ALBERT

Description: Regulated transcription controls the diversity, developmental pathways and spatial organization of the hundreds of cell types that make up a mammal. Using single-molecule cDNA sequencing, we mapped transcription start sites (TSSs) and their usage in human and mouse primary cells, cell lines and tissues to produce a comprehensive overview of mammalian gene expression across the human body. We find that few genes are truly 'housekeeping', whereas many mammalian promoters are composite entities composed of several closely separated TSSs, with independent cell-type-specific expression profiles. TSSs specific to different cell types evolve at different rates, whereas promoters of broadly expressed genes are the most conserved. Promoter-based expression analysis reveals key transcription factors defining cell states and links them to binding-site motifs. The functions of identified novel transcripts can be predicted by coexpression and sample ontology enrichment analyses. The functional annotation of the mammalian genome 5 (FANTOM5) project provides comprehensive expression profiles and functional annotation of mammalian cell-type-specific transcriptomes with wide applications in biomedical research.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4529748/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4529748/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉FANTOM Consortium and the RIKEN PMI and CLST (DGT) -- Forrest, Alistair R R -- Kawaji, Hideya -- Rehli, Michael -- Baillie, J Kenneth -- de Hoon, Michiel J L -- Haberle, Vanja -- Lassmann, Timo -- Kulakovskiy, Ivan V -- Lizio, Marina -- Itoh, Masayoshi -- Andersson, Robin -- Mungall, Christopher J -- Meehan, Terrence F -- Schmeier, Sebastian -- Bertin, Nicolas -- Jorgensen, Mette -- Dimont, Emmanuel -- Arner, Erik -- Schmidl, Christian -- Schaefer, Ulf -- Medvedeva, Yulia A -- Plessy, Charles -- Vitezic, Morana -- Severin, Jessica -- Semple, Colin A -- Ishizu, Yuri -- Young, Robert S -- Francescatto, Margherita -- Alam, Intikhab -- Albanese, Davide -- Altschuler, Gabriel M -- Arakawa, Takahiro -- Archer, John A C -- Arner, Peter -- Babina, Magda -- Rennie, Sarah -- Balwierz, Piotr J -- Beckhouse, Anthony G -- Pradhan-Bhatt, Swati -- Blake, Judith A -- Blumenthal, Antje -- Bodega, Beatrice -- Bonetti, Alessandro -- Briggs, James -- Brombacher, Frank -- Burroughs, A Maxwell -- Califano, Andrea -- Cannistraci, Carlo V -- Carbajo, Daniel -- Chen, Yun -- Chierici, Marco -- Ciani, Yari -- Clevers, Hans C -- Dalla, Emiliano -- Davis, Carrie A -- Detmar, Michael -- Diehl, Alexander D -- Dohi, Taeko -- Drablos, Finn -- Edge, Albert S B -- Edinger, Matthias -- Ekwall, Karl -- Endoh, Mitsuhiro -- Enomoto, Hideki -- Fagiolini, Michela -- Fairbairn, Lynsey -- Fang, Hai -- Farach-Carson, Mary C -- Faulkner, Geoffrey J -- Favorov, Alexander V -- Fisher, Malcolm E -- Frith, Martin C -- Fujita, Rie -- Fukuda, Shiro -- Furlanello, Cesare -- Furino, Masaaki -- Furusawa, Jun-ichi -- Geijtenbeek, Teunis B -- Gibson, Andrew P -- Gingeras, Thomas -- Goldowitz, Daniel -- Gough, Julian -- Guhl, Sven -- Guler, Reto -- Gustincich, Stefano -- Ha, Thomas J -- Hamaguchi, Masahide -- Hara, Mitsuko -- Harbers, Matthias -- Harshbarger, Jayson -- Hasegawa, Akira -- Hasegawa, Yuki -- Hashimoto, Takehiro -- Herlyn, Meenhard -- Hitchens, Kelly J -- Ho Sui, Shannan J -- Hofmann, Oliver M -- Hoof, Ilka -- Hori, Furni -- Huminiecki, Lukasz -- Iida, Kei -- Ikawa, Tomokatsu -- Jankovic, Boris R -- Jia, Hui -- Joshi, Anagha -- Jurman, Giuseppe -- Kaczkowski, Bogumil -- Kai, Chieko -- Kaida, Kaoru -- Kaiho, Ai -- Kajiyama, Kazuhiro -- Kanamori-Katayama, Mutsumi -- Kasianov, Artem S -- Kasukawa, Takeya -- Katayama, Shintaro -- Kato, Sachi -- Kawaguchi, Shuji -- Kawamoto, Hiroshi -- Kawamura, Yuki I -- Kawashima, Tsugumi -- Kempfle, Judith S -- Kenna, Tony J -- Kere, Juha -- Khachigian, Levon M -- Kitamura, Toshio -- Klinken, S Peter -- Knox, Alan J -- Kojima, Miki -- Kojima, Soichi -- Kondo, Naoto -- Koseki, Haruhiko -- Koyasu, Shigeo -- Krampitz, Sarah -- Kubosaki, Atsutaka -- Kwon, Andrew T -- Laros, Jeroen F J -- Lee, Weonju -- Lennartsson, Andreas -- Li, Kang -- Lilje, Berit -- Lipovich, Leonard -- Mackay-Sim, Alan -- Manabe, Ri-ichiroh -- Mar, Jessica C -- Marchand, Benoit -- Mathelier, Anthony -- Mejhert, Niklas -- Meynert, Alison -- Mizuno, Yosuke -- de Lima Morais, David A -- Morikawa, Hiromasa -- Morimoto, Mitsuru -- Moro, Kazuyo -- Motakis, Efthymios -- Motohashi, Hozumi -- Mummery, Christine L -- Murata, Mitsuyoshi -- Nagao-Sato, Sayaka -- Nakachi, Yutaka -- Nakahara, Fumio -- Nakamura, Toshiyuki -- Nakamura, Yukio -- Nakazato, Kenichi -- van Nimwegen, Erik -- Ninomiya, Noriko -- Nishiyori, Hiromi -- Noma, Shohei -- Noazaki, Tadasuke -- Ogishima, Soichi -- Ohkura, Naganari -- Ohimiya, Hiroko -- Ohno, Hiroshi -- Ohshima, Mitsuhiro -- Okada-Hatakeyama, Mariko -- Okazaki, Yasushi -- Orlando, Valerio -- Ovchinnikov, Dmitry A -- Pain, Arnab -- Passier, Robert -- Patrikakis, Margaret -- Persson, Helena -- Piazza, Silvano -- Prendergast, James G D -- Rackham, Owen J L -- Ramilowski, Jordan A -- Rashid, Mamoon -- Ravasi, Timothy -- Rizzu, Patrizia -- Roncador, Marco -- Roy, Sugata -- Rye, Morten B -- Saijyo, Eri -- Sajantila, Antti -- Saka, Akiko -- Sakaguchi, Shimon -- Sakai, Mizuho -- Sato, Hiroki -- Savvi, Suzana -- Saxena, Alka -- Schneider, Claudio -- Schultes, Erik A -- Schulze-Tanzil, Gundula G -- Schwegmann, Anita -- Sengstag, Thierry -- Sheng, Guojun -- Shimoji, Hisashi -- Shimoni, Yishai -- Shin, Jay W -- Simon, Christophe -- Sugiyama, Daisuke -- Sugiyama, Takaai -- Suzuki, Masanori -- Suzuki, Naoko -- Swoboda, Rolf K -- 't Hoen, Peter A C -- Tagami, Michihira -- Takahashi, Naoko -- Takai, Jun -- Tanaka, Hiroshi -- Tatsukawa, Hideki -- Tatum, Zuotian -- Thompson, Mark -- Toyodo, Hiroo -- Toyoda, Tetsuro -- Valen, Elvind -- van de Wetering, Marc -- van den Berg, Linda M -- Verado, Roberto -- Vijayan, Dipti -- Vorontsov, Ilya E -- Wasserman, Wyeth W -- Watanabe, Shoko -- Wells, Christine A -- Winteringham, Louise N -- Wolvetang, Ernst -- Wood, Emily J -- Yamaguchi, Yoko -- Yamamoto, Masayuki -- Yoneda, Misako -- Yonekura, Yohei -- Yoshida, Shigehiro -- Zabierowski, Susan E -- Zhang, Peter G -- Zhao, Xiaobei -- Zucchelli, Silvia -- Summers, Kim M -- Suzuki, Harukazu -- Daub, Carsten O -- Kawai, Jun -- Heutink, Peter -- Hide, Winston -- Freeman, Tom C -- Lenhard, Boris -- Bajic, Vladimir B -- Taylor, Martin S -- Makeev, Vsevolod J -- Sandelin, Albin -- Hume, David A -- Carninci, Piero -- Hayashizaki, Yoshihide -- BB/F003722/1/Biotechnology and Biological Sciences Research Council/United Kingdom -- BB/G022771/1/Biotechnology and Biological Sciences Research Council/United Kingdom -- BB/I001107/1/Biotechnology and Biological Sciences Research Council/United Kingdom -- MC_PC_U127597124/Medical Research Council/United Kingdom -- MC_UP_1102/1/Medical Research Council/United Kingdom -- R01 DE022969/DE/NIDCR NIH HHS/ -- R01 GM084875/GM/NIGMS NIH HHS/ -- England -- Nature. 2014 Mar 27;507(7493):462-70. doi: 10.1038/nature13182.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24670764" target="_blank"〉PubMed〈/a〉

Description: A20 is a negative regulator of the NF-kappaB pathway and was initially identified as being rapidly induced after tumour-necrosis factor-alpha stimulation. It has a pivotal role in regulation of the immune response and prevents excessive activation of NF-kappaB in response to a variety of external stimuli; recent genetic studies have disclosed putative associations of polymorphic A20 (also called TNFAIP3) alleles with autoimmune disease risk. However, the involvement of A20 in the development of human cancers is unknown. Here we show, using a genome-wide analysis of genetic lesions in 238 B-cell lymphomas, that A20 is a common genetic target in B-lineage lymphomas. A20 is frequently inactivated by somatic mutations and/or deletions in mucosa-associated tissue lymphoma (18 out of 87; 21.8%) and Hodgkin's lymphoma of nodular sclerosis histology (5 out of 15; 33.3%), and, to a lesser extent, in other B-lineage lymphomas. When re-expressed in a lymphoma-derived cell line with no functional A20 alleles, wild-type A20, but not mutant A20, resulted in suppression of cell growth and induction of apoptosis, accompanied by downregulation of NF-kappaB activation. The A20-deficient cells stably generated tumours in immunodeficient mice, whereas the tumorigenicity was effectively suppressed by re-expression of A20. In A20-deficient cells, suppression of both cell growth and NF-kappaB activity due to re-expression of A20 depended, at least partly, on cell-surface-receptor signalling, including the tumour-necrosis factor receptor. Considering the physiological function of A20 in the negative modulation of NF-kappaB activation induced by multiple upstream stimuli, our findings indicate that uncontrolled signalling of NF-kappaB caused by loss of A20 function is involved in the pathogenesis of subsets of B-lineage lymphomas.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kato, Motohiro -- Sanada, Masashi -- Kato, Itaru -- Sato, Yasuharu -- Takita, Junko -- Takeuchi, Kengo -- Niwa, Akira -- Chen, Yuyan -- Nakazaki, Kumi -- Nomoto, Junko -- Asakura, Yoshitaka -- Muto, Satsuki -- Tamura, Azusa -- Iio, Mitsuru -- Akatsuka, Yoshiki -- Hayashi, Yasuhide -- Mori, Hiraku -- Igarashi, Takashi -- Kurokawa, Mineo -- Chiba, Shigeru -- Mori, Shigeo -- Ishikawa, Yuichi -- Okamoto, Koji -- Tobinai, Kensei -- Nakagama, Hitoshi -- Nakahata, Tatsutoshi -- Yoshino, Tadashi -- Kobayashi, Yukio -- Ogawa, Seishi -- England -- Nature. 2009 Jun 4;459(7247):712-6. doi: 10.1038/nature07969. Epub 2009 May 3.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Cancer Genomics Project, Department of Pediatrics, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19412163" target="_blank"〉PubMed〈/a〉

Description: Influenza A viruses cause recurrent outbreaks at local or global scale with potentially severe consequences for human health and the global economy. Recently, a new strain of influenza A virus was detected that causes disease in and transmits among humans, probably owing to little or no pre-existing immunity to the new strain. On 11 June 2009 the World Health Organization declared that the infections caused by the new strain had reached pandemic proportion. Characterized as an influenza A virus of the H1N1 subtype, the genomic segments of the new strain were most closely related to swine viruses. Most human infections with swine-origin H1N1 influenza viruses (S-OIVs) seem to be mild; however, a substantial number of hospitalized individuals do not have underlying health issues, attesting to the pathogenic potential of S-OIVs. To achieve a better assessment of the risk posed by the new virus, we characterized one of the first US S-OIV isolates, A/California/04/09 (H1N1; hereafter referred to as CA04), as well as several other S-OIV isolates, in vitro and in vivo. In mice and ferrets, CA04 and other S-OIV isolates tested replicate more efficiently than a currently circulating human H1N1 virus. In addition, CA04 replicates efficiently in non-human primates, causes more severe pathological lesions in the lungs of infected mice, ferrets and non-human primates than a currently circulating human H1N1 virus, and transmits among ferrets. In specific-pathogen-free miniature pigs, CA04 replicates without clinical symptoms. The assessment of human sera from different age groups suggests that infection with human H1N1 viruses antigenically closely related to viruses circulating in 1918 confers neutralizing antibody activity to CA04. Finally, we show that CA04 is sensitive to approved and experimental antiviral drugs, suggesting that these compounds could function as a first line of defence against the recently declared S-OIV pandemic.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2748827/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2748827/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Itoh, Yasushi -- Shinya, Kyoko -- Kiso, Maki -- Watanabe, Tokiko -- Sakoda, Yoshihiro -- Hatta, Masato -- Muramoto, Yukiko -- Tamura, Daisuke -- Sakai-Tagawa, Yuko -- Noda, Takeshi -- Sakabe, Saori -- Imai, Masaki -- Hatta, Yasuko -- Watanabe, Shinji -- Li, Chengjun -- Yamada, Shinya -- Fujii, Ken -- Murakami, Shin -- Imai, Hirotaka -- Kakugawa, Satoshi -- Ito, Mutsumi -- Takano, Ryo -- Iwatsuki-Horimoto, Kiyoko -- Shimojima, Masayuki -- Horimoto, Taisuke -- Goto, Hideo -- Takahashi, Kei -- Makino, Akiko -- Ishigaki, Hirohito -- Nakayama, Misako -- Okamatsu, Masatoshi -- Takahashi, Kazuo -- Warshauer, David -- Shult, Peter A -- Saito, Reiko -- Suzuki, Hiroshi -- Furuta, Yousuke -- Yamashita, Makoto -- Mitamura, Keiko -- Nakano, Kunio -- Nakamura, Morio -- Brockman-Schneider, Rebecca -- Mitamura, Hiroshi -- Yamazaki, Masahiko -- Sugaya, Norio -- Suresh, M -- Ozawa, Makoto -- Neumann, Gabriele -- Gern, James -- Kida, Hiroshi -- Ogasawara, Kazumasa -- Kawaoka, Yoshihiro -- HHNSN266200700010C/NS/NINDS NIH HHS/ -- HHSN266200700010C/PHS HHS/ -- HHSN272200800060C/AI/NIAID NIH HHS/ -- R01 AI069274/AI/NIAID NIH HHS/ -- R01 AI069274-04/AI/NIAID NIH HHS/ -- U19 AI070503/AI/NIAID NIH HHS/ -- England -- Nature. 2009 Aug 20;460(7258):1021-5. doi: 10.1038/nature08260.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Pathology, Shiga University of Medical Science, Ohtsu, Shiga 520-2192, Japan.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19672242" target="_blank"〉PubMed〈/a〉

Description: Plasma concentrations of total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and triglycerides are among the most important risk factors for coronary artery disease (CAD) and are targets for therapeutic intervention. We screened the genome for common variants associated with plasma lipids in 〉100,000 individuals of European ancestry. Here we report 95 significantly associated loci (P 〈 5 x 10(-8)), with 59 showing genome-wide significant association with lipid traits for the first time. The newly reported associations include single nucleotide polymorphisms (SNPs) near known lipid regulators (for example, CYP7A1, NPC1L1 and SCARB1) as well as in scores of loci not previously implicated in lipoprotein metabolism. The 95 loci contribute not only to normal variation in lipid traits but also to extreme lipid phenotypes and have an impact on lipid traits in three non-European populations (East Asians, South Asians and African Americans). Our results identify several novel loci associated with plasma lipids that are also associated with CAD. Finally, we validated three of the novel genes-GALNT2, PPP1R3B and TTC39B-with experiments in mouse models. Taken together, our findings provide the foundation to develop a broader biological understanding of lipoprotein metabolism and to identify new therapeutic opportunities for the prevention of CAD.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3039276/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3039276/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Teslovich, Tanya M -- Musunuru, Kiran -- Smith, Albert V -- Edmondson, Andrew C -- Stylianou, Ioannis M -- Koseki, Masahiro -- Pirruccello, James P -- Ripatti, Samuli -- Chasman, Daniel I -- Willer, Cristen J -- Johansen, Christopher T -- Fouchier, Sigrid W -- Isaacs, Aaron -- Peloso, Gina M -- Barbalic, Maja -- Ricketts, Sally L -- Bis, Joshua C -- Aulchenko, Yurii S -- Thorleifsson, Gudmar -- Feitosa, Mary F -- Chambers, John -- Orho-Melander, Marju -- Melander, Olle -- Johnson, Toby -- Li, Xiaohui -- Guo, Xiuqing -- Li, Mingyao -- Shin Cho, Yoon -- Jin Go, Min -- Jin Kim, Young -- Lee, Jong-Young -- Park, Taesung -- Kim, Kyunga -- Sim, Xueling -- Twee-Hee Ong, Rick -- Croteau-Chonka, Damien C -- Lange, Leslie A -- Smith, Joshua D -- Song, Kijoung -- Hua Zhao, Jing -- Yuan, Xin -- Luan, Jian'an -- Lamina, Claudia -- Ziegler, Andreas -- Zhang, Weihua -- Zee, Robert Y L -- Wright, Alan F -- Witteman, Jacqueline C M -- Wilson, James F -- Willemsen, Gonneke -- Wichmann, H-Erich -- Whitfield, John B -- Waterworth, Dawn M -- Wareham, Nicholas J -- Waeber, Gerard -- Vollenweider, Peter -- Voight, Benjamin F -- Vitart, Veronique -- Uitterlinden, Andre G -- Uda, Manuela -- Tuomilehto, Jaakko -- Thompson, John R -- Tanaka, Toshiko -- Surakka, Ida -- Stringham, Heather M -- Spector, Tim D -- Soranzo, Nicole -- Smit, Johannes H -- Sinisalo, Juha -- Silander, Kaisa -- Sijbrands, Eric J G -- Scuteri, Angelo -- Scott, James -- Schlessinger, David -- Sanna, Serena -- Salomaa, Veikko -- Saharinen, Juha -- Sabatti, Chiara -- Ruokonen, Aimo -- Rudan, Igor -- Rose, Lynda M -- Roberts, Robert -- Rieder, Mark -- Psaty, Bruce M -- Pramstaller, Peter P -- Pichler, Irene -- Perola, Markus -- Penninx, Brenda W J H -- Pedersen, Nancy L -- Pattaro, Cristian -- Parker, Alex N -- Pare, Guillaume -- Oostra, Ben A -- O'Donnell, Christopher J -- Nieminen, Markku S -- Nickerson, Deborah A -- Montgomery, Grant W -- Meitinger, Thomas -- McPherson, Ruth -- McCarthy, Mark I -- McArdle, Wendy -- Masson, David -- Martin, Nicholas G -- Marroni, Fabio -- Mangino, Massimo -- Magnusson, Patrik K E -- Lucas, Gavin -- Luben, Robert -- Loos, Ruth J F -- Lokki, Marja-Liisa -- Lettre, Guillaume -- Langenberg, Claudia -- Launer, Lenore J -- Lakatta, Edward G -- Laaksonen, Reijo -- Kyvik, Kirsten O -- Kronenberg, Florian -- Konig, Inke R -- Khaw, Kay-Tee -- Kaprio, Jaakko -- Kaplan, Lee M -- Johansson, Asa -- Jarvelin, Marjo-Riitta -- Janssens, A Cecile J W -- Ingelsson, Erik -- Igl, Wilmar -- Kees Hovingh, G -- Hottenga, Jouke-Jan -- Hofman, Albert -- Hicks, Andrew A -- Hengstenberg, Christian -- Heid, Iris M -- Hayward, Caroline -- Havulinna, Aki S -- Hastie, Nicholas D -- Harris, Tamara B -- Haritunians, Talin -- Hall, Alistair S -- Gyllensten, Ulf -- Guiducci, Candace -- Groop, Leif C -- Gonzalez, Elena -- Gieger, Christian -- Freimer, Nelson B -- Ferrucci, Luigi -- Erdmann, Jeanette -- Elliott, Paul -- Ejebe, Kenechi G -- Doring, Angela -- Dominiczak, Anna F -- Demissie, Serkalem -- Deloukas, Panagiotis -- de Geus, Eco J C -- de Faire, Ulf -- Crawford, Gabriel -- Collins, Francis S -- Chen, Yii-der I -- Caulfield, Mark J -- Campbell, Harry -- Burtt, Noel P -- Bonnycastle, Lori L -- Boomsma, Dorret I -- Boekholdt, S Matthijs -- Bergman, Richard N -- Barroso, Ines -- Bandinelli, Stefania -- Ballantyne, Christie M -- Assimes, Themistocles L -- Quertermous, Thomas -- Altshuler, David -- Seielstad, Mark -- Wong, Tien Y -- Tai, E-Shyong -- Feranil, Alan B -- Kuzawa, Christopher W -- Adair, Linda S -- Taylor, Herman A Jr -- Borecki, Ingrid B -- Gabriel, Stacey B -- Wilson, James G -- Holm, Hilma -- Thorsteinsdottir, Unnur -- Gudnason, Vilmundur -- Krauss, Ronald M -- Mohlke, Karen L -- Ordovas, Jose M -- Munroe, Patricia B -- Kooner, Jaspal S -- Tall, Alan R -- Hegele, Robert A -- Kastelein, John J P -- Schadt, Eric E -- Rotter, Jerome I -- Boerwinkle, Eric -- Strachan, David P -- Mooser, Vincent -- Stefansson, Kari -- Reilly, Muredach P -- Samani, Nilesh J -- Schunkert, Heribert -- Cupples, L Adrienne -- Sandhu, Manjinder S -- Ridker, Paul M -- Rader, Daniel J -- van Duijn, Cornelia M -- Peltonen, Leena -- Abecasis, Goncalo R -- Boehnke, Michael -- Kathiresan, Sekar -- 068545/Z/02/Wellcome Trust/United Kingdom -- 076113/B/04/Z/Wellcome Trust/United Kingdom -- 077016/Z/05/Z/Wellcome Trust/United Kingdom -- 079895/Wellcome Trust/United Kingdom -- 1Z01 HG000024/HG/NHGRI NIH HHS/ -- 5R01DK06833603/DK/NIDDK NIH HHS/ -- 5R01DK07568102/DK/NIDDK NIH HHS/ -- 5R01HL087679-02/HL/NHLBI NIH HHS/ -- 5R01HL08770003/HL/NHLBI NIH HHS/ -- 5R01HL08821502/HL/NHLBI NIH HHS/ -- CA 047988/CA/NCI NIH HHS/ -- CZB/4/710/Chief Scientist Office/United Kingdom -- DK062370/DK/NIDDK NIH HHS/ -- DK063491/DK/NIDDK NIH HHS/ -- DK072193/DK/NIDDK NIH HHS/ -- DK078150/DK/NIDDK NIH HHS/ -- DK56350/DK/NIDDK NIH HHS/ -- ES10126/ES/NIEHS NIH HHS/ -- G0000934/Medical Research Council/United Kingdom -- G0401527/Medical Research Council/United Kingdom -- G0601966/Medical Research Council/United Kingdom -- G0700931/Medical Research Council/United Kingdom -- G0701863/Medical Research Council/United Kingdom -- G0801056/Medical Research Council/United Kingdom -- G0801566/Medical Research Council/United Kingdom -- G9521010/Medical Research Council/United Kingdom -- G9521010D/Medical Research Council/United Kingdom -- HHSN268200625226C/PHS HHS/ -- HL 04381/HL/NHLBI NIH HHS/ -- HL 080467/HL/NHLBI NIH HHS/ -- HL-54776/HL/NHLBI NIH HHS/ -- HL085144/HL/NHLBI NIH HHS/ -- K99 HL098364/HL/NHLBI NIH HHS/ -- K99 HL098364-01/HL/NHLBI NIH HHS/ -- K99HL094535/HL/NHLBI NIH HHS/ -- M01-RR00425/RR/NCRR NIH HHS/ -- MC_QA137934/Medical Research Council/United Kingdom -- MC_U106179471/Medical Research Council/United Kingdom -- MC_U106188470/Medical Research Council/United Kingdom -- MC_U127561128/Medical Research Council/United Kingdom -- N01 HC-15103/HC/NHLBI NIH HHS/ -- N01 HC-55222/HC/NHLBI NIH HHS/ -- N01-AG-12100/AG/NIA NIH HHS/ -- N01-HC-25195/HC/NHLBI NIH HHS/ -- N01-HC-35129/HC/NHLBI NIH HHS/ -- N01-HC-45133/HC/NHLBI NIH HHS/ -- N01-HC-55015/HC/NHLBI NIH HHS/ -- N01-HC-55016/HC/NHLBI NIH HHS/ -- N01-HC-55018/HC/NHLBI NIH HHS/ -- N01-HC-55019/HC/NHLBI NIH HHS/ -- N01-HC-55020/HC/NHLBI NIH HHS/ -- N01-HC-55021/HC/NHLBI NIH HHS/ -- N01-HC-55022/HC/NHLBI NIH HHS/ -- N01-HC-75150/HC/NHLBI NIH HHS/ -- N01-HC-85079/HC/NHLBI NIH HHS/ -- N01-HC-85080/HC/NHLBI NIH HHS/ -- N01-HC-85081/HC/NHLBI NIH HHS/ -- N01-HC-85082/HC/NHLBI NIH HHS/ -- N01-HC-85083/HC/NHLBI NIH HHS/ -- N01-HC-85084/HC/NHLBI NIH HHS/ -- N01-HC-85085/HC/NHLBI NIH HHS/ -- N01-HC-85086/HC/NHLBI NIH HHS/ -- N01-HG-65403/HG/NHGRI NIH HHS/ -- N02-HL-6-4278/HL/NHLBI NIH HHS/ -- PG/02/128/British Heart Foundation/United Kingdom -- PG/08/094/British Heart Foundation/United Kingdom -- PG/08/094/26019/British Heart Foundation/United Kingdom -- R01 DK072193/DK/NIDDK NIH HHS/ -- R01 DK078150/DK/NIDDK NIH HHS/ -- R01 HL087647/HL/NHLBI NIH HHS/ -- R01 HL087676/HL/NHLBI NIH HHS/ -- R01 HL089650/HL/NHLBI NIH HHS/ -- R01HL086694/HL/NHLBI NIH HHS/ -- R01HL087641/HL/NHLBI NIH HHS/ -- R01HL087652/HL/NHLBI NIH HHS/ -- R01HL59367/HL/NHLBI NIH HHS/ -- R24 HD050924/HD/NICHD NIH HHS/ -- RC1 HL099634/HL/NHLBI NIH HHS/ -- RC1 HL099634-02/HL/NHLBI NIH HHS/ -- RC1 HL099793/HL/NHLBI NIH HHS/ -- RC2 HL101864,/HL/NHLBI NIH HHS/ -- RC2 HL102419/HL/NHLBI NIH HHS/ -- RG/07/005/23633/British Heart Foundation/United Kingdom -- RR20649/RR/NCRR NIH HHS/ -- SP/08/005/25115/British Heart Foundation/United Kingdom -- T32 GM007092/GM/NIGMS NIH HHS/ -- T32 HG00040/HG/NHGRI NIH HHS/ -- T32HL007208/HL/NHLBI NIH HHS/ -- TW05596/TW/FIC NIH HHS/ -- U01 DK062370/DK/NIDDK NIH HHS/ -- U01 DK062418/DK/NIDDK NIH HHS/ -- U01 HL069757/HL/NHLBI NIH HHS/ -- U01 HL080295/HL/NHLBI NIH HHS/ -- U01HG004402/HG/NHGRI NIH HHS/ -- U54 RR020278/RR/NCRR NIH HHS/ -- UL1RR025005/RR/NCRR NIH HHS/ -- Intramural NIH HHS/ -- England -- Nature. 2010 Aug 5;466(7307):707-13. doi: 10.1038/nature09270.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Center for Statistical Genetics, Department of Biostatistics, University of Michigan, Ann Arbor, Michigan 48109, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20686565" target="_blank"〉PubMed〈/a〉

Description: Avian influenza A viruses rarely infect humans; however, when human infection and subsequent human-to-human transmission occurs, worldwide outbreaks (pandemics) can result. The recent sporadic infections of humans in China with a previously unrecognized avian influenza A virus of the H7N9 subtype (A(H7N9)) have caused concern owing to the appreciable case fatality rate associated with these infections (more than 25%), potential instances of human-to-human transmission, and the lack of pre-existing immunity among humans to viruses of this subtype. Here we characterize two early human A(H7N9) isolates, A/Anhui/1/2013 (H7N9) and A/Shanghai/1/2013 (H7N9); hereafter referred to as Anhui/1 and Shanghai/1, respectively. In mice, Anhui/1 and Shanghai/1 were more pathogenic than a control avian H7N9 virus (A/duck/Gunma/466/2011 (H7N9); Dk/GM466) and a representative pandemic 2009 H1N1 virus (A/California/4/2009 (H1N1pdm09); CA04). Anhui/1, Shanghai/1 and Dk/GM466 replicated well in the nasal turbinates of ferrets. In nonhuman primates, Anhui/1 and Dk/GM466 replicated efficiently in the upper and lower respiratory tracts, whereas the replicative ability of conventional human influenza viruses is typically restricted to the upper respiratory tract of infected primates. By contrast, Anhui/1 did not replicate well in miniature pigs after intranasal inoculation. Critically, Anhui/1 transmitted through respiratory droplets in one of three pairs of ferrets. Glycan arrays showed that Anhui/1, Shanghai/1 and A/Hangzhou/1/2013 (H7N9) (a third human A(H7N9) virus tested in this assay) bind to human virus-type receptors, a property that may be critical for virus transmissibility in ferrets. Anhui/1 was found to be less sensitive in mice to neuraminidase inhibitors than a pandemic H1N1 2009 virus, although both viruses were equally susceptible to an experimental antiviral polymerase inhibitor. The robust replicative ability in mice, ferrets and nonhuman primates and the limited transmissibility in ferrets of Anhui/1 suggest that A(H7N9) viruses have pandemic potential.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3891892/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3891892/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Watanabe, Tokiko -- Kiso, Maki -- Fukuyama, Satoshi -- Nakajima, Noriko -- Imai, Masaki -- Yamada, Shinya -- Murakami, Shin -- Yamayoshi, Seiya -- Iwatsuki-Horimoto, Kiyoko -- Sakoda, Yoshihiro -- Takashita, Emi -- McBride, Ryan -- Noda, Takeshi -- Hatta, Masato -- Imai, Hirotaka -- Zhao, Dongming -- Kishida, Noriko -- Shirakura, Masayuki -- de Vries, Robert P -- Shichinohe, Shintaro -- Okamatsu, Masatoshi -- Tamura, Tomokazu -- Tomita, Yuriko -- Fujimoto, Naomi -- Goto, Kazue -- Katsura, Hiroaki -- Kawakami, Eiryo -- Ishikawa, Izumi -- Watanabe, Shinji -- Ito, Mutsumi -- Sakai-Tagawa, Yuko -- Sugita, Yukihiko -- Uraki, Ryuta -- Yamaji, Reina -- Eisfeld, Amie J -- Zhong, Gongxun -- Fan, Shufang -- Ping, Jihui -- Maher, Eileen A -- Hanson, Anthony -- Uchida, Yuko -- Saito, Takehiko -- Ozawa, Makoto -- Neumann, Gabriele -- Kida, Hiroshi -- Odagiri, Takato -- Paulson, James C -- Hasegawa, Hideki -- Tashiro, Masato -- Kawaoka, Yoshihiro -- AI058113/AI/NIAID NIH HHS/ -- AI099274/AI/NIAID NIH HHS/ -- HHSN266200700010C/AI/NIAID NIH HHS/ -- HHSN266200700010C/PHS HHS/ -- T32 AI078985/AI/NIAID NIH HHS/ -- England -- Nature. 2013 Sep 26;501(7468):551-5. doi: 10.1038/nature12392. Epub 2013 Jul 10.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉ERATO Infection-Induced Host Responses Project, Japan Science and Technology Agency, Saitama 332-0012, Japan.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23842494" target="_blank"〉PubMed〈/a〉

Description: Targeted therapies have demonstrated efficacy against specific subsets of molecularly defined cancers. Although most patients with lung cancer are stratified according to a single oncogenic driver, cancers harbouring identical activating genetic mutations show large variations in their responses to the same targeted therapy. The biology underlying this heterogeneity is not well understood, and the impact of co-existing genetic mutations, especially the loss of tumour suppressors, has not been fully explored. Here we use genetically engineered mouse models to conduct a 'co-clinical' trial that mirrors an ongoing human clinical trial in patients with KRAS-mutant lung cancers. This trial aims to determine if the MEK inhibitor selumetinib (AZD6244) increases the efficacy of docetaxel, a standard of care chemotherapy. Our studies demonstrate that concomitant loss of either p53 (also known as Tp53) or Lkb1 (also known as Stk11), two clinically relevant tumour suppressors, markedly impaired the response of Kras-mutant cancers to docetaxel monotherapy. We observed that the addition of selumetinib provided substantial benefit for mice with lung cancer caused by Kras and Kras and p53 mutations, but mice with Kras and Lkb1 mutations had primary resistance to this combination therapy. Pharmacodynamic studies, including positron-emission tomography (PET) and computed tomography (CT), identified biological markers in mice and patients that provide a rationale for the differential efficacy of these therapies in the different genotypes. These co-clinical results identify predictive genetic biomarkers that should be validated by interrogating samples from patients enrolled on the concurrent clinical trial. These studies also highlight the rationale for synchronous co-clinical trials, not only to anticipate the results of ongoing human clinical trials, but also to generate clinically relevant hypotheses that can inform the analysis and design of human studies.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3385933/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3385933/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Chen, Zhao -- Cheng, Katherine -- Walton, Zandra -- Wang, Yuchuan -- Ebi, Hiromichi -- Shimamura, Takeshi -- Liu, Yan -- Tupper, Tanya -- Ouyang, Jing -- Li, Jie -- Gao, Peng -- Woo, Michele S -- Xu, Chunxiao -- Yanagita, Masahiko -- Altabef, Abigail -- Wang, Shumei -- Lee, Charles -- Nakada, Yuji -- Pena, Christopher G -- Sun, Yanping -- Franchetti, Yoko -- Yao, Catherine -- Saur, Amy -- Cameron, Michael D -- Nishino, Mizuki -- Hayes, D Neil -- Wilkerson, Matthew D -- Roberts, Patrick J -- Lee, Carrie B -- Bardeesy, Nabeel -- Butaney, Mohit -- Chirieac, Lucian R -- Costa, Daniel B -- Jackman, David -- Sharpless, Norman E -- Castrillon, Diego H -- Demetri, George D -- Janne, Pasi A -- Pandolfi, Pier Paolo -- Cantley, Lewis C -- Kung, Andrew L -- Engelman, Jeffrey A -- Wong, Kwok-Kin -- 1U01CA141576/CA/NCI NIH HHS/ -- CA122794/CA/NCI NIH HHS/ -- CA137008/CA/NCI NIH HHS/ -- CA137008-01/CA/NCI NIH HHS/ -- CA137181/CA/NCI NIH HHS/ -- CA140594/CA/NCI NIH HHS/ -- CA147940/CA/NCI NIH HHS/ -- K23 CA157631/CA/NCI NIH HHS/ -- P01 CA120964/CA/NCI NIH HHS/ -- P30 CA016086/CA/NCI NIH HHS/ -- P50 CA090578/CA/NCI NIH HHS/ -- P50 CA090578-06/CA/NCI NIH HHS/ -- P50CA090578/CA/NCI NIH HHS/ -- R01 CA122794/CA/NCI NIH HHS/ -- R01 CA122794-01/CA/NCI NIH HHS/ -- R01 CA137008/CA/NCI NIH HHS/ -- R01 CA137008-01/CA/NCI NIH HHS/ -- R01 CA137181/CA/NCI NIH HHS/ -- R01 CA137181-01A2/CA/NCI NIH HHS/ -- R01 CA140594/CA/NCI NIH HHS/ -- R01 CA140594-01/CA/NCI NIH HHS/ -- R01 CA163896/CA/NCI NIH HHS/ -- RC2 CA147940/CA/NCI NIH HHS/ -- RC2 CA147940-01/CA/NCI NIH HHS/ -- U01 CA141576/CA/NCI NIH HHS/ -- U01 CA141576-01/CA/NCI NIH HHS/ -- England -- Nature. 2012 Mar 18;483(7391):613-7. doi: 10.1038/nature10937.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22425996" target="_blank"〉PubMed〈/a〉

Description: Although the question of to whom a male directs his mating attempts is a critical one in social interactions, little is known about the molecular and cellular mechanisms controlling mammalian sexual preference. Here we report that the neurotransmitter 5-hydroxytryptamine (5-HT) is required for male sexual preference. Wild-type male mice preferred females over males, but males lacking central serotonergic neurons lost sexual preference although they were not generally defective in olfaction or in pheromone sensing. A role for 5-HT was demonstrated by the phenotype of mice lacking tryptophan hydroxylase 2 (Tph2), which is required for the first step of 5-HT synthesis in the brain. Thirty-five minutes after the injection of the intermediate 5-hydroxytryptophan (5-HTP), which circumvented Tph2 to restore 5-HT to the wild-type level, adult Tph2 knockout mice also preferred females over males. These results indicate that 5-HT and serotonergic neurons in the adult brain regulate mammalian sexual preference.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4094133/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4094133/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Liu, Yan -- Jiang, Yun'ai -- Si, Yunxia -- Kim, Ji-Young -- Chen, Zhou-Feng -- Rao, Yi -- R01 AR056318/AR/NIAMS NIH HHS/ -- England -- Nature. 2011 Apr 7;472(7341):95-9. doi: 10.1038/nature09822. Epub 2011 Mar 23.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉National Institute of Biological Sciences, Beijing 102206, China.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21441904" target="_blank"〉PubMed〈/a〉

Description: G-protein-coupled receptors (GPCRs) signal primarily through G proteins or arrestins. Arrestin binding to GPCRs blocks G protein interaction and redirects signalling to numerous G-protein-independent pathways. Here we report the crystal structure of a constitutively active form of human rhodopsin bound to a pre-activated form of the mouse visual arrestin, determined by serial femtosecond X-ray laser crystallography. Together with extensive biochemical and mutagenesis data, the structure reveals an overall architecture of the rhodopsin-arrestin assembly in which rhodopsin uses distinct structural elements, including transmembrane helix 7 and helix 8, to recruit arrestin. Correspondingly, arrestin adopts the pre-activated conformation, with a approximately 20 degrees rotation between the amino and carboxy domains, which opens up a cleft in arrestin to accommodate a short helix formed by the second intracellular loop of rhodopsin. This structure provides a basis for understanding GPCR-mediated arrestin-biased signalling and demonstrates the power of X-ray lasers for advancing the frontiers of structural biology.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4521999/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4521999/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kang, Yanyong -- Zhou, X Edward -- Gao, Xiang -- He, Yuanzheng -- Liu, Wei -- Ishchenko, Andrii -- Barty, Anton -- White, Thomas A -- Yefanov, Oleksandr -- Han, Gye Won -- Xu, Qingping -- de Waal, Parker W -- Ke, Jiyuan -- Tan, M H Eileen -- Zhang, Chenghai -- Moeller, Arne -- West, Graham M -- Pascal, Bruce D -- Van Eps, Ned -- Caro, Lydia N -- Vishnivetskiy, Sergey A -- Lee, Regina J -- Suino-Powell, Kelly M -- Gu, Xin -- Pal, Kuntal -- Ma, Jinming -- Zhi, Xiaoyong -- Boutet, Sebastien -- Williams, Garth J -- Messerschmidt, Marc -- Gati, Cornelius -- Zatsepin, Nadia A -- Wang, Dingjie -- James, Daniel -- Basu, Shibom -- Roy-Chowdhury, Shatabdi -- Conrad, Chelsie E -- Coe, Jesse -- Liu, Haiguang -- Lisova, Stella -- Kupitz, Christopher -- Grotjohann, Ingo -- Fromme, Raimund -- Jiang, Yi -- Tan, Minjia -- Yang, Huaiyu -- Li, Jun -- Wang, Meitian -- Zheng, Zhong -- Li, Dianfan -- Howe, Nicole -- Zhao, Yingming -- Standfuss, Jorg -- Diederichs, Kay -- Dong, Yuhui -- Potter, Clinton S -- Carragher, Bridget -- Caffrey, Martin -- Jiang, Hualiang -- Chapman, Henry N -- Spence, John C H -- Fromme, Petra -- Weierstall, Uwe -- Ernst, Oliver P -- Katritch, Vsevolod -- Gurevich, Vsevolod V -- Griffin, Patrick R -- Hubbell, Wayne L -- Stevens, Raymond C -- Cherezov, Vadim -- Melcher, Karsten -- Xu, H Eric -- DK071662/DK/NIDDK NIH HHS/ -- EY005216/EY/NEI NIH HHS/ -- EY011500/EY/NEI NIH HHS/ -- GM073197/GM/NIGMS NIH HHS/ -- GM077561/GM/NIGMS NIH HHS/ -- GM095583/GM/NIGMS NIH HHS/ -- GM097463/GM/NIGMS NIH HHS/ -- GM102545/GM/NIGMS NIH HHS/ -- GM103310/GM/NIGMS NIH HHS/ -- GM104212/GM/NIGMS NIH HHS/ -- GM108635/GM/NIGMS NIH HHS/ -- P30EY000331/EY/NEI NIH HHS/ -- P41 GM103310/GM/NIGMS NIH HHS/ -- P41GM103393/GM/NIGMS NIH HHS/ -- P41RR001209/RR/NCRR NIH HHS/ -- P50 GM073197/GM/NIGMS NIH HHS/ -- P50 GM073210/GM/NIGMS NIH HHS/ -- R01 DK066202/DK/NIDDK NIH HHS/ -- R01 DK071662/DK/NIDDK NIH HHS/ -- R01 EY011500/EY/NEI NIH HHS/ -- R01 GM087413/GM/NIGMS NIH HHS/ -- R01 GM109955/GM/NIGMS NIH HHS/ -- S10 RR027270/RR/NCRR NIH HHS/ -- U54 GM094586/GM/NIGMS NIH HHS/ -- U54 GM094599/GM/NIGMS NIH HHS/ -- U54 GM094618/GM/NIGMS NIH HHS/ -- England -- Nature. 2015 Jul 30;523(7562):561-7. doi: 10.1038/nature14656. Epub 2015 Jul 22.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Laboratory of Structural Sciences, Center for Structural Biology and Drug Discovery, Van Andel Research Institute, Grand Rapids, Michigan 49503, USA. ; Department of Chemistry and Biochemistry, and Center for Applied Structural Discovery, Biodesign Institute, Arizona State University, Tempe, Arizona 85287-1604, USA. ; Department of Chemistry, Bridge Institute, University of Southern California, Los Angeles, California 90089, USA. ; Center for Free Electron Laser Science, Deutsches Elektronen-Synchrotron DESY, 22607 Hamburg, Germany. ; Joint Center for Structural Genomics, Stanford Synchrotron Radiation Lightsource, SLAC National Accelerator Laboratory, Menlo Park, California 94025, USA. ; 1] Laboratory of Structural Sciences, Center for Structural Biology and Drug Discovery, Van Andel Research Institute, Grand Rapids, Michigan 49503, USA [2] Department of Obstetrics &Gynecology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore. ; The National Resource for Automated Molecular Microscopy, New York Structural Biology Center, New York, New York 10027, USA. ; Department of Molecular Therapeutics, The Scripps Research Institute, Scripps Florida, Jupiter, Florida 33458, USA. ; Jules Stein Eye Institute and Department of Chemistry and Biochemistry, University of California, Los Angeles, California 90095, USA. ; Department of Biochemistry, University of Toronto, Toronto, Ontario M5S 1A8, Canada. ; Department of Pharmacology, Vanderbilt University, Nashville, Tennessee 37232, USA. ; Linac Coherent Light Source (LCLS), SLAC National Accelerator Laboratory, Menlo Park, California 94025, USA. ; 1] Linac Coherent Light Source (LCLS), SLAC National Accelerator Laboratory, Menlo Park, California 94025, USA [2] BioXFEL, NSF Science and Technology Center, 700 Ellicott Street, Buffalo, New York 14203, USA. ; 1] Department of Chemistry and Biochemistry, and Center for Applied Structural Discovery, Biodesign Institute, Arizona State University, Tempe, Arizona 85287-1604, USA [2] Department of Physics, Arizona State University, Tempe, Arizona 85287, USA. ; 1] Department of Chemistry and Biochemistry, and Center for Applied Structural Discovery, Biodesign Institute, Arizona State University, Tempe, Arizona 85287-1604, USA [2] Beijing Computational Science Research Center, Haidian District, Beijing 10084, China. ; 1] Department of Chemistry and Biochemistry, and Center for Applied Structural Discovery, Biodesign Institute, Arizona State University, Tempe, Arizona 85287-1604, USA [2] Department of Physics, University of Wisconsin-Milwaukee, Milwaukee, Wisconsin 53211, USA. ; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China. ; Department of Obstetrics &Gynecology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore. ; Swiss Light Source at Paul Scherrer Institute, CH-5232 Villigen, Switzerland. ; Department of Biological Sciences, Bridge Institute, University of Southern California, Los Angeles, California 90089, USA. ; School of Medicine and School of Biochemistry and Immunology, Trinity College, Dublin 2, Ireland. ; 1] BioXFEL, NSF Science and Technology Center, 700 Ellicott Street, Buffalo, New York 14203, USA [2] Ben May Department for Cancer Research, University of Chicago, Chicago, Illinois 60637, USA. ; Laboratory of Biomolecular Research at Paul Scherrer Institute, CH-5232 Villigen, Switzerland. ; Department of Biology, Universitat Konstanz, 78457 Konstanz, Germany. ; Beijing Synchrotron Radiation Facility, Institute of High Energy Physics, Chinese Academy of Sciences, Beijing 100049, China. ; 1] Center for Free Electron Laser Science, Deutsches Elektronen-Synchrotron DESY, 22607 Hamburg, Germany [2] Centre for Ultrafast Imaging, 22761 Hamburg, Germany. ; 1] Department of Biochemistry, University of Toronto, Toronto, Ontario M5S 1A8, Canada [2] Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5S 1A8, Canada. ; 1] Department of Chemistry, Bridge Institute, University of Southern California, Los Angeles, California 90089, USA [2] Department of Biological Sciences, Bridge Institute, University of Southern California, Los Angeles, California 90089, USA [3] iHuman Institute, ShanghaiTech University, 2F Building 6, 99 Haike Road, Pudong New District, Shanghai 201210, China. ; 1] Laboratory of Structural Sciences, Center for Structural Biology and Drug Discovery, Van Andel Research Institute, Grand Rapids, Michigan 49503, USA [2] VARI-SIMM Center, Center for Structure and Function of Drug Targets, CAS-Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26200343" target="_blank"〉PubMed〈/a〉

Description: RNA interference (RNAi) is a mechanism by which double-stranded RNAs (dsRNAs) suppress specific transcripts in a sequence-dependent manner. dsRNAs are processed by Dicer to 21-24-nucleotide small interfering RNAs (siRNAs) and then incorporated into the argonaute (Ago) proteins. Gene regulation by endogenous siRNAs has been observed only in organisms possessing RNA-dependent RNA polymerase (RdRP). In mammals, where no RdRP activity has been found, biogenesis and function of endogenous siRNAs remain largely unknown. Here we show, using mouse oocytes, that endogenous siRNAs are derived from naturally occurring dsRNAs and have roles in the regulation of gene expression. By means of deep sequencing, we identify a large number of both approximately 25-27-nucleotide Piwi-interacting RNAs (piRNAs) and approximately 21-nucleotide siRNAs corresponding to messenger RNAs or retrotransposons in growing oocytes. piRNAs are bound to Mili and have a role in the regulation of retrotransposons. siRNAs are exclusively mapped to retrotransposons or other genomic regions that produce transcripts capable of forming dsRNA structures. Inverted repeat structures, bidirectional transcription and antisense transcripts from various loci are sources of the dsRNAs. Some precursor transcripts of siRNAs are derived from expressed pseudogenes, indicating that one role of pseudogenes is to adjust the level of the founding source mRNA through RNAi. Loss of Dicer or Ago2 results in decreased levels of siRNAs and increased levels of retrotransposon and protein-coding transcripts complementary to the siRNAs. Thus, the RNAi pathway regulates both protein-coding transcripts and retrotransposons in mouse oocytes. Our results reveal a role for endogenous siRNAs in mammalian oocytes and show that organisms lacking RdRP activity can produce functional endogenous siRNAs from naturally occurring dsRNAs.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Watanabe, Toshiaki -- Totoki, Yasushi -- Toyoda, Atsushi -- Kaneda, Masahiro -- Kuramochi-Miyagawa, Satomi -- Obata, Yayoi -- Chiba, Hatsune -- Kohara, Yuji -- Kono, Tomohiro -- Nakano, Toru -- Surani, M Azim -- Sakaki, Yoshiyuki -- Sasaki, Hiroyuki -- England -- Nature. 2008 May 22;453(7194):539-43. doi: 10.1038/nature06908. Epub 2008 Apr 10.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Human Genetics, Department of Integrated Genetics, National Institute of Genetics, Research Organization of Information and Systems, Mishima 411-8540, Japan. toshwata@lab.nig.ac.jp〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18404146" target="_blank"〉PubMed〈/a〉

Description: Calcium (Ca(2+))-activated chloride channels are fundamental mediators in numerous physiological processes including transepithelial secretion, cardiac and neuronal excitation, sensory transduction, smooth muscle contraction and fertilization. Despite their physiological importance, their molecular identity has remained largely unknown. Here we show that transmembrane protein 16A (TMEM16A, which we also call anoctamin 1 (ANO1)) is a bona fide Ca(2+)-activated chloride channel that is activated by intracellular Ca(2+) and Ca(2+)-mobilizing stimuli. With eight putative transmembrane domains and no apparent similarity to previously characterized channels, ANO1 defines a new family of ionic channels. The biophysical properties as well as the pharmacological profile of ANO1 are in full agreement with native Ca(2+)-activated chloride currents. ANO1 is expressed in various secretory epithelia, the retina and sensory neurons. Furthermore, knockdown of mouse Ano1 markedly reduced native Ca(2+)-activated chloride currents as well as saliva production in mice. We conclude that ANO1 is a candidate Ca(2+)-activated chloride channel that mediates receptor-activated chloride currents in diverse physiological processes.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Yang, Young Duk -- Cho, Hawon -- Koo, Jae Yeon -- Tak, Min Ho -- Cho, Yeongyo -- Shim, Won-Sik -- Park, Seung Pyo -- Lee, Jesun -- Lee, Byeongjun -- Kim, Byung-Moon -- Raouf, Ramin -- Shin, Young Ki -- Oh, Uhtaek -- Wellcome Trust/United Kingdom -- England -- Nature. 2008 Oct 30;455(7217):1210-5. doi: 10.1038/nature07313. Epub 2008 Aug 24.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Sensory Research Center, CRI, College of Pharmacy, Seoul National University, Seoul 151-742, Korea.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18724360" target="_blank"〉PubMed〈/a〉