain S, Kumar S, Maity M, Majumder G, Mazumdar K, Sarkar T, Wickramage N, Chauhan S, Dube S, Hegde V, Kapoor A, Kothekar K, Pandey S, Rane A, Sharma S, Chenarani S, Tadavani EE, Etesami SM, Khakzad M, Najafabadi MM, Naseri M, Mehdiabadi SP, Hosseinabadi FR, Safarzadeh B, Zeinali M, Felcini M, Grunewald M, Abbrescia M, Calabria C, Colaleo A, Creanza D, Cristella L, De Filippis N, De Palma M, Di Florio A, Errico F, Fiore L, Iaselli G, Lezki S, Maggi G, Maggi M, Marangelli B, Miniello G, My S, Nuzzo S, Pompili A, Pugliese G, Radogna R, Ranieri A, Selvaggi G, Sharma A, Silvestris L, Venditti R, Verwilligen P, Zito G, Abbiendi G, Battilana C, Bonacorsi D, Borgonovi L, Braibant-Giacomelli S, 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, Iemmi F, Marcellini S, Masetti G, Montanari A, Navarria FL, Perrotta A, Rossi AM, Rovelli T, Siroli GP, Tosi N, Albergo S, Costa S, Di Mattia A, Giordano F, Potenza R, Tricomi A, Tuve C, Barbagli G, Chatterjee K, Ciulli V, Civinini C, D'Alessandro R, Focardi E, Latino G, Lenzi P, Meschini M, Paoletti S, Russo L, Sguazzoni G, Strom D, Viliani L, Benussi L, Bianco S, Fabbri F, Piccolo D, Primavera F, Calvelli V, Ferro F, Ravera F, Robutti E, Tosi S, Benaglia A, Beschi A, Brianza L, Brivio F, Ciriolo V, Dinardo ME, Fiorendi S, Gennai S, Ghezzi A, Govoni P, Malberti M, Malvezzi S, Manzoni RA, Menasce D, Moroni L, Paganoni M, Pauwels K, Pedrini D, Pigazzini S, Ragazzi S, de Fatis TT, Buontempo S, Cavallo N, Di Guida S, Fabozzi F, Fienga F, Iorio AOM, Khan WA, Lista L, Meola S, Paolucci P, Sciacca C, Thyssen F, Azzi P, Bacchetta N, Benato L, Bisello D, Boletti A, Carlin R, De Oliveira ACA, Checchia P, Dall'Osso M, Manzano PD, Dorigo T, Dosselli U, Gasparini U, Gozzelino A, Lacaprara S, Lujan P, Margoni M, Meneguzzo AT, Pozzobon N, Ronchese P, Rossin R, Simonetto F, Tiko A, Torassa E, Zanetti M, Zotto P, Zumerle G, Braghieri A, Magnani A, Montagna P, Ratti SP, Re V, Ressegotti M, Riccardi C, Salvini P, Vai I, Vitulo P, Solestizi LA, Biasini M, Bilei GM, Cecchi C, Ciangottini D, Fano L, Lariccia P, Leonardi R, Manoni E, Mantovani G, Mariani V, Menichelli M, Rossi A, Santocchia A, Spiga D, Androsov K, Azzurri P, Bagliesi G, Bianchini L, Boccali T, Borrello L, Castaldi R, Ciocci MA, Dell'Orso R, Fedi G, Giannini L, Giassi A, Grippo MT, Ligabue F, Lomtadze T, Manca E, Mandorli G, Messineo A, Palla F, Rizzi A, Spagnolo P, Tenchini R, Tonelli G, Venturi A, Verdini PG, Barone L, Cavallari F, Cipriani M, Daci N, Del Re D, Di Marco E, Diemoz M, Gelli S, Longo E, Margaroli F, Marzocchi B, Meridiani P, Organtini G, Paramatti R, Preiato F, Rahatlou S, Rovelli C, Santanastasio F, Amapane N, Arcidiacono R, Argiro S, Arneodo M, Bartosik N, Bellan R, Biino C, Cartiglia N, Castello R, Cenna F, Costa M, Covarelli R, Degano A, Demaria N, Kiani B, Mariotti C, Maselli S, Migliore AE, Monaco V, Monteil E, Monteno M, Obertino MM, Pacher L, Pastrone N, Pelliccioni M, Angioni GLP, Romero A, Ruspa M, Sacchi R, Shchelina K, Sola V, Solano A, Staiano A, Traczyk P, Belforte S, Casarsa M, Cossutti F, Della Ricca G, Zanetti A, Kim DH, Kim GN, Kim MS, Lee J, Lee S, Lee SW, Moon CS, Oh YD, Sekmen S, Son DC, Yang YC, Kim H, Moon DH, Oh G, Cifuentes JAB, Goh J, Kim TJ, Cho S, Choi S, Go Y, Gyun D, Ha S, Hong B, Jo Y, Kim Y, Lee K, Lee KS, Lee S, Lim J, Park SK, Roh Y, Almond J, Kim J, Kim JS, Lee H, Lee K, Nam K, Oh SB, Radburn-Smith BC, Seo SH, Yang UK, Yoo HD, Yu GB, Kim H, Kim JH, Lee JSH, Park IC, Choi Y, Hwang C, Lee J, Yu I, Dudenas V, Juodagalvis A, Vaitkus J, Ahmed I, Ibrahim ZA, Ali MABM, Idris FM, Abdullah WATW, Yusli MN, Zolkapli Z, Reyes-Almanza R, Ramirez-Sanchez G, Duran-Osuna MC, Castilla-Valdez H, De la Cruz-Burelo E, Heredia-De La Cruz I, Rabadan-Trejo RI, Lopez-Fernandez R, Guisao JM, Sanchez-Hernandez A, Moreno SC, Barrera CO, Valencia FV, Eysermans J, Pedraza I, Ibarguen HAS, Estrada CU, Pineda AM, Krofcheck D, Butler PH, Ahmad A, Ahmad M, Hassan Q, Hoorani HR, Saddique A, Shah MA, Shoaib M, Waqas M, Bialkowska H, Bluj M, Boimska B, Frueboes T, Gorski M, Kazana M, Nawrocki K, Szleper M, Zalewski P, Bunkowski K, Byszuk A, Doroba K, Kalinowski A, Konecki M, Krolikowski J, Misiura M, Olszewski M, Pyskir A, Walczak M, Bargassa P, Silva CBDE, Di Francesco A, Faccioli P, Galinhas B, Gallinaro M, Hollar J, Leonardo N, Iglesias LL, Nemallapudi MV, Seixas J, Strong G, Toldaiev O, Vadruccio D, Varela J, Afanasiev S, Bunin P, Gavrilenko M, Golutvin I, Gorbunov I, Kamenev A, Karjavin V, Lanev A, Malakhov A, Matveev V, Moisenz P, Palichik V, Perelygin V, Shmatov S, Shulha S, Skatchkov N, Smirnov V, Voytishin N, Zarubin A, Ivanov Y, Kim V, Kuznetsova E, Levchenko P, Murzin V, Oreshkin V, Smirnov I, Sosnov D, 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, Stepennov A, Stolin V, Toms M, Vlasov E, Zhokin A, Aushev T, Bylinkin A, Chistov R, Danilov M, Parygin P, Philippov D, Polikarpov S, Tarkovskii E, Andreev V, Azarkin M, Dremin I, Kirakosyan M, Rusakov SV, Terkulov A, Baskakov A, Belyaev A, Boos E, Dubinin M, Dudko L, Ershov A, Gribushin A, Klyukhin V, Kodolova O, Lokhtin I, Miagkov I, Obraztsov S, Petrushanko S, Savrin V, Snigirev A, Blinov V, Shtol D, Skovpen Y, Azhgirey I, Bayshev I, Bitioukov S, Elumakhov D, Godizov A, Kachanov V, Kalinin A, Konstantinov D, Mandrik P, Petrov V, Ryutin R, Sobol A, Troshin S, Tyurin N, Uzunian A, Volkov A, Babaev A, Adzic P, Cirkovic P, Devetak D, Dordevic M, Milosevic J, Maestre JA, Bachiller I, Luna MB, Cerrada M, Colino N, De la Cruz B, Peris AD, Bedoya CF, Ramos JPF, Flix J, Fouz MC, Lopez OG, Lopez SG, Hernandez JM, Josa MI, Moran D, Yzquierdo APC, Pelayo JP, Redondo I, Romero L, Soares MS, Triossi A, Fernandez AA, Albajar C, de Troconiz JF, Cuevas J, Erice C, Menendez JF, Folgueras S, Caballero IG, Fernandez JRG, Cortezon EP, Cruz SS, Vischia P, Garcia JMV, Cabrillo IJ, Calderon A, Quero BC, Campderros JD, Fernandez M, Manteca PJF, Garcia-Ferrero J, Alonso AG, Gomez G, Virto AL, Marco J, Rivero CM, del Arbol PMR, Matorras F, Gomez JP, Prieels C, Rodrigo T, Ruiz-Jimeno A, Scodellaro L, Trevisani N, Vila I, Cortabitarte RV, Abbaneo D, Akgun B, Auffray E, Baillon P, Ball AH, Barney D, Bendavid J, Bianco M, Bocci A, Botta C, Camporesi T, Cepeda M, Cerminara G, Chapon E, Chen Y, d'Enterria D, Dabrowski A, Daponte V, David A, De Gruttola M, De Roeck A, 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Ruggles T, Savin A, Smith N, Smith WH, Woods N
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Search for a W ' boson decaying to a tau lepton and a neutrino in proton-proton collisions at root s=13 TeV

PHYSICS LETTERS B 2019 MAY 10; 792(?):107-131
A search for a new high-mass resonance decaying to a tau lepton and a neutrino is reported. The analysis uses proton-proton collision data collected by the CMS experiment at the LHC at root s= 13 TeV, corresponding to an integrated luminosity of 35.9 fb(-1). The search utilizes hadronically decaying tau leptons. No excess in the event yield is observed at high transverse masses of the tau and missing transverse momentum. An interpretation of results within the sequential standard model excludes W' boson masses below 4.0 TeV at 95% confidence level. Existing limits are also improved on models in which the W' boson decays preferentially to fermions of the third generation. Heavy W' bosons with masses less than 1.7-3.9 TeV, depending on the coupling in the non-universal G(221) model, are excluded at 95% confidence level. These are the most stringent limits on this model to date. (C) 2019 The Author(s). Published by Elsevier B.V.
Lama L, Adura C, Xie W, Tomita D, Kamei T, Kuryavyi V, Gogakos T, Steinberg JI, Miller M, Ramos-Espiritu L, Asano Y, Hashizume S, Aida J, Imaeda T, Okamoto R, Jennings AJ, Michino M, Kuroita T, Stamford A, Gao P, Meinke P, Glickman JF, Patel DJ, Tuschl T
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Development of human cGAS-specific small-molecule inhibitors for repression of dsDNA-triggered interferon expression

NATURE COMMUNICATIONS 2019 MAY 21; 10(?):? Article 2261
Cyclic GMP-AMP synthase (cGAS) is the primary sensor for aberrant intracellular dsDNA producing the cyclic dinucleotide cGAMP, a second messenger initiating cytokine production in subsets of myeloid lineage cell types. Therefore, inhibition of the enzyme cGAS may act anti-inflammatory. Here we report the discovery of human-cGAS-specific small-molecule inhibitors by high-throughput screening and the targeted medicinal chemistry optimization for two molecular scaffolds. Lead compounds from one scaffold co-crystallize with human cGAS and occupy the ATP- and GTP-binding active site. The specificity and potency of these drug candidates is further documented in human myeloid cells including primary macrophages. These novel cGAS inhibitors with cell-based activity will serve as probes into cGAS-dependent innate immune pathways and warrant future pharmacological studies for treatment of cGAS-dependent inflammatory diseases.
Weisenburger S, Tejera F, Demas J, Chen B, Manley J, Sparks FT, Traub FM, Daigle T, Zeng HK, Losonczy A, Vaziri A
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Volumetric Ca2+ Imaging in the Mouse Brain Using Hybrid Multiplexed Sculpted Light Microscopy

CELL 2019 MAY 2; 177(4):1050-1066.e14
Calcium imaging using two-photon scanning microscopy has become an essential tool in neuroscience. However, in its typical implementation the tradeoffs between fields of view, acquisition speeds, and depth restrictions in scattering brain tissue pose severe limitations. Here, using an integrated systems-wide optimization approach combined with multiple technical innovations, we introduce a new design paradigm for optical microscopy based on maximizing biological information while maintaining the fidelity of obtained neuron signals. Our modular design utilizes hybrid multi-photon acquisition and allows volumetric recording of neuroactivity at single-cell resolution within up to 1 x 1 x 1.22 mm volumes at up to 17 Hz in awake behaving mice. We establish the capabilities and potential of the different configurations of our imaging system at depth and across brain regions by applying it to in vivo recording of up to 12,000 neurons in mouse auditory cortex, posterior parietal cortex, and hippocampus.