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381 results on '"George, E"'

1. Structure of human telomerase holoenzyme with bound telomeric DNA

Author

Ghanim, George E, Fountain, Adam J, van Roon, Anne-Marie M, Rangan, Ramya, Das, Rhiju, Collins, Kathleen, and Nguyen, Thi Hoang Duong

Subjects
Genetics, 2.1 Biological and endogenous factors, Aetiology, 1.1 Normal biological development and functioning, Underpinning research, Generic health relevance, Binding Sites, Catalytic Domain, Cryoelectron Microscopy, DNA, Histones, Holoenzymes, Humans, Models, Molecular, Mutation, Nucleic Acid Conformation, Nucleotide Motifs, Protein Subunits, RNA, Ribonucleoproteins, Telomerase, Telomere, General Science & Technology
Abstract

Telomerase adds telomeric repeats at chromosome ends to compensate for the telomere loss that is caused by incomplete genome end replication1. In humans, telomerase is upregulated during embryogenesis and in cancers, and mutations that compromise the function of telomerase result in disease2. A previous structure of human telomerase at a resolution of 8 Å revealed a vertebrate-specific composition and architecture3, comprising a catalytic core that is flexibly tethered to an H and ACA (hereafter, H/ACA) box ribonucleoprotein (RNP) lobe by telomerase RNA. High-resolution structural information is necessary to develop treatments that can effectively modulate telomerase activity as a therapeutic approach against cancers and disease. Here we used cryo-electron microscopy to determine the structure of human telomerase holoenzyme bound to telomeric DNA at sub-4 Å resolution, which reveals crucial DNA- and RNA-binding interfaces in the active site of telomerase as well as the locations of mutations that alter telomerase activity. We identified a histone H2A-H2B dimer within the holoenzyme that was bound to an essential telomerase RNA motif, which suggests a role for histones in the folding and function of telomerase RNA. Furthermore, this structure of a eukaryotic H/ACA RNP reveals the molecular recognition of conserved RNA and protein motifs, as well as interactions that are crucial for understanding the molecular pathology of many mutations that cause disease. Our findings provide the structural details of the assembly and active site of human telomerase, which paves the way for the development of therapeutic agents that target this enzyme.

Published
2021

2. SLC19A1 transports immunoreactive cyclic dinucleotides.

Author

Luteijn, Rutger D, Zaver, Shivam A, Gowen, Benjamin G, Wyman, Stacia K, Garelis, Nick E, Onia, Liberty, McWhirter, Sarah M, Katibah, George E, Corn, Jacob E, Woodward, Joshua J, and Raulet, David H

Subjects
Cytosol, Animals, Humans, Inflammation, Nucleotidyltransferases, DNA, Nucleotides, Cyclic, Interferon Regulatory Factor-3, Reduced Folate Carrier Protein, Nucleotides, Cyclic, General Science & Technology
Abstract

The accumulation of DNA in the cytosol serves as a key immunostimulatory signal associated with infections, cancer and genomic damage1,2. Cytosolic DNA triggers immune responses by activating the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway3. The binding of DNA to cGAS activates its enzymatic activity, leading to the synthesis of a second messenger, cyclic guanosine monophosphate-adenosine monophosphate (2'3'-cGAMP)4-7. This cyclic dinucleotide (CDN) activates STING8, which in turn activates the transcription factors interferon regulatory factor 3 (IRF3) and nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB), promoting the transcription of genes encoding type I interferons and other cytokines and mediators that stimulate a broader immune response. Exogenous 2'3'-cGAMP produced by malignant cells9 and other CDNs, including those produced by bacteria10-12 and synthetic CDNs used in cancer immunotherapy13,14, must traverse the cell membrane to activate STING in target cells. How these charged CDNs pass through the lipid bilayer is unknown. Here we used a genome-wide CRISPR-interference screen to identify the reduced folate carrier SLC19A1, a folate-organic phosphate antiporter, as the major transporter of CDNs. Depleting SLC19A1 in human cells inhibits CDN uptake and functional responses, and overexpressing SLC19A1 increases both uptake and functional responses. In human cell lines and primary cells ex vivo, CDN uptake is inhibited by folates as well as two medications approved for treatment of inflammatory diseases, sulfasalazine and the antifolate methotrexate. The identification of SLC19A1 as the major transporter of CDNs into cells has implications for the immunotherapeutic treatment of cancer13, host responsiveness to CDN-producing pathogenic microorganisms11 and-potentially-for some inflammatory diseases.

Published
2019

3. Isomerization of BRCA1-BARD1 promotes replication fork protection

Author

Daza-Martin, Manuel, Starowicz, Katarzyna, Jamshad, Mohammed, Tye, Stephanie, Ronson, George E., MacKay, Hannah L., and Chauhan, Anoop Singh

Subjects
Research, Genetic aspects, Replication fork -- Research, Genetic research, Isomerization -- Genetic aspects, BRCA genes -- Research, Genetic regulation -- Research
Abstract

Author(s): Manuel Daza-Martin [sup.1] [sup.3] , Katarzyna Starowicz [sup.1] , Mohammed Jamshad [sup.1] , Stephanie Tye [sup.2] , George E. Ronson [sup.1] , Hannah L. MacKay [sup.1] , Anoop Singh [...], The integrity of genomes is constantly threatened by problems encountered by the replication fork. BRCA1, BRCA2 and a subset of Fanconi anaemia proteins protect stalled replication forks from degradation by nucleases, through pathways that involve RAD51. The contribution and regulation of BRCA1 in replication fork protection, and how this role relates to its role in homologous recombination, is unclear. Here we show that BRCA1 in complex with BARD1, and not the canonical BRCA1-PALB2 interaction, is required for fork protection. BRCA1-BARD1 is regulated by a conformational change mediated by the phosphorylation-directed prolyl isomerase PIN1. PIN1 activity enhances BRCA1-BARD1 interaction with RAD51, thereby increasing the presence of RAD51 at stalled replication structures. We identify genetic variants of BRCA1-BARD1 in patients with cancer that exhibit poor protection of nascent strands but retain homologous recombination proficiency, thus defining domains of BRCA1-BARD1 that are required for fork protection and associated with cancer development. Together, these findings reveal a BRCA1-mediated pathway that governs replication fork protection. BRCA1-BARD1 has a role in replication fork protection that is mediated by a mechanism of phosphorylation-targeted isomerization of BRCA1 and is independent of the canonical interaction between BRCA1 and PALB2.

Published
2019
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4. Publisher Correction: Hydroclimatic vulnerability of peat carbon in the central Congo Basin

Author

Garcin, Yannick, primary, Schefuß, Enno, additional, Dargie, Greta C., additional, Hawthorne, Donna, additional, Lawson, Ian T., additional, Sebag, David, additional, Biddulph, George E., additional, Crezee, Bart, additional, Bocko, Yannick E., additional, Ifo, Suspense A., additional, Mampouya Wenina, Y. Emmanuel, additional, Mbemba, Mackline, additional, Ewango, Corneille E. N., additional, Emba, Ovide, additional, Bola, Pierre, additional, Kanyama Tabu, Joseph, additional, Tyrrell, Genevieve, additional, Young, Dylan M., additional, Gassier, Ghislain, additional, Girkin, Nicholas T., additional, Vane, Christopher H., additional, Adatte, Thierry, additional, Baird, Andy J., additional, Boom, Arnoud, additional, Gulliver, Pauline, additional, Morris, Paul J., additional, Page, Susan E., additional, Sjögersten, Sofie, additional, and Lewis, Simon L., additional

Published
2022
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5. Hydroclimatic vulnerability of peat carbon in the central Congo Basin

Author

Garcin, Yannick, primary, Schefuß, Enno, additional, Dargie, Greta C., additional, Hawthorne, Donna, additional, Lawson, Ian T., additional, Sebag, David, additional, Biddulph, George E., additional, Crezee, Bart, additional, Bocko, Yannick E., additional, Ifo, Suspense A., additional, Mampouya Wenina, Y. Emmanuel, additional, Mbemba, Mackline, additional, Ewango, Corneille E. N., additional, Emba, Ovide, additional, Bola, Pierre, additional, Kanyama Tabu, Joseph, additional, Tyrrell, Genevieve, additional, Young, Dylan M., additional, Gassier, Ghislain, additional, Girkin, Nicholas T., additional, Vane, Christopher H., additional, Adatte, Thierry, additional, Baird, Andy J., additional, Boom, Arnoud, additional, Gulliver, Pauline, additional, Morris, Paul J., additional, Page, Susan E., additional, Sjögersten, Sofie, additional, and Lewis, Simon L., additional

Published
2022
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6. Beating the stoner criterion using molecular interfaces

Author

Ma'Mari, Fatma Al, Moorsom, Timothy, Teobaldi, Gilberto, Deacon, William, Prokscha, Thomas, Luetkens, Hubertus, Lee, Steve, Sterbinsky, George E., Arena, Dario A., MacLaren, Donald A., Flokstra, Machiel, Ali, Mannan, Wheeler, May C., Burnell, Gavin, Hickey, Bryan J., and Cespedes, Oscar

Subjects
Magnetic properties, Analysis, Transition metals -- Magnetic properties, Ferromagnetism -- Analysis, Thin films -- Analysis, Dielectric films -- Analysis, Transition metals
Abstract

Multifunctional materials with the spin degree of freedom, such as multiferroics, magnetic semiconductors and molecular magnets, have aroused interest as potentially transformative components in quantum technologies (8-12). Strategies used to [...], Only three elements are ferromagnetic at room temperature: the transition metals iron, cobalt and nickel. The Stoner criterion explains why iron is ferromagnetic but manganese, for example, is not, even though both elements have an unfilled 3d shell and are adjacent in the periodic table: according to this criterion, the product of the density of states and the exchange integral must be greater than unity for spontaneous spin ordering to emerge (1,2). Here we demonstrate that it is possible to alter the electronic states of non-ferromagnetic materials, such as diamagnetic copper and paramagnetic manganese, to overcome the Stoner criterion and make them ferromagnetic at room temperature. This effect is achieved via interfaces between metallic thin films and [C.sub.60] molecular layers. The emergent ferromagnetic state exists over several layers of the metal before being quenched at large sample thicknesses by the material's bulk properties. Although the induced magnetization is easily measurable by magnetometry, low-energy muon spin spectroscopy (3) provides insight into its distribution by studying the depolarization process of low-energy muons implanted in the sample. This technique indicates localized spin-ordered states at, and close to, the metal-molecule interface. Density functional theory simulations suggest a mechanism based on magnetic hardening of the metal atoms, owing to electron transfer (4, 5). This mechanism might allow for the exploitation of molecular coupling to design magnetic metamaterials using abundant, non-toxic components such as organic semiconductors. Charge transfer at molecular interfaces may thus be used to control spin polarization or magnetization, with consequences for the design of devices for electronic, power or computing applications (see, for example, refs 6 and 7).

Published
2015

7. Lytic to temperate switching of viral communities

Author

Knowles, B., Silveira, C. B., Bailey, B. A., Barott, K., Cantu, V. A., Cobián-Güemes, A. G., Coutinho, F. H., Dinsdale, E. A., Felts, B., Furby, K. A., George, E. E., Green, K. T., Gregoracci, G. B., Haas, A. F., Haggerty, J. M., Hester, E. R., Hisakawa, N., Kelly, L. W., Lim, Y. W., Little, M., Luque, A., McDole-Somera, T., McNair, K., de Oliveira, L. S., Quistad, S. D., Robinett, N. L., Sala, E., Salamon, P., Sanchez, S. E., Sandin, S., Silva, G. G. Z., Smith, J., Sullivan, C., Thompson, C., Vermeij, M. J. A., Youle, M., Young, C., Zgliczynski, B., Brainard, R., Edwards, R. A., Nulton, J., Thompson, F., and Rohwer, F.

Published
2016
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8. Beating the Stoner criterion using molecular interfaces

Author

MaʼMari, Fatma Al, Moorsom, Timothy, Teobaldi, Gilberto, Deacon, William, Prokscha, Thomas, Luetkens, Hubertus, Lee, Steve, Sterbinsky, George E., Arena, Dario A., MacLaren, Donald A., Flokstra, Machiel, Ali, Mannan, Wheeler, May C., Burnell, Gavin, Hickey, Bryan J., and Cespedes, Oscar

Published
2015
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9. Non-blinking semiconductor nanocrystals

Author

Wang, Xiaoyong, Ren, Xiaofan, Kahen, Keith, Hahn, Megan A., Rajeswaran, Manju, Maccagnano-Zacher, Sara, Silcox, John, Cragg, George E., Efros, Alexander L., and Krauss, Todd D.

Subjects
Semiconductors -- Usage -- Optical properties, Nanocrystals -- Usage -- Optical properties, Environmental issues, Science and technology, Zoology and wildlife conservation, Usage, Optical properties
Abstract

The photoluminescence from a variety of individual molecules (1) and nanometre-sized crystallites (2) is defined by large intensity fluctuations, known as 'blinking', whereby their photoluminescence turns 'on' and 'off' intermittently, even under continuous photo-excitation (2). For semiconductor nanocrystals, it was originally proposed (3) that these 'off' periods corresponded to a nanocrystal with an extra charge. A charged nanocrystal could have its photoluminescence temporarily quenched owing to the high efficiency of non-radiative (for example, Auger) recombination processes between the extra charge and a subsequently excited electron--hole pair; photoluminescence would resume only after the nanocrystal becomes neutralized again. Despite over a decade of research, completely non-blinking nanocrystals (4,5) have not been synthesized and an understanding of the blinking phenomenon (6) remains elusive. Here we report ternary core/shell CdZnSe/ZnSe semiconductor nanocrystals that individually exhibit continuous, non-blinking photoluminescence. Unexpectedly, these nanocrystals strongly photoluminesce despite being charged, as indicated by a multi-peaked photoluminescence spectral shape and short lifetime. To model the unusual photoluminescence properties of the CdZnSe/ZnSe nanocrystals, we softened the abrupt confinement potential of a typical core/shell nanocrystal, suggesting that the structure is a radially graded alloy of CdZnSe into ZnSe. As photoluminescence blinking severely limits the usefulness of nanocrystals in applications requiring a continuous output of single photons, these non-blinking nanocrystals may enable substantial advances in fields ranging from single-molecule biological labelling (7) to low-threshold lasers (8)., Semiconductor nanocrystals have size-tunable optical properties that open up possibilities for revolutionary advances in lasers (8), light-emitting diodes (9), solar cells (10) and biological imaging (11-13). However, the photoluminescence from [...]

Published
2009

10. Precise genome modification in the crop species Zea mays using zinc-finger nucleases

Author

Shukla, Vipula K., Doyon, Yannick, Miller, Jeffrey C., DeKelver, Russell C., Moehle, Erica A., Worden, Sarah E., Mitchell, Jon C., Arnold, Nicole L., Gopalan, Sunita, Meng, Xiangdong, Choi, Vivian M., Rock, Jeremy M., Wu, Ying-Ying, Katibah, George E., Zhifang, Gao, McCaskill, David, Simpson, Matthew A., Blakeslee, Beth, Greenwalt, Scott A., Butler, Holly J., Hinkley, Sarah J., Zhang, Lei, Rebar, Edward J., Gregory, Philip D., and Urnov, Fyodor D.

Subjects
Corn -- Genetic aspects, Zinc finger proteins -- Usage, Genomics -- Research, Agricultural biotechnology -- Research, Environmental issues, Science and technology, Zoology and wildlife conservation, Usage, Genetic aspects, Research
Abstract

Agricultural biotechnology is limited by the inefficiencies of conventional random mutagenesis and transgenesis. Because targeted genome modification in plants has been intractable (1), plant trait engineering remains a laborious, time-consuming [...]

Published
2009

11. North Pacific seasonality and the glaciation of North America 2.7 million years ago

Author

Haug, Gerald H., Ganopolski, Andrey, Sigman, Daniel M., Rosell-Mele, Antoni, Swann, George E. A., Tiedemann, Ralf, Jaccard, Samuel L., Bollmann, Jorg, Maslin, Mark A., Leng, Melanie J., and Eglinton, Geoffrey

Subjects
Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

Author(s): Gerald H. Haug (corresponding author) [1]; Andrey Ganopolski [2]; Daniel M. Sigman [3]; Antoni Rosell-Mele [4]; George E. A. Swann [5]; Ralf Tiedemann [6]; Samuel L. Jaccard [7]; Jörg [...]

Published
2005
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12. Dusty starburst galaxies in the early Universe as revealed by gravitational lensing

Author

Vieira, J. D., Marrone, D. P., Chapman, S. C., De Breuck, C., Hezaveh, Y. D., Wei, A., Aguirre, J. E., Aird, K. A., Aravena, M., Ashby, M. L. N., Bayliss, M., Benson, B. A., Biggs, A. D., Bleem, L. E., Bock, J. J., Bothwell, M., Bradford, C. M., Brodwin, M., Carlstrom, J. E., Chang, C. L., Crawford, T. M., Crites, A. T., de Haan, T., Dobbs, M. A., Fomalont, E. B., Fassnacht, C. D., George, E. M., Gladders, M. D., Gonzalez, A. H., Greve, T. R., Gullberg, B., Halverson, N. W., High, F. W., Holder, G. P., Holzapfel, W. L., Hoover, S., Hrubes, J. D., Hunter, T. R., Keisler, R., Lee, A. T., Leitch, E. M., Lueker, M., Luong-Van, D., Malkan, M., McIntyre, V., McMahon, J. J., Mehl, J., Menten, K. M., Meyer, S. S., Mocanu, L. M., Murphy, E. J., Natoli, T., Padin, S., Plagge, T., Reichardt, C. L., Rest, A., Ruel, J., Ruhl, J. E., Sharon, K., Schaffer, K. K., Shaw, L., Shirokoff, E., Spilker, J. S., Stalder, B., Staniszewski, Z., Stark, A. A., Story, K., Vanderlinde, K., Welikala, N., and Williamson, R.

Published
2013
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13. A massive, cooling-flow-induced starburst in the core of a luminous cluster of galaxies

Author

McDonald, M., Bayliss, M., Benson, B. A., Foley, R. J., Ruel, J., Sullivan, P., Veilleux, S., Aird, K. A., Ashby, M. L. N., Bautz, M., Bazin, G., Bleem, L. E., Brodwin, M., Carlstrom, J. E., Chang, C. L., Cho, H. M., Clocchiatti, A., Crawford, T. M., Crites, A. T., de Haan, T., Desai, S., Dobbs, M. A., Dudley, J. P., Egami, E., Forman, W. R., Garmire, G. P., George, E. M., Gladders, M. D., Gonzalez, A. H., Halverson, N. W., Harrington, N. L., High, F. W., Holder, G. P., Holzapfel, W. L., Hoover, S., Hrubes, J. D., Jones, C., Joy, M., Keisler, R., Knox, L., Lee, A. T., Leitch, E. M., Liu, J., Lueker, M., Luong-Van, D., Mantz, A., Marrone, D. P., McMahon, J. J., Mehl, J., Meyer, S. S., Miller, E. D., Mocanu, L., Mohr, J. J., Montroy, T. E., Murray, S. S., Natoli, T., Padin, S., Plagge, T., Pryke, C., Rawle, T. D., Reichardt, C. L., Rest, A., Rex, M., Ruhl, J. E., Saliwanchik, B. R., Saro, A., Sayre, J. T., Schaffer, K. K., Shaw, L., Shirokoff, E., Simcoe, R., Song, J., Spieler, H. G., Stalder, B., Staniszewski, Z., Stark, A. A., Story, K., Stubbs, C. W., Šuhada, R., van Engelen, A., Vanderlinde, K., Vieira, J. D., Vikhlinin, A., Williamson, R., Zahn, O., and Zenteno, A.

Published
2012
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14. Author Correction: SLC19A1 transports immunoreactive cyclic dinucleotides

Author

Luteijn, Rutger D., primary, Zaver, Shivam A., additional, Gowen, Benjamin G., additional, Wyman, Stacia K., additional, Garelis, Nick E., additional, Onia, Liberty, additional, McWhirter, Sarah M., additional, Katibah, George E., additional, Corn, Jacob E., additional, Woodward, Joshua J., additional, and Raulet, David H., additional

Published
2020
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15. Sox18 induces development of the lymphatic vasculature in mice

Author

François, Mathias, Caprini, Andrea, Hosking, Brett, Orsenigo, Fabrizio, Wilhelm, Dagmar, Browne, Catherine, Paavonen, Karri, Karnezis, Tara, Shayan, Ramin, Downes, Meredith, Davidson, Tara, Tutt, Desmond, Cheah, Kathryn S. E., Stacker, Steven A., Muscat, George E. O., Achen, Marc G., Dejana, Elisabetta, and Koopman, Peter

Published
2008

16. Corrigendum: Lytic to temperate switching of viral communities

Author

Knowles, B., Silveira, C. B., Bailey, B. A., Barott, K., Cantu, V. A., Cobin-Gemes, A. G., Coutinho, F. H., Dinsdale, E. A., Felts, B., Furby, K. A., George, E. E., Green, K. T., Gregoracci, G. B., Haas, A. F., Haggerty, J. M., Hester, E. R., Hisakawa, N., Kelly, L. W., Lim, Y. W., Little, M., Luque, A., McDole-Somera, T., McNair, K., de Oliveira, L. S., Quistad, S. D., Robinett, N. L., Sala, E., Salamon, P., Sanchez, S. E., Sandin, S., Silva, G. G. Z., Smith, J., Sullivan, C., Thompson, C., Vermeij, M. J. A., Youle, M., Young, C., Zgliczynski, B., Brainard, R., Edwards, R. A., Nulton, J., Thompson, F., and Rohwer, F.

Abstract

Author(s): B. Knowles; C. B. Silveira; B. A. Bailey; K. Barott; V. A. Cantu; A. G. Cobin-Gemes; F. H. Coutinho; E. A. Dinsdale; B. Felts; K. A. Furby; E. E. [...]

Published
2016
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20. Atomic structure of a fragment of human CD4 containing two immunoglobulin-like domains

Author

Wang, Jiahuai, Yan, Youwei, Garrett, Thomas P.J., Liu, Jinhuan, Rodgers, David W., Garlick, Robert L., Tarr, George E., Husain, Yasmin, Reinherz, Ellis L., and Harrison, Stephen C.

Subjects
Atomic structure -- Analysis, HIV (Viruses) -- Receptors, Viruses -- Receptors, Glycoproteins -- Research, Environmental issues, Science and technology, Zoology and wildlife conservation
Published
1990

22. Comprehensive genomic characterization of head and neck squamous cell carcinomas

Author

Ni Zhao, Carter Van Waes, Lori Boice, Ashley H. Salazar, Petar Stojanov, Michael B. Prystowsky, Akinyemi I. Ojesina, Tara M. Lichtenberg, Nikolaus Schultz, Joshua M. Stuart, Mitchell J. Frederick, Julie M. Gastier-Foster, Jeffrey N. Myers, Bradley A. Ozenberger, Margaret L. Gulley, Jean C. Zenklusen, Inanc Birol, Christina Yau, Mark E. Sherman, Saianand Balu, Angela Hadjipanayis, Barry S. Taylor, Piotr A. Mieczkowski, Anthony Saleh, Carol G. Shores, Ezra E.W. Cohen, Joonil Jung, Ari B. Kahn, Lisa Wise, Peter S. Hammerman, Pei Lin, Marc Ladanyi, Mark C. Weissler, Scott L. Carter, Michele C. Hayward, Rehan Akbani, Todd Pihl, J. Jack Lee, Sophie C. Egea, Harshad S. Mahadeshwar, Leigh B. Thorne, Matthew G. Soloway, Troy Shelton, Andrea Haddad, William N. William, Wiktoria Maria Suchorska, Johanna Gardner, Marco A. Marra, Julie Ahn, Travis I. Zack, Lihua Zou, Bayardo Perez-Ordonez, David A. Wheeler, Daniel Crain, Adrian Ally, Deepak Srinivasan, Jay Bowen, Aaron D. Black, Jing Wang, Ludmila Danilova, Roy Tarnuzzer, Brenda Diergaarde, Tod D. Casasent, Dean Cheng, Giovanni Ciriello, Ken Burnett, Jeff Bruce, Wojciech Golusiński, Jonathan G. Seidman, Corbin D. Jones, Daniel J. Weisenberger, Lisa A. Peterson, Thomas M. Harris, Angeliki Pantazi, Nina Thiessen, Curtis R. Pickering, Chandra Sekhar Pedamallu, Yingchun Liu, William Lee, Andrzej Mackiewicz, Hailei Zhang, Ronglai Shen, B. Arman Aksoy, Lixing Yang, Jeffrey Roach, Simion I. Chiosea, John Waldron, David Van Den Berg, James Stephen Marron, Tanja Davidsen, Liming Yang, Maciej Wiznerowicz, Benjamin Gross, Paul M. Weinberger, Yufeng Liu, Reanne Bowlby, Zhixiang Zuo, Bartosz Szybiak, Roni J. Bollag, Samuel S. Freeman, Heather M. Walline, Gad Getz, Scott Morris, Michael S. Noble, Charles Saller, Sahil Seth, Richard A. Gibbs, Jonathan C. Irish, Hollie A. Harper, George E. Sandusky, S. Onur Sumer, Trevor Hackman, Gordon B. Mills, Carol R. Bradford, Payal Sipahimalani, Nipun Kakkar, Robert Penny, Jennifer Drummond, Adam M. Zanation, Rebecca Carlsen, Andrew J. Mungall, Harshavardhan Doddapaneni, James G. Herman, Sylvia Wrenn, Andy Chu, Nilsa C. Ramirez, Patrick Kwok Shing Ng, Patrick K. Kimes, Tina Wong, Mark E. Prince, Han Si, Kristian Cibulskis, Katherine Tarvin, Peter W. Laird, Jiabin Tang, Raja R. Seethala, Michael Parfenov, Jan F. Prins, Erin Curley, Hui Cheng, Donna M. Muzny, Lynda Chin, D. Neil Hayes, Margi Sheth, Carmen Gomez-Fernandez, Jessica Walton, Paul C. Boutros, Ariane Nguyen, Kristen M. Leraas, Robert L. Ferris, Greg Eley, Christopher C. Benz, Jaegil Kim, Thomas E. Carey, Douglas B. Chepeha, Janae V. Simons, Jiexin Zhang, Laura S. Rozek, Maureen A. Sartor, Christopher A. Bristow, Justin A. Bishop, Adel K. El-Naggar, Nishant Agrawal, Yiling Lu, Carrie Sougnez, Evan G. Taylor, Raju Kucherlapati, Scott M. Lippman, Colleen Mitchell, Wendell G. Yarbrough, Chu Chen, Donghui Tan, Bhishamjit S. Chera, Michael Mayo, Wenbin Liu, Ranabir Guin, W. Kimryn Rathmell, Mayya Malakh, Jessica Frick, John N. Weinstein, Kevin Lau, Michelle Q. Pham, Gideon Dresdner, Luc G. T. Morris, David Mallery, Zhining Wang, Yichao Sun, Lynn M. Herbert, Christine M. Komarck, Lauren Averett Byers, Angela Tam, Thomas Bodenheimer, Doug Voet, Christie Kovar, Junyuan Wu, Walker Hale, Charles M. Perou, Angela B.Y. Hui, Kenna R. Mills Shaw, Timothy J. Triche, Dong Zeng, Steven J.M. Jones, Matthew D. Wilkerson, Jinze Liu, Yan Guo, Hsu Chao, Tamara R. Jones, Katherine A. Hoadley, Stuart R. Jefferys, Thomas C. Motter, Matthew Meyerson, Konstanty Korski, Timothy A. Chan, Mark A. Jensen, Julien Baboud, Alexei Protopopov, David I. Heiman, Nils Gehlenborg, Heidi J. Sofia, Aaron D. Tward, Eric S. Lander, Yunhu Wan, Scot Waring, Peggy Yena, Robert I. Haddad, Daniel DiCara, Gordon Saksena, Juok Cho, Richard A. Moore, Darshan Singh, Peter J. Park, Matthew Ibbs, Robert A. Holt, Andrew D. Cherniack, Tanguy Y. Seiwert, Lee Lichtenstein, Anders Jacobsen, Rameen Beroukhim, Brandee T. Brown, Stephen C. Benz, Paweł Golusiński, Vonn Walter, Lixia Diao, Erik Zmuda, Scott Frazer, Michael S. Lawrence, Nils Weinhold, Jacqueline E. Schein, Xiaojia Ren, Denise Brooks, Elizabeth Buda, Jianjiong Gao, Jianhua Zhang, William W. Shockley, J. Todd Auman, Xingzhi Song, Jennifer R. Grandis, Jonathan B. McHugh, Stacey Gabriel, Martin L. Ferguson, Jeffrey S. Reid, Joseph Paulauskis, Umadevi Veluvolu, John A. Demchok, Moiz S. Bootwalla, Fei-Fei Liu, Alan P. Hoyle, Shaowu Meng, Mei Huang, Ann Marie Egloff, Christina Beard, Liu Xi, Ricardo Ramirez, Donna Morton, Lisle E. Mose, Leslie Cope, Marjorie Romkes, Zubair Khan, Noreen Dhalla, Candace Shelton, Boris Reva, Stephen B. Baylin, Miruna Balasundaram, Psalm Haseley, Andrew Wei Xu, Yan Shi, A. Gordon Robertson, Gregory T. Wolf, Darlene Lee, Steven E. Schumacher, Semin Lee, Rileen Sinha, Dennis T. Maglinte, Haiyan I. Li, William K. Funkhouser, Yi Han, Sam Ng, Joel S. Parker, Kai Wang, Zhong Chen, You Hong Fan, Yaron S.N. Butterfield, Jeffrey S. Moyer, Robert A. Burton, David Pot, Chris Sander, Daryl Waggott, Joseph A. Califano, Netty Santoso, and Kyle Chang

Subjects
Male, DNA Copy Number Variations, Somatic cell, Biology, Article, 03 medical and health sciences, 0302 clinical medicine, CDKN2A, Humans, HRAS, Molecular Targeted Therapy, RNA, Neoplasm, Gene, neoplasms, 030304 developmental biology, Genetics, 0303 health sciences, Multidisciplinary, Oncogene, Genome, Human, Squamous Cell Carcinoma of Head and Neck, Wnt signaling pathway, DNA, Neoplasm, Genomics, Oncogenes, Cell cycle, 3. Good health, Gene Expression Regulation, Neoplastic, Head and Neck Neoplasms, 030220 oncology & carcinogenesis, Mutation, Cancer research, Carcinoma, Squamous Cell, Female, FAT1, Signal Transduction, Transcription Factors
Abstract

The Cancer Genome Atlas profiled 279 head and neck squamous cell carcinomas (HNSCCs) to provide a comprehensive landscape of somatic genomic alterations. Here we show that human-papillomavirus-associated tumours are dominated by helical domain mutations of the oncogene PIK3CA, novel alterations involving loss of TRAF3, and amplification of the cell cycle gene E2F1. Smoking-related HNSCCs demonstrate near universal loss-of-function TP53 mutations and CDKN2A inactivation with frequent copy number alterations including amplification of 3q26/28 and 11q13/22. A subgroup of oral cavity tumours with favourable clinical outcomes displayed infrequent copy number alterations in conjunction with activating mutations of HRAS or PIK3CA, coupled with inactivating mutations of CASP8, NOTCH1 and TP53. Other distinct subgroups contained loss-of-function alterations of the chromatin modifier NSD1, WNT pathway genes AJUBA and FAT1, and activation of oxidative stress factor NFE2L2, mainly in laryngeal tumours. Therapeutic candidate alterations were identified in most HNSCCs.

Published
2015

23. Oncogenically active MYD88 mutations in human lymphoma

Author

Erlend B. Smeland, Elaine S. Jaffe, Richard I. Fisher, Randy D. Gascoyne, Kian-Huat Lim, Sameer Jhavar, Vu N. Ngo, George E. Wright, Louis M. Staudt, Roland Schmitz, Elias Campo, Holger Kohlhammer, Hans K. Müller-Hermelink, German Ott, Paul B. Romesser, Arthur L. Shaffer, Ryan M. Young, Lisa M. Rimsza, Yandan Yang, Denny D. Weisenburger, John Powell, James R. Cook, Jan Delabie, Wenming Xiao, Wing C. Chan, Joseph M. Connors, Weihong Xu, Raymond R. Tubbs, Andreas Rosenwald, Rita M. Braziel, and Hong Zhao

Subjects
STAT3 Transcription Factor, Cell Survival, Molecular Sequence Data, Biology, medicine.disease_cause, Article, immune system diseases, Cell Line, Tumor, hemic and lymphatic diseases, medicine, Humans, Amino Acid Sequence, Phosphorylation, Kinase activity, Janus Kinases, Mutation, Multidisciplinary, Sequence Analysis, RNA, Kinase, Toll-Like Receptors, NF-kappa B, High-Throughput Nucleotide Sequencing, Receptors, Interleukin-1, Lymphoma, B-Cell, Marginal Zone, Oncogenes, IRAK4, medicine.disease, Burkitt Lymphoma, Protein Structure, Tertiary, Lymphoma, Interleukin-1 Receptor-Associated Kinases, Amino Acid Substitution, Myeloid Differentiation Factor 88, Cancer research, Cytokines, Mutant Proteins, RNA Interference, Lymphoma, Large B-Cell, Diffuse, Carcinogenesis, Janus kinase, Hydrophobic and Hydrophilic Interactions, Diffuse large B-cell lymphoma, Signal Transduction
Abstract

The activated B-cell-like (ABC) subtype of diffuse large B-cell lymphoma (DLBCL) remains the least curable form of this malignancy despite recent advances in therapy1. Constitutive nuclear factor (NF)-κB and JAK kinase signalling promotes malignant cell survival in these lymphomas, but the genetic basis for this signalling is incompletely understood. Here we describe the dependence of ABC DLBCLs on MYD88, an adaptor protein that mediates toll and interleukin (IL)-1 receptor signalling2,3, and the discovery of highly recurrent oncogenic mutations affecting MYD88 in ABC DLBCL tumours. RNA interference screening revealed that MYD88 and the associated kinases IRAK1 and IRAK4 are essential for ABC DLBCL survival. High-throughput RNA resequencing uncovered MYD88 mutations in ABC DLBCL lines. Notably, 29% of ABC DLBCL tumours harboured the same amino acid substitution, L265P, in the MYD88 Toll/IL-1 receptor (TIR) domain at an evolutionarily invariant residue in its hydrophobic core. This mutation was rare or absent in other DLBCL subtypes and Burkitt’s lymphoma, but was observed in 9% of mucosa-associated lymphoid tissue lymphomas. At a lower frequency, additional mutations were observed in the MYD88 TIR domain, occurring in both the ABC and germinal centre B-cell-like (GCB) DLBCL subtypes. Survival of ABC DLBCL cells bearing the L265P mutation was sustained by the mutant but not the wild-type MYD88 isoform, demonstrating that L265P is a gain-of-function driver mutation. The L265P mutant promoted cell survival by spontaneously assembling a protein complex containing IRAK1 and IRAK4, leading to IRAK4 kinase activity, IRAK1 phosphorylation, NF-κB signalling, JAK kinase activation of STAT3, and secretion of IL-6, IL-10 and interferon-β. Hence, theMYD88 signalling pathway is integral to the pathogenesis of ABC DLBCL, supporting the development of inhibitors of IRAK4 kinase and other components of this pathway for the treatment of tumours bearing oncogenic MYD88 mutations.

Published
2010
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24. Precise genome modification in the crop species Zea mays using zinc-finger nucleases

Author

Edward J. Rebar, Sunita Gopalan, George E. Katibah, Vipula K. Shukla, David McCaskill, Sarah J. Hinkley, Ying-Ying Wu, Sarah E. Worden, Holly Jean Butler, Beth Blakeslee, Lei Zhang, Nicole L. Arnold, Matthew A. Simpson, Yannick Doyon, Russell Dekelver, Gao Zhifang, Philip D. Gregory, Jon C. Mitchell, Erica A. Moehle, Jeremy M. Rock, Jeffrey C. Miller, Scott A. Greenwalt, Xiangdong Meng, Vivian M. Choi, and Fyodor D. Urnov

Subjects
Genetics, Zinc finger, Multidisciplinary, fungi, food and beverages, Locus (genetics), Genetically modified crops, Biology, Agricultural biotechnology, Genome, Gene, Zinc finger nuclease, Genetically modified organism
Abstract

Agricultural biotechnology is limited by the inefficiencies of conventional random mutagenesis and transgenesis. Because targeted genome modification in plants has been intractable, plant trait engineering remains a laborious, time-consuming and unpredictable undertaking. Here we report a broadly applicable, versatile solution to this problem: the use of designed zinc-finger nucleases (ZFNs) that induce a double-stranded break at their target locus. We describe the use of ZFNs to modify endogenous loci in plants of the crop species Zea mays. We show that simultaneous expression of ZFNs and delivery of a simple heterologous donor molecule leads to precise targeted addition of an herbicide-tolerance gene at the intended locus in a significant number of isolated events. ZFN-modified maize plants faithfully transmit these genetic changes to the next generation. Insertional disruption of one target locus, IPK1, results in both herbicide tolerance and the expected alteration of the inositol phosphate profile in developing seeds. ZFNs can be used in any plant species amenable to DNA delivery; our results therefore establish a new strategy for plant genetic manipulation in basic science and agricultural applications.

Published
2009
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25. Beating the Stoner criterion using molecular interfaces

Author

Gavin Burnell, M. G. Flokstra, Steve Lee, Oscar Cespedes, Timothy Moorsom, George E. Sterbinsky, Mannan Ali, B. J. Hickey, Thomas Prokscha, Dario Arena, Gilberto Teobaldi, Hubertus Luetkens, May C. Wheeler, Donald A. MacLaren, William M. Deacon, Fatma Al Ma’Mari, EPSRC, University of St Andrews. School of Physics and Astronomy, and University of St Andrews. Condensed Matter Physics

Subjects
Physics, Multidisciplinary, Spin polarization, Condensed matter physics, ~DC~, DAS, Nanotechnology, Muon spin spectroscopy, Magnetization, Paramagnetism, Condensed Matter::Materials Science, QC Physics, Ferromagnetism, Stoner criterion, Density of states, Diamagnetism, Condensed Matter::Strongly Correlated Electrons, BDC, R2C, QC
Abstract

This work was supported by the Engineering and Physical Sciences Research Council through grants EP/K00512X/1, EP/K036408/1, EP/J01060X/1 and EP/I004483/1. Only three elements are ferromagnetic at room temperature: the transition metals iron, cobalt and nickel. The Stoner criterion explains why iron is ferromagnetic but manganese, for example, is not, even though both elements have an unfilled 3d shell and are adjacent in the periodic table: according to this criterion, the product of the density of states and the exchange integral must be greater than unity for spontaneous spin ordering to emerge. Here we demonstrate that it is possible to alter the electronic states of non-ferromagnetic materials, such as diamagnetic copper and paramagnetic manganese, to overcome the Stoner criterion and make them ferromagnetic at room temperature. This effect is achieved via interfaces between metallic thin films and C60 molecular layers. The emergent ferromagnetic state exists over several layers of the metal before being quenched at large sample thicknesses by the materiala € s bulk properties. Although the induced magnetization is easily measurable by magnetometry, low-energy muon spin spectroscopy provides insight into its distribution by studying the depolarization process of low-energy muons implanted in the sample. This technique indicates localized spin-ordered states at, and close to, the metal-molecule interface. Density functional theory simulations suggest a mechanism based on magnetic hardening of the metal atoms, owing to electron transfer. This mechanism might allow for the exploitation of molecular coupling to design magnetic metamaterials using abundant, non-toxic components such as organic semiconductors. Charge transfer at molecular interfaces may thus be used to control spin polarization or magnetization, with consequences for the design of devices for electronic, power or computing applications (see, for example, refs 6 and 7). Postprint

Published
2014

26. Correction: Corrigendum: Lytic to temperate switching of viral communities

Author

Knowles, B., primary, Silveira, C. B., additional, Bailey, B. A., additional, Barott, K., additional, Cantu, V. A., additional, Cobián-Güemes, A. G., additional, Coutinho, F. H., additional, Dinsdale, E. A., additional, Felts, B., additional, Furby, K. A., additional, George, E. E., additional, Green, K. T., additional, Gregoracci, G. B., additional, Haas, A. F., additional, Haggerty, J. M., additional, Hester, E. R., additional, Hisakawa, N., additional, Kelly, L. W., additional, Lim, Y. W., additional, Little, M., additional, Luque, A., additional, McDole-Somera, T., additional, McNair, K., additional, de Oliveira, L. S., additional, Quistad, S. D., additional, Robinett, N. L., additional, Sala, E., additional, Salamon, P., additional, Sanchez, S. E., additional, Sandin, S., additional, Silva, G. G. Z., additional, Smith, J., additional, Sullivan, C., additional, Thompson, C., additional, Vermeij, M. J. A., additional, Youle, M., additional, Young, C., additional, Zgliczynski, B., additional, Brainard, R., additional, Edwards, R. A., additional, Nulton, J., additional, Thompson, F., additional, and Rohwer, F., additional

Published
2016
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27. Comprehensive molecular characterization of urothelial bladder carcinoma

Author

Elizabeth Buda, Nikolaus Schultz, Donghui Tan, Pat Swanson, Xingzhi Song, Jennifer Owens, Carmelo Gaudioso, Liming Yang, Kenna R. Mills Shaw, Sophie C. Egea, John N. Weinstein, Lihua Zou, Dmitry A. Gordenin, Gad Getz, Stuart R. Jefferys, Wiam Bshara, David Haussler, Ari B. Kahn, Mary Iacocca, Brady Bernard, Charles M. Perou, Leigh B. Thorne, Kimberly R. Christ, Eric S. Lander, Yunhu Wan, Timothy J. Triche, Dong Zeng, Bogdan Czerniak, Wenbin Liu, Jianhua Zhang, David Mallery, B. Arman Aksoy, Lynn M. Herbert, Hailei Zhang, Jennifer DiPiero, Tod D. Casasent, Sugy Kodeeswaran, Daniel DiCara, Jacqueline E. Schein, Scott L. Carter, Umadevi Veluvolu, John M. S. Bartlett, Theresa M. Koppie, Ji Yeon Yang, Ronglai Shen, Yingchun Liu, Daniel J. Weisenberger, Ranabir Guin, Myra M. George, Marc Ladanyi, J. Todd Auman, Moiz S. Bootwalla, Shaowu Meng, Mark S. Soloway, Tatjana Antic, Greg Eley, Hikmat Al-Ahmadie, Carolyn M. Hutter, Jonathan G. Seidman, Corbin D. Jones, Lori Boice, Xiaoping Su, Jay Bowen, Raju Kucherlapati, Hui Shen, Benjamin Gross, Reanne Bowlby, Lawrence A. Donehower, Phan Thi Hanh, David J. McConkey, Saianand Balu, Jiexin Zhang, Tina Wong, Juok Cho, Alexei Protopopov, Carolyn L. Smith, Yuexin Liu, Angeliki Pantazi, Jason R. Gee, Xuan Van Le, Ricardo Ramirez, Ami S. Bhatt, Samuel S. Freeman, Jaegil Kim, Bui Duc Phu, Michael Ittman, Charles C. Guo, Carmen Gomez-Fernandez, Norm D. Smith, S. Onur Sumer, Bradley A. Ozenberger, Paul M. Weinberger, George E. Sandusky, Troy Shelton, Seth P. Lerner, Charles Saller, Nicholas J. Petrelli, Nguyen Van Bang, Sahil Seth, Richard A. Gibbs, Lisle E. Mose, Aaron D. Black, Yair Lotan, Carrie Sougnez, Jessie Au, Martin L. Ferguson, Ashley Marie Regazzi, Matthew Meyerson, Joel B. Nelson, Natasja Wye, Daniel E. Carlin, Nils Weinhold, Tom Bodenheimer, Nilsa C. Ramirez, Michael Ryan, Anders Jacobsen, Eric J. Burks, Lee Lichtenstein, Erin Curley, Angela Hadjipanayis, Nils Gehlenborg, Hector Rovira, Bernard Kohl, Jean C. Zenklusen, Travis Sullivan, Margaret Morgan, Rajiv Dhir, Julie M. Gastier-Foster, Gary D. Steinberg, Mathew G. Soloway, Nina Thiessen, Jianjiong Gao, Lisa Wise, Barry S. Taylor, Gordon Saksena, Hui Yao, David Van Den Berg, Jiabin Tang, Robert Penny, Nguyen Viet Tien, Jeffrey R. Gingrich, Jing Zhu, Ronald L. Hrebinko, Dick Kreisberg, Pei Lin, Christopher A. Bristow, Andrey Sivachenko, Andy Chu, Peter W. Laird, Thomas Barr, Junyuan Wu, Robert A. Holt, Harshad S. Mahadeshwar, Piotr A. Mieczkowski, Steven A. Roberts, Victor E. Reuter, Jeffrey S. Damrauer, Roni J. Bollag, Chad J. Creighton, Johanna Gardner, Michael Parfenov, Qiang Li, Phillip H. Lai, Thomas C. Motter, Alireza Moinzadeh, Jodi K. Maranchie, Christopher C. Benz, Lynda Chin, Angela Tam, Margi Sheth, David B. Solit, Erik Zmuda, Lixing Yang, Peter J. Park, Marco A. Marra, Katherine A. Hoadley, Eila C. Skinner, Scott Frazer, Roy Tarnuzzer, Heidi J. Sofia, Bradley M. Broom, Zhining Wang, David I. Heiman, Sebrina A Tello, Lori Huelsenbeck-Dill, Steven J.M. Jones, Antonia H. Holway, Ilana Rebecca Garcia-Grossman, Merce Jorda, Roeland Verhaak, Ilya Shmulevich, W.K. Rathmell, Bernard H. Bochner, Scot Waring, Kenneth Aldape, Richard A. Moore, Toshinori Hinoue, Carrie Hirst, Mark A. Jensen, Payal Kapur, Andrew D. Cherniack, Dean F. Bajorin, Evano Paull, Cheryl M. Lewis, William Y. Kim, Giovanni Ciriello, David C. Fargo, Gordon B. Mills, Michael S. Noble, Stephanie Weaver, Whitney D. McClenden, Benjamin Davies, Payal Sipahimalani, Vina Alexopoulou, Bo Peng, Stephen B. Baylin, Michael Mayo, Rameen Beroukhim, Boris Reva, Anil V. Parwani, Joshua M. Stuart, David J. Kwiatkowski, Stacey B. Gabrie, Janae V. Simons, Rehan Akbani, Todd Pihl, Nianxiang Zhang, Suzie Carter, Michael S. Lawrence, Carmen Helsel, Carl Morrison, Xiaojia Ren, Jeffrey Roach, Peter H. O'Donnell, Miruna Balasundaram, Yevgeniy Antipin, Gideon Dresdner, Cynthia McAllister, Tanja Davidsen, Brenda Rabeno, Jolanta Bondaruk, Kristian Cibulskis, Chip Stewart, Matthew D. Wilkerson, Jonathan E. Rosenberg, Brian D. Robinson, Patricia Castro, Wei Zhang, Chandra Sekhar Pedamallu, Allison Beaver, Andrew Wei Xu, Adrian Ally, Andrea Sorcini, Andrew J. Mungall, Katherine Tarvin, Christine Czerwinski, Petar Stojanov, Philip L. Lorenzi, Alan P. Hoyle, Jay Engel, Tara M. Lichtenberg, D. Neil Hayes, John A. Demchok, Eric Chuah, Benjamin Hanf, Deepak Srinivasan, Donna E. Hansel, Noreen Dhalla, Zhenlin Ju, Leszek J. Klimczak, Trevor J. Pugh, Richard Thorp, A. Gordon Robertson, Darlene Lee, Steven E. Schumacher, Semin Lee, Sheldon I. Bastacky, Rileen Sinha, Haiyan I. Li, William Lee, Sam Ng, Joel S. Parker, Sheila Reynolds, Teresa R. Tabler, Yaron S.N. Butterfield, David Pot, Chris Sander, Wenyi Wang, Weiguo Jian, Le Quang Vinh, Netty Santoso, Doug Voet, and Joonil Jung

Subjects
Metastatic Urothelial Carcinoma, Invasive urothelial carcinoma, Virus Integration, Down-Regulation, Disease, Bioinformatics, Malignancy, Article, Phosphatidylinositol 3-Kinases, Cancer genome, medicine, Carcinoma, Humans, Molecular Targeted Therapy, RNA, Messenger, Urothelial carcinoma, Multidisciplinary, business.industry, TOR Serine-Threonine Kinases, Cell Cycle, Creative commons, medicine.disease, Chromatin, 3. Good health, Gene Expression Regulation, Neoplastic, MicroRNAs, Oxidative Stress, Urinary Bladder Neoplasms, business, Protein Kinases, Proto-Oncogene Proteins c-akt, Signal Transduction
Abstract

Urothelial carcinoma of the bladder is a common malignancy that causes approximately 150,000 deaths per year worldwide. So far, no molecularly targeted agents have been approved for treatment of the disease. As part of The Cancer Genome Atlas project, we report here an integrated analysis of 131 urothelial carcinomas to provide a comprehensive landscape of molecular alterations. There were statistically significant recurrent mutations in 32 genes, including multiple genes involved in cell-cycle regulation, chromatin regulation, and kinase signalling pathways, as well as 9 genes not previously reported as significantly mutated in any cancer. RNA sequencing revealed four expression subtypes, two of which (papillary-like and basal/squamous-like) were also evident in microRNA sequencing and protein data. Whole-genome and RNA sequencing identified recurrent in-frame activating FGFR3-TACC3 fusions and expression or integration of several viruses (including HPV16) that are associated with gene inactivation. Our analyses identified potential therapeutic targets in 69% of the tumours, including 42% with targets in the phosphatidylinositol-3-OH kinase/AKT/mTOR pathway and 45% with targets (including ERBB2) in the RTK/MAPK pathway. Chromatin regulatory genes were more frequently mutated in urothelial carcinoma than in any other common cancer studied so far, indicating the future possibility of targeted therapy for chromatin abnormalities.

Published
2013

28. Comprehensive molecular profiling of lung adenocarcinoma

Author

Amie Radenbaugh, Noreen Dhalla, Christina Williamson, Charles Saller, James Suh, Ramaswamy Govindan, Travis I. Zack, Paul T. Spellman, Daniel DiCara, Harvey I. Pass, Deepak Srinivasan, William G. Richards, Robert J. Cerfolio, Igor Letovanec, A. Gordon Robertson, Gabriel Sica, Chad J. Creighton, Hendrik Dienemann, Jeffrey A. Borgia, Boris Reva, Bryan F. Meyers, Yiling Lu, Nikolaus Schultz, Christopher I. Amos, Dante Trusty, Carmelo Gaudioso, Michael Meister, James T. Robinson, Lihua Zou, James Shin, Jeremy Parfitt, Darlene Lee, Junyuan Wu, Carl Morrison, Scott L. Carter, Giovanni Ciriello, Nils Weinhold, Elena Nemirovich-Danchenko, Andrew Wei Xu, Christopher G. Maher, Lori Boice, Irina Zaytseva, Dennis A. Wigle, Kenna R. Mills Shaw, Matthew G. Soloway, Matthew Meyerson, Peng Chieh Chen, Frank Schneider, Troy Shelton, Douglas Voet, Steven E. Schumacher, D L Rotin, Saianand Balu, Stuart R. Jefferys, Tom Bodenheimer, Bradley A. Ozenberger, Eric S. Lander, Edward Gabrielson, Konstantin V. Fedosenko, Rehan Akbani, William D. Travis, Ari B. Kahn, Marcin Imielinski, Jacqueline E. Schein, Thomas L. Bauer, Kai Ye, Samuel A. Yousem, Robert C. Onofrio, Thomas Muley, Ayesha S. Bryant, Michael K. Asiedu, Monique Albert, Pei Lin, Corbin D. Jones, Edwina Duhig, Jean C. Zenklusen, Lucinda Fulton, Christina Yau, J. Todd Auman, Leigh B. Thorne, Elena Helman, Richard T. Cheney, William Lee, Patrick K. Kimes, Juok Cho, Alexei Protopopov, Wenbin Liu, Lee Lichtenstein, Jing Wang, Lixing Yang, W. Kimryn Rathmell, Jo Ellen Weaver, David A. Wheeler, Leslie Cope, Mark A. Watson, Heidi J. Sofia, Angeliki Pantazi, Ronglai Shen, Jeffrey Roach, Eric A. Collisson, Patrick Kwok Shing Ng, Angela Hadjipanayis, Peter S. Hammerman, David Van Den Berg, Kwun M. Fong, Nils Gehlenborg, Natasha Rekhtman, William K. Funkhouser, D. Neil Hayes, Harshad S. Mahadeshwar, Semin Lee, Martin Peifer, David Mallery, Piotr A. Mieczkowski, Ranabir Guin, Madhusmita Behera, Philipp A. Schnabel, Jill M. Siegfried, Carmen Gomez-Fernandez, Johanna Gardner, Lynn M. Herbert, Hailei Zhang, Robert S. Fulton, Travis Sullivan, Sahil Seth, Sam Ng, Chandra Sekhar Pedamallu, Barry S. Taylor, Venkatraman E. Seshan, Valerie W. Rusch, Jinze Liu, Daniel P. Raymond, Jianjiong Gao, Nathan A. Pennell, Marco A. Marra, Jan F. Prins, Payal Sipahimalani, Janae V. Simons, Joel S. Parker, Rileen Sinha, Lindy Hunter, Raju Kucherlapati, Dennis T. Maglinte, Fedor Moiseenko, Eric E. Snyder, Roy Tarnuzzer, Beverly Lee, James Stephen Marron, Kristian Cibulskis, Jerome Myers, Haiyan I. Li, Robert Penny, Hartmut Juhl, Richard K. Wilson, Zhining Wang, Eran Hodis, Carrie Sougnez, Jiabin Tang, William Mallard, Bryan Hernandez, Liming Yang, Jennifer Brown, Gad Getz, Farhad Kosari, Catrina Fronick, Juliann Chmielecki, Jianhua Zhang, Suresh S. Ramalingam, Michael Parfenov, Peter J. Park, Tanja Davidsen, Philip H. Lai, Jeff Boyd, Dang Huy Quoc Thinh, Harmanjatinder S. Sekhon, Malcolm V. Brock, Mark Pool, Margi Sheth, Kimberly M. Rieger-Christ, Michael J. Liptay, E. Getz, S. Onur Sumer, Ian A. Yang, B. Arman Aksoy, Douglas B. Flieder, Bradley M. Broom, Carrie Hirst, Solange Peters, Joshua M. Stuart, Khurram Z. Khan, Scott Morris, Donghui Tan, Andrew J. Mungall, Ming-Sound Tsao, Gordon B. Mills, Stephen B. Baylin, Rebecca Carlsen, Sanja Dacic, Julien Baboud, Brenda Rabeno, Richard A. Hajek, Lauren Averett Byers, Yaron S.N. Butterfield, Miruna Balasundaram, Chip Stewart, Katherine Tarvin, Peter B. Illei, James G. Herman, David J. Kwiatkowski, Andy Chu, David Haussler, Natasja Wye, Charles M. Perou, Peter W. Laird, Timothy J. Triche, Yan Shi, Jill P. Mesirov, Angela N. Brooks, Lori Huelsenbeck-Dill, Steven J.M. Jones, Antonia H. Holway, Lixia Diao, Anthony A. Gal, David G. Beer, Angela Tam, Ashley H. Salazar, Mark A. Jensen, Robert A. Holt, Katherine A. Hoadley, John A. Demchok, Sandra McDonald, Chandra Goparaju, David Pot, Belinda E. Clarke, Gordon Robertson, Michael C. Wendl, Helga Thorvaldsdottir, Kristen Rogers, Joshua D. Campbell, Chris Sander, Rayleen V. Bowman, Marc Danie Nazaire, Michael Mayo, Olga Voronina, Ludmila Danilova, Paul Zippile, Netty Santoso, John V. Heymach, Matthew D. Wilkerson, John Eckman, Morgan Windsor, Cureline Oleg Dolzhanskiy, Nina Thiessen, Mara Rosenberg, Gideon Dresdner, Levi A. Garraway, Eric Chuah, Richard Varhol, Elizabeth Buda, Li Ding, Alice H. Berger, Xingzhi Song, John M. S. Bartlett, Michael D. McLellan, Olga Potapova, Joseph Paulauskis, Igor Jurisica, Benjamin Gross, Jaegil Kim, John N. Weinstein, Kevin Lau, Christopher R. Cabanski, Philip Bonomi, Michael S. Noble, Maureen F. Zakowski, George E. Sandusky, Mary Iacocca, Eric J. Burks, Erin Curley, Lynda Chin, Rajiv Dhir, Singer Ma, Sophie C. Egea, Umadevi Veluvolu, Sugy Kodeeswaran, Christopher A. Miller, Moiz S. Bootwalla, Daniel J. Weisenberger, Shaowu Meng, Mei Huang, Elaine R. Mardis, Gordon Saksena, Nicholas J. Petrelli, Yvonne Owusu-Sarpong, Christopher C. Benz, Bernard Kohl, Jingchun Zhu, David I. Heiman, Carol Farver, Scot Waring, Richard A. Moore, Darshan Singh, Andrew D. Cherniack, Rameen Beroukhim, Michael S. Lawrence, Xiaojia Ren, Marc Ladanyi, Stacey Gabriel, Christine Czerwinski, Alan P. Hoyle, Cancer Genome Atlas Research Network, Collisson, E. A., Campbell, J.D., Brooks, A.N., Berger, A.H., Lee, W., Chmielecki, J., Beer, D.G., Cope, L., Creighton, C.J., Danilova, L., Ding, L., Getz, G., Hammerman, P.S., Hayes, D.N., Hernandez, B., Herman, J.G., Heymach, J.V., Jurisica, I., Kucherlapati, R., Kwiatkowski, D., Ladanyi, M., Robertson, G., Schultz, N., Shen, R., Sinha, R., Sougnez, C., Tsao, M.S., Travis, W.D., Weinstein, J.N., Wigle, D.A., Wilkerson, M.D., Chu, A., Cherniack, A.D., Hadjipanayis, A., Rosenberg, M., Weisenberger, D.J., Laird, P.W., Radenbaugh, A., Ma, S., Stuart, J.M., Averett Byers, L., Baylin, S.B., Govindan, R., Meyerson, M., Gabriel, S.B., Cibulskis, K., Kim, J., Stewart, C., Lichtenstein, L., Lander, E.S., Lawrence, M.S., Kandoth, C., Fulton, R., Fulton, L.L., McLellan, M.D., Wilson, R.K., Ye, K., Fronick, C.C., Maher, C.A., Miller, C.A., Wendl, M.C., Cabanski, C., Mardis, E., Wheeler, D., Balasundaram, M., Butterfield, Y.S., Carlsen, R., Chuah, E., Dhalla, N., Guin, R., Hirst, C., Lee, D., Li, H.I., Mayo, M., Moore, R.A., Mungall, A.J., Schein, J.E., Sipahimalani, P., Tam, A., Varhol, R., Robertson, A., Wye, N., Thiessen, N., Holt, R.A., Jones, S.J., Marra, M.A., Imielinski, M., Onofrio, R.C., Hodis, E., Zack, T., Helman, E., Sekhar Pedamallu, C., Mesirov, J., Saksena, G., Schumacher, S.E., Carter, S.L., Garraway, L., Beroukhim, R., Lee, S., Mahadeshwar, H.S., Pantazi, A., Protopopov, A., Ren, X., Seth, S., Song, X., Tang, J., Yang, L., Zhang, J., Chen, P.C., Parfenov, M., Wei Xu, A., Santoso, N., Chin, L., Park, P.J., Hoadley, K.A., Auman, J.T., Meng, S., Shi, Y., Buda, E., Waring, S., Veluvolu, U., Tan, D., Mieczkowski, P.A., Jones, C.D., Simons, J.V., Soloway, M.G., Bodenheimer, T., Jefferys, S.R., Roach, J., Hoyle, A.P., Wu, J., Balu, S., Singh, D., Prins, J.F., Marron, J.S., Parker, J.S., Perou, C.M., Liu, J., Maglinte, D.T., Lai, P.H., Bootwalla, M.S., Van Den Berg, D.J., Triche, T., Cho, J., DiCara, D., Heiman, D., Lin, P., Mallard, W., Voet, D., Zhang, H., Zou, L., Noble, M.S., Gehlenborg, N., Thorvaldsdottir, H., Nazaire, M.D., Robinson, J., Aksoy, B.A., Ciriello, G., Taylor, B.S., Dresdner, G., Gao, J., Gross, B., Seshan, V.E., Reva, B., Sumer, S.O., Weinhold, N., Sander, C., Ng, S., Zhu, J., Benz, C.C., Yau, C., Haussler, D., Spellman, P.T., Kimes, P.K., Broom, B.M., Wang, J., Lu, Y., Kwok Shing Ng, P., Diao, L., Liu, W., Amos, C.I., Akbani, R., Mills, G.B., Curley, E., Paulauskis, J., Lau, K., Morris, S., Shelton, T., Mallery, D., Gardner, J., Penny, R., Saller, C., Tarvin, K., Richards, W.G., Cerfolio, R., Bryant, A., Raymond, D.P., Pennell, N.A., Farver, C., Czerwinski, C., Huelsenbeck-Dill, L., Iacocca, M., Petrelli, N., Rabeno, B., Brown, J., Bauer, T., Dolzhanskiy, O., Potapova, O., Rotin, D., Voronina, O., Nemirovich-Danchenko, E., Fedosenko, K.V., Gal, A., Behera, M., Ramalingam, S.S., Sica, G., Flieder, D., Boyd, J., Weaver, J., Kohl, B., Huy Quoc Thinh, D., Sandusky, G., Juhl, H., Duhig, E., Illei, P., Gabrielson, E., Shin, J., Lee, B., Rodgers, K., Trusty, D., Brock, M.V., Williamson, C., Burks, E., Rieger-Christ, K., Holway, A., Sullivan, T., Asiedu, M.K., Kosari, F., Rekhtman, N., Zakowski, M., Rusch, V.W., Zippile, P., Suh, J., Pass, H., Goparaju, C., Owusu-Sarpong, Y., Bartlett, J.M., Kodeeswaran, S., Parfitt, J., Sekhon, H., Albert, M., Eckman, J., Myers, J.B., Cheney, R., Morrison, C., Gaudioso, C., Borgia, J.A., Bonomi, P., Pool, M., Liptay, M.J., Moiseenko, F., Zaytseva, I., Dienemann, H., Meister, M., Schnabel, P.A., Muley, T.R., Peifer, M., Gomez-Fernandez, C., Herbert, L., Egea, S., Huang, M., Thorne, L.B., Boice, L., Hill Salazar, A., Funkhouser, W.K., Rathmell, W.K., Dhir, R., Yousem, S.A., Dacic, S., Schneider, F., Siegfried, J.M., Hajek, R., Watson, M.A., McDonald, S., Meyers, B., Clarke, B., Yang, I.A., Fong, K.M., Hunter, L., Windsor, M., Bowman, R.V., Peters, S., Letovanec, I., Khan, K.Z., Jensen, M.A., Snyder, E.E., Srinivasan, D., Kahn, A.B., Baboud, J., Pot, D.A., Mills Shaw, K.R., Sheth, M., Davidsen, T., Demchok, J.A., Wang, Z., Tarnuzzer, R., Zenklusen, J.C., Ozenberger, B.A., Sofia, H.J., Massachusetts Institute of Technology. Department of Biology, and Lander, Eric S.

Subjects
Male, Lung Neoplasms, Adenocarcinoma/genetics, Adenocarcinoma/pathology, Cell Cycle Proteins/genetics, Female, Gene Dosage, Gene Expression Regulation, Neoplastic, Genomics, Humans, Lung Neoplasms/genetics, Lung Neoplasms/pathology, Molecular Typing, Mutation/genetics, Oncogenes/genetics, Sex Factors, Transcriptome/genetics, Adenocarcinoma of Lung, Cell Cycle Proteins, Biology, Adenocarcinoma, Exon, Germline mutation, microRNA, Adenocarcinoma of the lung, medicine, Gene, Multidisciplinary, Oncogene, Oncogenes, medicine.disease, MET Exon 14 Skipping Mutation, Molecular biology, 3. Good health, Mutation, Transcriptome
Abstract

Adenocarcinoma of the lung is the leading cause of cancer death worldwide. Here we report molecular profiling of 230 resected lung adenocarcinomas using messenger RNA, microRNA and DNA sequencing integrated with copy number, methylation and proteomic analyses. High rates of somatic mutation were seen (mean 8.9 mutations per megabase). Eighteen genes were statistically significantly mutated, including RIT1 activating mutations and newly described loss-of-function MGA mutations which are mutually exclusive with focal MYC amplification. EGFR mutations were more frequent in female patients, whereas mutations in RBM10 were more common in males. Aberrations in NF1, MET, ERBB2 and RIT1 occurred in 13% of cases and were enriched in samples otherwise lacking an activated oncogene, suggesting a driver role for these events in certain tumours. DNA and mRNA sequence from the same tumour highlighted splicing alterations driven by somatic genomic changes, including exon 14 skipping in MET mRNA in 4% of cases. MAPK and PI(3)K pathway activity, when measured at the protein level, was explained by known mutations in only a fraction of cases, suggesting additional, unexplained mechanisms of pathway activation. These data establish a foundation for classification and further investigations of lung adenocarcinoma molecular pathogenesis.

Published
2013

29. Constraints on early Earth differentiation from hafnium and neodymium isotopes

Author

Allen P. Nutman, P. J. Patchett, George E. Gehrels, and Jeffrey D. Vervoort

Subjects
Multidisciplinary, Isotope fractionation, Continental crust, Isua Greenstone Belt, Geochemistry, Crust, Samarium-neodymium dating, Early Earth, Mantle (geology), Geology, Zircon
Abstract

INFERENCES about the early evolution of the Earth's crust and mantle have come largely from the study of isotope systematics— in particular, those of neodymium1–5. Neodymium isotope data from the oldest preserved rocks have been interpreted4,6–8 as reflecting early large-scale chemical depletion of the mantle (presumably resulting from the extraction of continental crust), but these data have remained controversial, in view of the potential for disturbances to the samarium–neodymium system during these rocks' long history9–11. Here we provide an independent evaluation of the Nd isotope compositions of ten early Archaean (3.6–3.8 Gyr old) gneisses, by investigating the hafnium isotope systematics of zircons from these rocks. The Hf data are consistent with the Nd record in indicating early depletion of the mantle, but fail to verify the scale and variability of this depletion. We conclude that Nd isotopes of early Archaean gneisses do not faithfully record isotopic variations in the early Earth, and therefore that these data need to be examined more critically before they can be used to constrain the early history of crust–mantle differentiation.

Published
1996
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30. Retraction Note: Non-blinking semiconductor nanocrystals

Author

Wang, Xiaoyong, primary, Ren, Xiaofan, additional, Kahen, Keith, additional, Hahn, Megan A., additional, Rajeswaran, Manju, additional, Maccagnano-Zacher, Sara, additional, Silcox, John, additional, Cragg, George E., additional, Efros, Alexander L., additional, and Krauss, Todd D., additional

Published
2015
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31. Beating the Stoner criterion using molecular interfaces

Author

Ma’Mari, Fatma Al, primary, Moorsom, Timothy, additional, Teobaldi, Gilberto, additional, Deacon, William, additional, Prokscha, Thomas, additional, Luetkens, Hubertus, additional, Lee, Steve, additional, Sterbinsky, George E., additional, Arena, Dario A., additional, MacLaren, Donald A., additional, Flokstra, Machiel, additional, Ali, Mannan, additional, Wheeler, May C., additional, Burnell, Gavin, additional, Hickey, Bryan J., additional, and Cespedes, Oscar, additional

Published
2015
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32. Chronic active B-cell-receptor signalling in diffuse large B-cell lymphoma

Author

Erlend B. Smeland, Georg Lenz, Jan Delabie, Randy D. Gascoyne, Craig J. Thomas, Nathalie A. Johnson, Jian Kang Jiang, Arthur L. Shaffer, Joseph M. Connors, Laurence Lamy, R. Eric Davis, Rita M. Braziel, Hong Zhao, Andreas Rosenwald, John Powell, Vu N. Ngo, James R. Cook, Hans K. Müller-Hermelink, Wing C. Chan, Louis M. Staudt, Susan K. Pierce, Holger Kohlhammer, Richard I. Fisher, Elaine S. Jaffe, Yandan Yang, Weihong Xu, Lisa M. Rimsza, Wyndham H. Wilson, Raymond R. Tubbs, Elias Campo, German Ott, Ryan M. Young, Pavel Tolar, Paul B. Romesser, Wenming Xiao, Dennis D. Weisenburger, and George E. Wright

Subjects
Cell Survival, B-cell receptor, Amino Acid Motifs, Receptors, Antigen, B-Cell, Biology, Article, LYN, hemic and lymphatic diseases, Cell Line, Tumor, medicine, Agammaglobulinaemia Tyrosine Kinase, Humans, B-Lymphocytes, Multidisciplinary, Cell Membrane, breakpoint cluster region, Large-cell lymphoma, BCR Signaling Pathway, Protein-Tyrosine Kinases, CD79A, medicine.disease, CARD Signaling Adaptor Proteins, src-Family Kinases, Guanylate Cyclase, Mutation, Cancer research, RNA Interference, Lymphoma, Large B-Cell, Diffuse, Diffuse large B-cell lymphoma, Tyrosine kinase, CD79 Antigens, Signal Transduction
Abstract

A role for B-cell-receptor (BCR) signalling in lymphomagenesis has been inferred by studying immunoglobulin genes in human lymphomas and by engineering mouse models, but genetic and functional evidence for its oncogenic role in human lymphomas is needed. Here we describe a form of 'chronic active' BCR signalling that is required for cell survival in the activated B-cell-like (ABC) subtype of diffuse large B-cell lymphoma (DLBCL). The signalling adaptor CARD11 is required for constitutive NF-kappaB pathway activity and survival in ABC DLBCL. Roughly 10% of ABC DLBCLs have mutant CARD11 isoforms that activate NF-kappaB, but the mechanism that engages wild-type CARD11 in other ABC DLBCLs was unknown. An RNA interference genetic screen revealed that a BCR signalling component, Bruton's tyrosine kinase, is essential for the survival of ABC DLBCLs with wild-type CARD11. In addition, knockdown of proximal BCR subunits (IgM, Ig-kappa, CD79A and CD79B) killed ABC DLBCLs with wild-type CARD11 but not other lymphomas. The BCRs in these ABC DLBCLs formed prominent clusters in the plasma membrane with low diffusion, similarly to BCRs in antigen-stimulated normal B cells. Somatic mutations affecting the immunoreceptor tyrosine-based activation motif (ITAM) signalling modules of CD79B and CD79A were detected frequently in ABC DLBCL biopsy samples but rarely in other DLBCLs and never in Burkitt's lymphoma or mucosa-associated lymphoid tissue lymphoma. In 18% of ABC DLBCLs, one functionally critical residue of CD79B, the first ITAM tyrosine, was mutated. These mutations increased surface BCR expression and attenuated Lyn kinase, a feedback inhibitor of BCR signalling. These findings establish chronic active BCR signalling as a new pathogenetic mechanism in ABC DLBCL, suggesting several therapeutic strategies.

Published
2009

33. Non-blinking semiconductor nanocrystals

Author

George E. Cragg, Xiaofan Ren, Manju Rajeswaran, John Silcox, Sara Maccagnano-Zacher, Todd D. Krauss, Xiaoyong Wang, Megan A. Hahn, Keith B. Kahen, and Alexander L. Efros

Subjects
Multidisciplinary, Photoluminescence, Materials science, Cadmium selenide, Auger effect, business.industry, Fluorescence intermittency, Electron hole, chemistry.chemical_compound, symbols.namesake, chemistry, Nanocrystal, symbols, Optoelectronics, Zinc selenide, Atomic physics, business, Non-radiative recombination
Abstract

The photoluminescence from a variety of individual molecules and nanometre-sized crystallites is defined by large intensity fluctuations, known as 'blinking', whereby their photoluminescence turns 'on' and 'off' intermittently, even under continuous photoexcitation. For semiconductor nanocrystals, it was originally proposed that these 'off' periods corresponded to a nanocrystal with an extra charge. A charged nanocrystal could have its photoluminescence temporarily quenched owing to the high efficiency of non-radiative (for example, Auger) recombination processes between the extra charge and a subsequently excited electron-hole pair; photoluminescence would resume only after the nanocrystal becomes neutralized again. Despite over a decade of research, completely non-blinking nanocrystals have not been synthesized and an understanding of the blinking phenomenon remains elusive. Here we report ternary core/shell CdZnSe/ZnSe semiconductor nanocrystals that individually exhibit continuous, non-blinking photoluminescence. Unexpectedly, these nanocrystals strongly photoluminesce despite being charged, as indicated by a multi-peaked photoluminescence spectral shape and short lifetime. To model the unusual photoluminescence properties of the CdZnSe/ZnSe nanocrystals, we softened the abrupt confinement potential of a typical core/shell nanocrystal, suggesting that the structure is a radially graded alloy of CdZnSe into ZnSe. As photoluminescence blinking severely limits the usefulness of nanocrystals in applications requiring a continuous output of single photons, these non-blinking nanocrystals may enable substantial advances in fields ranging from single-molecule biological labelling to low-threshold lasers.

Published
2009

34. IRF4 addiction in multiple myeloma

Author

John Powell, Wenming Xiao, Arthur L. Shaffer, Xin Yu, George E. Wright, Yuxin Zeng, Louis M. Staudt, Joshua Epstein, Sandeep S. Dave, N. C. Tolga Emre, Laurence Lamy, Bangzheng Chen, Vu N. Ngo, and Hong Zhao

Subjects
Transcriptional Activation, Chromatin Immunoprecipitation, Cell Survival, Genes, myc, Biology, Article, Proto-Oncogene Proteins c-myc, Transactivation, Mice, medicine, Animals, Humans, Multiple myeloma, Cells, Cultured, Regulation of gene expression, B-Lymphocytes, Multidisciplinary, Gene Expression Profiling, medicine.disease, Gene expression profiling, Gene Expression Regulation, Neoplastic, Cell Transformation, Neoplastic, Immunology, Interferon Regulatory Factors, Cancer research, RNA Interference, Clone (B-cell biology), Multiple Myeloma, IRF4, Interferon regulatory factors, Genetic screen
Abstract

The transcription factor IRF4 (interferon regulatory factor 4) is required during an immune response for lymphocyte activation and the generation of immunoglobulin-secreting plasma cells. Multiple myeloma, a malignancy of plasma cells, has a complex molecular aetiology with several subgroups defined by gene expression profiling and recurrent chromosomal translocations. Moreover, the malignant clone can sustain multiple oncogenic lesions, accumulating genetic damage as the disease progresses. Current therapies for myeloma can extend survival but are not curative. Hence, new therapeutic strategies are needed that target molecular pathways shared by all subtypes of myeloma. Here we show, using a loss-of-function, RNA-interference-based genetic screen, that IRF4 inhibition is toxic to myeloma cell lines, regardless of transforming oncogenic mechanism. Gene expression profiling and genome-wide chromatin immunoprecipitation analysis uncovered an extensive network of IRF4 target genes and identified MYC as a direct target of IRF4 in activated B cells and myeloma. Unexpectedly, IRF4 was itself a direct target of MYC transactivation, generating an autoregulatory circuit in myeloma cells. Although IRF4 is not genetically altered in most myelomas, they are nonetheless addicted to an aberrant IRF4 regulatory network that fuses the gene expression programmes of normal plasma cells and activated B cells.

Published
2008

35. Retraction Note: Non-blinking semiconductor nanocrystals

Author

Xiaofan Ren, Megan A. Hahn, Todd D. Krauss, Alexander L. Efros, Keith B. Kahen, George E. Cragg, Xiaoyong Wang, Manju Rajeswaran, Sara Maccagnano-Zacher, and John Silcox

Subjects
chemistry.chemical_compound, Multidisciplinary, Fluorophore, Materials science, chemistry, Silica glass, business.industry, Quantum dot, Optoelectronics, Semiconductor nanocrystals, business, Fluorescence
Abstract

In this Letter, we reported the unusual non-blinking characteristics of the fluorescence from individual CdZnSe/ZnSe alloyed quantum dots. However, it has recently come to our attention that similar fluorescence behaviour was seen by Celso de MelloDonega, Daniel Vanmaekelbergh and co-workers from a single fluorophore on bare silica glass.

Published
2015
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36. Endothelial tubes assemble from intracellular vacuoles in vivo

Author

Kayla J. Bayless, W. Brian Saunders, Louis Dye, George E. Davis, Brant M. Weinstein, and Makoto Kamei

Subjects
Tube formation, Multidisciplinary, Endothelium, Angiogenesis, Intracellular Space, Neovascularization, Physiologic, CDC42, Vacuole, Biology, Cell biology, Animals, Genetically Modified, medicine.anatomical_structure, In vivo, Tube morphogenesis, Vacuoles, medicine, Morphogenesis, Animals, Blood Vessels, Humans, Endothelium, Vascular, Intracellular, Zebrafish
Abstract

Epithelial tubes are important structural components in many different tissues, including the vascular system, where because of the interest in angiogenesis inhibitors as anticancer drugs, they are pharmacologically important too. It has been difficult to establish their exact mechanism of formation. Now high resolution time-lapse imaging of blood vessel formation in living (and conveniently transparent) zebrafish shows that the lumen of the blood vessels is formed by coalescence of intracellular vacuoles, followed by fusion to the plasma membrane. The study finally provides in vivo confirmation of the century-old fusion model for endothelial lumen formation, and finally lays to rest alternative models and concerns about cell culture artefacts. High-resolution time-lapse imaging from zebrafish shows that the lumen of blood vessels is formed by coalescence of intracellular vacuoles, followed by fusion to the plasma membrane. The formation of epithelial tubes is crucial for the proper development of many different tissues and organs, and occurs by means of a variety of different mechanisms1. Morphogenesis of seamless, properly patterned endothelial tubes is essential for the development of a functional vertebrate circulatory system, but the mechanism of vascular lumenization in vivo remains unclear. Evidence dating back more than 100 years has hinted at an important function for endothelial vacuoles in lumen formation2. More than 25 years ago, in some of the first endothelial cell culture experiments in vitro, Folkman and Haudenschild described “longitudinal vacuoles” that “appeared to be extruded and connected from one cell to the next”3,4, observations confirmed and extended by later studies in vitro showing that intracellular vacuoles arise from integrin-dependent and cdc42/Rac1-dependent pinocytic events downstream of integrin–extracellular-matrix signalling interactions5,6,7,8,9,10. Despite compelling data supporting a model for the assembly of endothelial tubes in vitro through the formation and fusion of vacuoles, conclusive evidence in vivo has been lacking, primarily because of difficulties associated with imaging the dynamics of subcellular endothelial vacuoles deep within living animals. Here we use high-resolution time-lapse two-photon imaging of transgenic zebrafish to examine how endothelial tubes assemble in vivo, comparing our results with time-lapse imaging of human endothelial-cell tube formation in three-dimensional collagen matrices in vitro. Our results provide strong support for a model in which the formation and intracellular and intercellular fusion of endothelial vacuoles drives vascular lumen formation.

Published
2006

37. North Pacific seasonality and the glaciation of North America 2.7 million years ago

Author

Samuel L Jaccard, Jörg Bollmann, Ralf Tiedemann, Melanie J. Leng, Andrey Ganopolski, Mark A. Maslin, Gerald H. Haug, George E. A. Swann, Daniel M. Sigman, Antoni Rosell-Melé, Geoffrey Eglinton, and 5.2 Climate Dynamics and Landscape Evolution, 5.0 Earth Surface Processes, Departments, GFZ Publication Database, Deutsches GeoForschungsZentrum

Subjects
Geologic Sediments, Time Factors, 550 - Earth sciences, Huronian glaciation, Snow, Cryosphere, Ice Cover, Seawater, Glacial period, History, Ancient, Diatoms, geography, Multidisciplinary, geography.geographical_feature_category, Pacific Ocean, Arctic Regions, Northern Hemisphere, Temperature, Cold Climate, Oxygen, Oceanography, Wisconsin glaciation, Thermohaline circulation, Seasons, Bull Lake glaciation, Ice sheet, Geology
Abstract

In the context of gradual Cenozoic cooling, the timing of the onset of significant Northern Hemisphere glaciation 2.7 million years ago is consistent with Milankovitch's orbital theory, which posited that ice sheets grow when polar summertime insolation and temperature are low. However, the role of moisture supply in the initiation of large Northern Hemisphere ice sheets has remained unclear. The subarctic Pacific Ocean represents a significant source of water vapour to boreal North America, but it has been largely overlooked in efforts to explain Northern Hemisphere glaciation. Here we present alkenone unsaturation ratios and diatom oxygen isotope ratios from a sediment core in the western subarctic Pacific Ocean, indicating that 2.7 million years ago late-summer sea surface temperatures in this ocean region rose in response to an increase in stratification. At the same time, winter sea surface temperatures cooled, winter floating ice became more abundant and global climate descended into glacial conditions. We suggest that the observed summer warming extended into the autumn, providing water vapour to northern North America, where it precipitated and accumulated as snow, and thus allowed the initiation of Northern Hemisphere glaciation.

Published
2004

41. Takhtajania perrieri rediscovered

Author

Annick Ramisamihantanirina, Porter P. Lowry, and George E. Schatz

Subjects
Multidisciplinary, Extant taxon, biology, Darwin (ADL), Winteraceae, Ethnology, Zoology, Context (language use), Takhtajania, biology.organism_classification, Living fossil, Cretaceous
Abstract

Spectacular finds of early Cretaceous fossil flowers during the past decade have fuelled a resurgence of research into the origin of flowering plants1, the “abominable mystery” that so captivated Darwin. Now Takhtajania perrieri (Capuron) Baranova & J.-F. Leroy, the only extant Africa/ Madagascar representative of the family Winteraceae, has been rediscovered in northeastern Madagascar, 85 years after its original finding. Scientists will thus once again have a ‘living fossil’ to study and place in the context of both extinct and other extant primitive angiosperms.

Published
1998
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48. North Pacific seasonality and the glaciation of North America 2.7?million years ago.

Author

Haug, Gerald H., Ganopolski, Andrey, Sigman, Daniel M., Rosell-Mele, Antoni, Swann, George E. A., Tiedemann, Ralf, Jaccard, Samuel L., Bollmann, Jörg, Maslin, Mark A., Leng, Melanie J., and Eglinton, Geoffrey

Subjects
GLACIAL climates, SEASONS, ATMOSPHERE, TEMPERATURE
Abstract

In the context of gradual Cenozoic cooling, the timing of the onset of significant Northern Hemisphere glaciation 2.7 million years ago is consistent with Milankovitch's orbital theory, which posited that ice sheets grow when polar summertime insolation and temperature are low. However, the role of moisture supply in the initiation of large Northern Hemisphere ice sheets has remained unclear. The subarctic Pacific Ocean represents a significant source of water vapour to boreal North America, but it has been largely overlooked in efforts to explain Northern Hemisphere glaciation. Here we present alkenone unsaturation ratios and diatom oxygen isotope ratios from a sediment core in the western subarctic Pacific Ocean, indicating that 2.7 million years ago late-summer sea surface temperatures in this ocean region rose in response to an increase in stratification. At the same time, winter sea surface temperatures cooled, winter floating ice became more abundant and global climate descended into glacial conditions. We suggest that the observed summer warming extended into the autumn, providing water vapour to northern North America, where it precipitated and accumulated as snow, and thus allowed the initiation of Northern Hemisphere glaciation. [ABSTRACT FROM AUTHOR]

Published
2005
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49. NF-K B and HIV

Author

George E. Griffin, Gary J. Nabel, Thomas M. Folks, Kwanyee Leung, and Steven Kunkel

Subjects
Multidisciplinary, Human immunodeficiency virus (HIV), medicine, Biology, medicine.disease_cause, Virology
Published
1990
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