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1,070 results on '"Johnson, Randy"'

8. SPTAN1/NUMB axis senses cell density to restrain cell growth and oncogenesis through Hippo signaling

Author

Su, Dongxue, Li, Yuxi, Zhang, Weiji, Gao, Huan, Cheng, Yao, Hou, Yongqiang, Li, Junhong, Ye, Yi, Lai, Zhangjian, Li, Zhe, Huang, Haitao, Li, Jiaxin, Li, Jinhuan, Cheng, Mengyu, Nian, Cheng, Wu, Na, Zhou, Zhien, Xing, Yunzhi, Zhao, Yu, Liu, He, Tang, Jiayu, Chen, Qinghua, Hong, Lixin, Li, Wengang, Peng, Zhihai, Zhao, Bin, Johnson, Randy L., Liu, Pingguo, Hong, Wanjin, Chen, Lanfen, and Zhou, Dawang

Subjects
Carcinogenesis -- Growth, Liver cancer, Membrane proteins -- Growth, Company growth, Health care industry
Abstract

The loss of contact inhibition is a key step during carcinogenesis. The Hippo-Yes-associated protein (Hippo/YAP) pathway is an important regulator of cell growth in a cell density-dependent manner. However, how Hippo signaling senses cell density in this context remains elusive. Here, we report that high cell density induced the phosphorylation of spectrin a chain, nonerythrocytic 1 (SPTAN1), a plasma membrane-stabilizing protein, to recruit NUMB endocytic adaptor protein isoforms 1 and 2 (NUMB1/2), which further sequestered microtubule affinity-regulating kinases (MARKs) in the plasma membrane and rendered them inaccessible for phosphorylation and inhibition of the Hippo kinases sterile 20-like kinases MST1 and MST2 (MST1/2). WW45 interaction with MST1/2 was thereby enhanced, resulting in the activation of Hippo signaling to block YAP activity for cell contact inhibition. Importantly, low cell density led to SPTAN1 dephosphorylation and NUMB cytoplasmic location, along with MST1/2 inhibition and, consequently, YAP activation. Moreover, double KO of NUMB and WW45 in the liver led to appreciable organ enlargement and rapid tumorigenesis. Interestingly, NUMB isoforms 3 and 4, which have a truncated phosphotyrosine-binding (PTB) domain and are thus unable to interact with phosphorylated SPTAN1 and activate MST1/2, were selectively upregulated in liver cancer, which correlated with YAP activation. We have thus revealed a SPTAN1/ NUMB1/2 axis that acts as a cell density sensor to restrain cell growth and oncogenesis by coupling external cell-cell contact signals to intracellular Hippo signaling., Introduction Cells within multicellular organisms are able to sense cell-cell contact and their density to control the proper tissue morphogenesis and organ size (1, 2). When cell density increases, contact [...]

Published
2023
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9. Correct $\Delta m^2_{ij}$ Dependence for Neutrino Oscillation Formulae

Author

Johnson, Randy A.

Subjects
High Energy Physics - Phenomenology
Abstract

The time translation operator for neutrino mass states is often taken to be $e^{-iEt/\hbar}$. This is not relativistically invariant. In kaon mixing, physicists use $e^{-imc^2\tau/\hbar}$ where $\tau$ is the proper time of the kaon state. The factor $mc^2\tau$ is the rest frame value of the four vector product $p_\mu x^\mu$ which is an invariant quantity. If $-i p_\mu x^\mu$ is used in neutrino oscillation formulae instead of $-iEt$, the scale of the $\Delta m^2_{ij}$ is reduced by a factor of two., Comment: 1 page

Published
2017

10. Integrated Genomic Comparison of Mouse Models Reveals Their Clinical Resemblance to Human Liver Cancer

Author

Yim, Sun Young, Shim, Jae-Jun, Shin, Ji-Hyun, Jeong, Yun Seong, Kang, Sang-Hee, Kim, Sang-Bae, Eun, Young Gyu, Lee, Dong Jin, Conner, Elizabeth A, Factor, Valentina M, Moore, David D, Johnson, Randy L, Thorgeirsson, Snorri S, and Lee, Ju-Seog

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Immunology, Liver Disease, Genetics, Liver Cancer, Orphan Drug, Biotechnology, Rare Diseases, Human Genome, Cancer, Digestive Diseases, Aetiology, Development of treatments and therapeutic interventions, 5.1 Pharmaceuticals, 2.1 Biological and endogenous factors, Good Health and Well Being, Animals, Carcinoma, Hepatocellular, Disease Models, Animal, Genomics, Humans, Liver Neoplasms, Liver Neoplasms, Experimental, Mice, Prognosis, Developmental Biology, Oncology & Carcinogenesis, Biochemistry and cell biology, Oncology and carcinogenesis
Abstract

Hepatocellular carcinoma (HCC) is a heterogeneous disease. Mouse models are commonly used as preclinical models to study hepatocarcinogenesis, but how well these models recapitulate molecular subtypes of human HCC is unclear. Here, integration of genomic signatures from molecularly and clinically defined human HCC (n = 11) and mouse models of HCC (n = 9) identified the mouse models that best resembled subtypes of human HCC and determined the clinical relevance of each model. Mst1/2 knockout (KO), Sav1 KO, and SV40 T antigen mouse models effectively recapitulated subtypes of human HCC with a poor prognosis, whereas the Myc transgenic model best resembled human HCCs with a more favorable prognosis. The Myc model was also associated with activation of β-catenin. E2f1, E2f1/Myc, E2f1/Tgfa, and diethylnitrosamine (DEN)-induced models were heterogeneous and were unequally split into poor and favorable prognoses. Mst1/2 KO and Sav1 KO models best resemble human HCC with hepatic stem cell characteristics. Applying a genomic predictor for immunotherapy, the six-gene IFNγ score, the Mst1/2 KO, Sav1 KO, SV40, and DEN models were predicted to be the least responsive to immunotherapy. Further analysis showed that elevated expression of immune-inhibitory genes (Cd276 and Nectin2/Pvrl2) in Mst1/2 KO, Sav1 KO, and SV40 models and decreased expression of immune stimulatory gene (Cd86) in the DEN model might be accountable for the lack of predictive response to immunotherapy.Implication: The current genomic approach identified the most relevant mouse models to human liver cancer and suggests immunotherapeutic potential for the treatment of specific subtypes. Mol Cancer Res; 16(11); 1713-23. ©2018 AACR.

Published
2018

13. Glycogen accumulation and phase separation drives liver tumor initiation

Author

Liu, Qingxu, Li, Jiaxin, Zhang, Weiji, Xiao, Chen, Zhang, Shihao, Nian, Cheng, Li, Junhong, Su, Dongxue, Chen, Lihong, Zhao, Qian, Shao, Hui, Zhao, Hao, Chen, Qinghua, Li, Yuxi, Geng, Jing, Hong, Lixin, Lin, Shuhai, Wu, Qiao, Deng, Xianming, Ke, Rongqin, Ding, Jin, Johnson, Randy L., Liu, Xiaolong, Chen, Lanfen, and Zhou, Dawang

Published
2021
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17. Large tumor suppressor homologs 1 and 2 regulate mouse liver progenitor cell proliferation and maturation through antagonism of the coactivators YAP and TAZ.

Author

Yi, Jing, Lu, Li, Yanger, Kilangsungla, Wang, Wenqi, Sohn, Bo Hwa, Stanger, Ben Z, Zhang, Min, Martin, James F, Ajani, Jaffer A, Chen, Junjie, Lee, Ju-Seog, Song, Shumei, and Johnson, Randy L

Subjects
Liver, Hepatocytes, Stem Cells, Animals, Mice, Adaptor Proteins, Signal Transducing, Cell Cycle Proteins, Trans-Activators, Tumor Suppressor Proteins, Phosphoproteins, Cell Differentiation, Cell Proliferation, YAP-Signaling Proteins, Protein Serine-Threonine Kinases, Rare Diseases, Digestive Diseases, Stem Cell Research - Nonembryonic - Non-Human, Liver Disease, Cancer, Stem Cell Research, Genetics, Biotechnology, Aetiology, 2.1 Biological and endogenous factors, Underpinning research, 1.1 Normal biological development and functioning, Oral and gastrointestinal, Medical Biochemistry and Metabolomics, Clinical Sciences, Immunology, Gastroenterology & Hepatology
Abstract

In the adult liver, the Hippo pathway mammalian STE20-like protein kinases 1 and 2 and large tumor suppressor homologs 1 and 2 (LATS1/2) control activation of the transcriptional coactivators Yes-associated protein (YAP) and WW domain containing transcription regulator 1 (TAZ) in hepatocytes and biliary epithelial cells, thereby regulating liver cell proliferation, differentiation, and malignant transformation. Less is known about the contribution of Hippo signaling to liver development. We used conditional mutagenesis to show that the Hippo signaling pathway kinases LATS1 and LATS2 are redundantly required during mouse liver development to repress YAP and TAZ in both the biliary epithelial and hepatocyte lineages. In the absence of LATS1/2, biliary epithelial cells exhibit excess proliferation while hepatoblasts fail to mature into hepatocytes, defects that result in perinatal lethality. Using an in vitro hepatocyte differentiation assay, we demonstrate that YAP activity decreases and Hippo pathway kinase activities increase upon differentiation. In addition, we show that YAP activation in vitro, resulting from either depletion of its negative regulators LATS1/2 or expression of a mutant form of YAP that is less efficiently phosphorylated by LATS1/2, results in transcriptional suppression of genes that normally accompany hepatocyte maturation. Moreover, we provide evidence that YAP activity is repressed by Hippo pathway activation upon hepatocytic maturation in vitro. Finally, we examine the localization of YAP during fetal liver development and show that higher levels of YAP are found in biliary epithelial cells, while in hepatocytes YAP levels decrease with hepatocyte maturation.ConclusionHippo signaling, mediated by the LATS1 and LATS2 kinases, is required to restrict YAP and TAZ activation during both biliary and hepatocyte differentiation. These findings suggest that dynamic regulation of the Hippo signaling pathway plays an important role in differentiation and functional maturation of the liver. (Hepatology 2016;64:1757-1772).

Published
2016

20. AMPK modulates Hippo pathway activity to regulate energy homeostasis

Author

Wang, Wenqi, Xiao, Zhen-Dong, Li, Xu, Aziz, Kathryn E, Gan, Boyi, Johnson, Randy L, and Chen, Junjie

Subjects
Biochemistry and Cell Biology, Biological Sciences, Prevention, Nutrition, Cancer, Genetics, Underpinning research, 1.1 Normal biological development and functioning, AMP-Activated Protein Kinases, Adaptor Proteins, Signal Transducing, Animals, Cell Cycle Proteins, Cell Line, Tumor, Colonic Neoplasms, Energy Metabolism, Enzyme Activation, Female, Glucose, Glucose Transporter Type 3, Glycolysis, HEK293 Cells, HeLa Cells, Hippo Signaling Pathway, Humans, Liver Neoplasms, Mice, Mice, Inbred C57BL, Phosphoproteins, Phosphorylation, Protein Serine-Threonine Kinases, Starvation, Transcription, Genetic, YAP-Signaling Proteins, rho GTP-Binding Proteins, Hela Cells, Medical and Health Sciences, Developmental Biology, Biochemistry and cell biology
Abstract

The Hippo pathway was discovered as a conserved tumour suppressor pathway restricting cell proliferation and apoptosis. However, the upstream signals that regulate the Hippo pathway in the context of organ size control and cancer prevention are largely unknown. Here, we report that glucose, the ubiquitous energy source used for ATP generation, regulates the Hippo pathway downstream effector YAP. We show that both the Hippo pathway and AMP-activated protein kinase (AMPK) were activated during glucose starvation, resulting in phosphorylation of YAP and contributing to its inactivation. We also identified glucose-transporter 3 (GLUT3) as a YAP-regulated gene involved in glucose metabolism. Together, these results demonstrate that glucose-mediated energy homeostasis is an upstream event involved in regulation of the Hippo pathway and, potentially, an oncogenic function of YAP in promoting glycolysis, thereby providing an exciting link between glucose metabolism and the Hippo pathway in tissue maintenance and cancer prevention.

Published
2015

21. The Long-Baseline Neutrino Experiment: Exploring Fundamental Symmetries of the Universe

Author

LBNE Collaboration, Adams, Corey, Adams, David, Akiri, Tarek, Alion, Tyler, Anderson, Kris, Andreopoulos, Costas, Andrews, Mike, Anghel, Ioana, Anjos, João Carlos Costa dos, Antonello, Maddalena, Arrieta-Diaz, Enrique, Artuso, Marina, Asaadi, Jonathan, Bai, Xinhua, Baibussinov, Bagdat, Baird, Michael, Balantekin, Baha, Baller, Bruce, Baptista, Brian, Barker, D'Ann, Barker, Gary, Barletta, William A., Barr, Giles, Bartoszek, Larry, Bashyal, Amit, Bass, Matt, Bellini, Vincenzo, Benetti, Pietro Angelo, Berger, Bruce E., Bergevin, Marc, Berman, Eileen, Berns, Hans-Gerd, Bernstein, Adam, Bernstein, Robert, Bhandari, Babu, Bhatnagar, Vipin, Bhuyan, Bipul, Bian, Jianming, Bishai, Mary, Blake, Andrew, Blaszczyk, Flor, Blaufuss, Erik, Bleakley, Bruce, Blucher, Edward, Blusk, Steve, Bocean, Virgil, Boffelli, F., Boissevain, Jan, Bolton, Timothy, Bonesini, Maurizio, Boyd, Steve, Brandt, Andrew, Breedon, Richard, Bromberg, Carl, Brown, Ralph, Brunetti, Giullia, Buchanan, Norman, Bugg, Bill, Busenitz, Jerome, Calligarich, E., Camilleri, Leslie, Carminati, Giada, Carr, Rachel, Castromonte, Cesar, Cavanna, Flavio, Centro, Sandro, Chen, Alex, Chen, Hucheng, Chen, Kai, Cherdack, Daniel, Chi, Cheng-Yi, Childress, Sam, Choudhary, Brajesh Chandra, Christodoulou, Georgios, Christofferson, Cabot-Ann, Church, Eric, Cline, David, Coan, Thomas, Cocco, Alfredo, Coelho, Joao, Coleman, Stephen, Conrad, Janet M., Convery, Mark, Corey, Robert, Corwin, Luke, Cranshaw, Jack, Cronin-Hennessy, Daniel, Curioni, A., da Motta, Helio, Davenne, Tristan, Davies, Gavin S., Dazeley, Steven, De, Kaushik, de Gouvea, Andre, de Jong, Jeffrey K., Demuth, David, Densham, Chris, Diwan, Milind, Djurcic, Zelimir, Dolfini, R., Dolph, Jeffrey, Drake, Gary, Dye, Stephen, Dyuang, Hongue, Edmunds, Daniel, Elliott, Steven, Elnimr, Muhammad, Eno, Sarah, Enomoto, Sanshiro, Escobar, Carlos O., Evans, Justin, Falcone, A., Falk, Lisa, Farbin, Amir, Farnese, Christian, Fava, Angela, Felde, John, Fernandes, S., Ferroni, Fernando, Feyzi, Farshid, Fields, Laura, Finch, Alex, Fitton, Mike, Fleming, Bonnie, Fowler, Jack, Fox, Walt, Friedland, Alex, Fuess, Stu, Fujikawa, Brian, Gallagher, Hugh, Gandhi, Raj, Garvey, Gerald, Gehman, Victor M., de Geronimo, Gianluigi, Gibin, Daniele, Gill, Ronald, Gomes, Ricardo A., Goodman, Maury C., Goon, Jason, Graf, Nicholas, Graham, Mathew, Gran, Rik, Grant, Christopher, Grant, Nick, Greenlee, Herbert, Greenler, Leland, Grullon, Sean, Guardincerri, Elena, Guarino, Victor, Guarnaccia, Evan, Guedes, Germano, Guenette, Roxanne, Guglielmi, Alberto, Guzzo, Marcelo M., Habig, Alec T., Hackenburg, Robert W., Hadavand, Haleh, Hahn, Alan, Haigh, Martin, Haines, Todd, Handler, Thomas, Hans, Sunej, Hartnell, Jeff, Harton, John, Hatcher, Robert, Hatzikoutelis, Athans, Hays, Steven, Hazen, Eric, Headley, Mike, Heavey, Anne, Heeger, Karsten, Heise, Jaret, Hellauer, Robert, Hewes, V, Himmel, Alexander, Hogan, Matthew, Holanda, Pedro, Holin, Anna, Horton-Smith, Glenn, Howell, Joe, Hurh, Patrick, Huston, Joey, Hylen, James, Imlay, Richard, Insler, Jonathan, Introzzi, G., Isvan, Zeynep, Jackson, Chris, Jacobsen, John, Jaffe, David E., James, Cat, Jen, Chun-Min, Johnson, Marvin, Johnson, Randy, Johnson, Robert, Johnson, Scott, Johnston, William, Johnstone, John, Jones, Ben J. P., Jostlein, H., Junk, Thomas, Kadel, Richard, Kaess, Karl, Karagiorgi, Georgia, Kaspar, Jarek, Katori, Teppei, Kayser, Boris, Kearns, Edward, Keener, Paul, Kemp, Ernesto, Kettell, Steve H., Kirby, Mike, Klein, Joshua, Koizumi, Gordon, Kopp, Sacha, Kormos, Laura, Kropp, William, Kudryavtsev, Vitaly A., Kumar, Ashok, Kumar, Jason, Kutter, Thomas, La Zia, Franco, Lande, Kenneth, Lane, Charles, Lang, Karol, Lanni, Francesco, Lanza, Richard, Latorre, Tony, Learned, John, Lee, David, Lee, Kevin, Li, Qizhong, Li, Shaorui, Li, Yichen, Li, Zepeng, Libo, Jiang, Linden, Steve, Ling, Jiajie, Link, Jonathan, Littenberg, Laurence, Liu, Hu, Liu, Qiuguang, Liu, Tiankuan, Losecco, John, Louis, William, Lundberg, Byron, Lundin, Tracy, Lundy, Jay, Machado, Ana Amelia, Maesano, Cara, Magill, Steve, Mahler, George, Malon, David, Malys, Stephen, Mammoliti, Francesco, Mandal, Samit Kumar, Mann, Anthony, Mantsch, Paul, Marchionni, Alberto, Marciano, William, Mariani, Camillo, Maricic, Jelena, Marino, Alysia, Marshak, Marvin, Marshall, John, Matsuno, Shiegenobu, Mauger, Christopher, Mavrokoridis, Konstantinos, Mayer, Nate, McCauley, Neil, McCluskey, Elaine, McDonald, Kirk, McFarland, Kevin, McKee, David, McKeown, Robert, McTaggart, Robert, Mehdiyev, Rashid, Mei, Dongming, Menegolli, A., Meng, Guang, Meng, Yixiong, Mertins, David, Messier, Mark, Metcalf, William, Milincic, Radovan, Miller, William, Mills, Geoff, Mishra, Sanjib R., Mokhov, Nikolai, Montanari, Claudio, Montanari, David, Moore, Craig, Morfin, Jorge, Morgan, Ben, Morse, William, Moss, Zander, Moura, Célio A., Mufson, Stuart, Muller, David, Musser, Jim, Naples, Donna, Napolitano, Jim, Newcomer, Mitch, Nichol, Ryan, Nicholls, Tim, Niner, Evan, Norris, Barry, Nowak, Jaroslaw, O'Keeffe, Helen, Oliveira, Roberto, Olson, Travis, Page, Brian, Pakvasa, Sandip, Palamara, Ornella, Paley, Jon, Paolone, Vittorio, Papadimitriou, Vaia, Park, Seongtae, Parsa, Zohreh, Partyka, Kinga, Paulos, Bob, Pavlovic, Zarko, Peeters, Simon, Perch, Andy, Perkin, Jon D., Petti, Roberto, Petukhov, Andre, Pietropaolo, Francesco, Plunkett, Robert, Polly, Chris, Pordes, Stephen, Potekhin, Maxim, Potenza, Renato, Prakash, Arati, Prokofiev, Oleg, Qian, Xin, Raaf, Jennifer L., Radeka, Veljko, Rakhno, Igor, Ramachers, Yorck, Rameika, Regina, Ramsey, John, Rappoldi, A., Raselli, G. L., Ratoff, Peter, Ravindra, Shreyas, Rebel, Brian, Reichenbacher, Juergen, Reitzner, Dianne, Rescia, Sergio, Richardson, Martin, Rielage, Kieth, Riesselmann, Kurt, Robinson, Matt, Rochester, Leon, Ronquest, Michael, Rosen, Marc, Rossella, M., Rubbia, Carlo, Rucinski, Russ, Sahijpal, Sandeep, Sahoo, Himansu, Sala, Paola, Salmiera, Delia, Samios, Nicholas, Sanchez, Mayly, Scaramelli, Alberto, Schellman, Heidi, Schmitt, Richard, Schmitz, David, Schneps, Jack, Scholberg, Kate, Segreto, Ettore, Seibert, Stanley, Sexton-Kennedy, Liz, Shaevitz, Mike, Shanahan, Peter, Sharma, Rahul, Shaw, Terri, Simos, Nikolaos, Singh, Venktesh, Sinnis, Gus, Sippach, William, Skwarnicki, Tomasz, Smy, Michael, Sobel, Henry, Soderberg, Mitch, Sondericker, John, Sondheim, Walter, Sousa, Alexandre, Spooner, Neil J. C., Stancari, Michelle, Stancu, Ion, Stefan, Dorota, Stefanik, Andy, Stewart, James, Stone, Sheldon, Strait, James, Strait, Matthew, Striganov, Sergei, Sullivan, Gregory, Sun, Yujing, Suter, Louise, Svenson, Andrew, Svoboda, Robert, Szczerbinska, Barbara, Szelc, Andrzej, Szydagis, Matthew, Söldner-Rembold, Stefan, Talaga, Richard, Tamsett, Matthew, Tariq, Salman, Tayloe, Rex, Taylor, Charles, Taylor, David, Teymourian, Artin, Themann, Harry, Thiesse, Matthew, Thomas, Jenny, Thompson, Lee F., Thomson, Mark, Thorn, Craig, Thorpe, Matt, Tian, Xinchun, Tiedt, Doug, Toki, Walter, Tolich, Nikolai, Torti, M., Toups, Matt, Touramanis, Christos, Tripathi, Mani, Tropin, Igor, Tsai, Yun-Tse, Tull, Craig, Tzanov, Martin, Urheim, Jon, Usman, Shawn, Vagins, Mark, Valdiviesso, Gustavo, Van Berg, Rick, Van de Water, Richard, Van Gemmeren, Peter, Varanini, Filippo, Varner, Gary, Vaziri, Kamran, Velev, Gueorgui, Ventura, Sandro, Vignoli, Chiara, Viren, Brett, Wahl, Dan, Waldron, Abby, Walter, Christopher W., Wang, Hanguo, Wang, Wei, Warburton, Karl, Warner, David, Wasserman, Ryan, Watson, Blake, Weber, Alfons, Wei, Wenzhao, Wells, Douglas, Wetstein, Matthew, White, Andy, White, Hywel, Whitehead, Lisa, Whittington, Denver, Willhite, Joshua, Wilson, Robert J., Winslow, Lindley, Wood, Kevin, Worcester, Elizabeth, Worcester, Matthew, Xin, Tian, Yarritu, Kevin, Ye, Jingbo, Yeh, Minfang, Yu, Bo, Yu, Jae, Yuan, Tianlu, Zani, A., Zeller, Geralyn P., Zhang, Chao, Zimmerman, Eric D., and Zwaska, Robert

Subjects
High Energy Physics - Experiment, High Energy Physics - Phenomenology, Physics - Accelerator Physics, Physics - Instrumentation and Detectors
Abstract

The preponderance of matter over antimatter in the early Universe, the dynamics of the supernova bursts that produced the heavy elements necessary for life and whether protons eventually decay --- these mysteries at the forefront of particle physics and astrophysics are key to understanding the early evolution of our Universe, its current state and its eventual fate. The Long-Baseline Neutrino Experiment (LBNE) represents an extensively developed plan for a world-class experiment dedicated to addressing these questions. LBNE is conceived around three central components: (1) a new, high-intensity neutrino source generated from a megawatt-class proton accelerator at Fermi National Accelerator Laboratory, (2) a near neutrino detector just downstream of the source, and (3) a massive liquid argon time-projection chamber deployed as a far detector deep underground at the Sanford Underground Research Facility. This facility, located at the site of the former Homestake Mine in Lead, South Dakota, is approximately 1,300 km from the neutrino source at Fermilab -- a distance (baseline) that delivers optimal sensitivity to neutrino charge-parity symmetry violation and mass ordering effects. This ambitious yet cost-effective design incorporates scalability and flexibility and can accommodate a variety of upgrades and contributions. With its exceptional combination of experimental configuration, technical capabilities, and potential for transformative discoveries, LBNE promises to be a vital facility for the field of particle physics worldwide, providing physicists from around the globe with opportunities to collaborate in a twenty to thirty year program of exciting science. In this document we provide a comprehensive overview of LBNE's scientific objectives, its place in the landscape of neutrino physics worldwide, the technologies it will incorporate and the capabilities it will possess., Comment: Major update of previous version. This is the reference document for LBNE science program and current status. Chapters 1, 3, and 9 provide a comprehensive overview of LBNE's scientific objectives, its place in the landscape of neutrino physics worldwide, the technologies it will incorporate and the capabilities it will possess. 288 pages, 116 figures

Published
2013

30. Recovering Exadata

Author

Bach, Martin, Arao, Karl, Colvin, Andy, Hoogland, Frits, Osborne, Kerry, Johnson, Randy, Poder, Tanel, Bach, Martin, Arao, Karl, Colvin, Andy, Hoogland, Frits, Osborne, Kerry, Johnson, Randy, and Poder, Tanel

Published
2015
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31. Resource Management

Author

Bach, Martin, Arao, Karl, Colvin, Andy, Hoogland, Frits, Osborne, Kerry, Johnson, Randy, Poder, Tanel, Bach, Martin, Arao, Karl, Colvin, Andy, Hoogland, Frits, Osborne, Kerry, Johnson, Randy, and Poder, Tanel

Published
2015
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32. Exadata Parallel Operations

Author

Bach, Martin, Arao, Karl, Colvin, Andy, Hoogland, Frits, Osborne, Kerry, Johnson, Randy, Poder, Tanel, Bach, Martin, Arao, Karl, Colvin, Andy, Hoogland, Frits, Osborne, Kerry, Johnson, Randy, and Poder, Tanel

Published
2015
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33. Configuring Exadata

Author

Bach, Martin, Arao, Karl, Colvin, Andy, Hoogland, Frits, Osborne, Kerry, Johnson, Randy, Poder, Tanel, Bach, Martin, Arao, Karl, Colvin, Andy, Hoogland, Frits, Osborne, Kerry, Johnson, Randy, and Poder, Tanel

Published
2015
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34. Exadata Wait Events

Author

Bach, Martin, Arao, Karl, Colvin, Andy, Hoogland, Frits, Osborne, Kerry, Johnson, Randy, Poder, Tanel, Bach, Martin, Arao, Karl, Colvin, Andy, Hoogland, Frits, Osborne, Kerry, Johnson, Randy, and Poder, Tanel

Published
2015
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35. Exadata Smart Flash Cache

Author

Bach, Martin, Arao, Karl, Colvin, Andy, Hoogland, Frits, Osborne, Kerry, Johnson, Randy, Poder, Tanel, Bach, Martin, Arao, Karl, Colvin, Andy, Hoogland, Frits, Osborne, Kerry, Johnson, Randy, and Poder, Tanel

Published
2015
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36. Storage Indexes

Author

Bach, Martin, Arao, Karl, Colvin, Andy, Hoogland, Frits, Osborne, Kerry, Johnson, Randy, Poder, Tanel, Bach, Martin, Arao, Karl, Colvin, Andy, Hoogland, Frits, Osborne, Kerry, Johnson, Randy, and Poder, Tanel

Published
2015
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37. exachk

Author

Bach, Martin, Arao, Karl, Colvin, Andy, Hoogland, Frits, Osborne, Kerry, Johnson, Randy, Poder, Tanel, Bach, Martin, Arao, Karl, Colvin, Andy, Hoogland, Frits, Osborne, Kerry, Johnson, Randy, and Poder, Tanel

Published
2015
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38. Hybrid Columnar Compression

Author

Bach, Martin, Arao, Karl, Colvin, Andy, Hoogland, Frits, Osborne, Kerry, Johnson, Randy, Poder, Tanel, Bach, Martin, Arao, Karl, Colvin, Andy, Hoogland, Frits, Osborne, Kerry, Johnson, Randy, and Poder, Tanel

Published
2015
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39. What Is Exadata?

Author

Bach, Martin, Arao, Karl, Colvin, Andy, Hoogland, Frits, Osborne, Kerry, Johnson, Randy, Poder, Tanel, Bach, Martin, Arao, Karl, Colvin, Andy, Hoogland, Frits, Osborne, Kerry, Johnson, Randy, and Poder, Tanel

Published
2015
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40. Offloading / Smart Scan

Author

Bach, Martin, Arao, Karl, Colvin, Andy, Hoogland, Frits, Osborne, Kerry, Johnson, Randy, Poder, Tanel, Bach, Martin, Arao, Karl, Colvin, Andy, Hoogland, Frits, Osborne, Kerry, Johnson, Randy, and Poder, Tanel

Published
2015
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41. Diagnostic Scripts

Author

Bach, Martin, Arao, Karl, Colvin, Andy, Hoogland, Frits, Osborne, Kerry, Johnson, Randy, Poder, Tanel, Bach, Martin, Arao, Karl, Colvin, Andy, Hoogland, Frits, Osborne, Kerry, Johnson, Randy, and Poder, Tanel

Published
2015
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42. CELLCLI and DCLI

Author

Bach, Martin, Arao, Karl, Colvin, Andy, Hoogland, Frits, Osborne, Kerry, Johnson, Randy, Poder, Tanel, Bach, Martin, Arao, Karl, Colvin, Andy, Hoogland, Frits, Osborne, Kerry, Johnson, Randy, and Poder, Tanel

Published
2015
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43. Unlearning Some Things We Thought We Knew

Author

Bach, Martin, Arao, Karl, Colvin, Andy, Hoogland, Frits, Osborne, Kerry, Johnson, Randy, Poder, Tanel, Bach, Martin, Arao, Karl, Colvin, Andy, Hoogland, Frits, Osborne, Kerry, Johnson, Randy, and Poder, Tanel

Published
2015
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44. Patching Exadata

Author

Bach, Martin, Arao, Karl, Colvin, Andy, Hoogland, Frits, Osborne, Kerry, Johnson, Randy, Poder, Tanel, Bach, Martin, Arao, Karl, Colvin, Andy, Hoogland, Frits, Osborne, Kerry, Johnson, Randy, and Poder, Tanel

Published
2015
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45. Compute Node Layout

Author

Bach, Martin, Arao, Karl, Colvin, Andy, Hoogland, Frits, Osborne, Kerry, Johnson, Randy, Poder, Tanel, Bach, Martin, Arao, Karl, Colvin, Andy, Hoogland, Frits, Osborne, Kerry, Johnson, Randy, and Poder, Tanel

Published
2015
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46. Migrating to Exadata

Author

Bach, Martin, Arao, Karl, Colvin, Andy, Hoogland, Frits, Osborne, Kerry, Johnson, Randy, Poder, Tanel, Bach, Martin, Arao, Karl, Colvin, Andy, Hoogland, Frits, Osborne, Kerry, Johnson, Randy, and Poder, Tanel

Published
2015
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47. Storage Layout

Author

Bach, Martin, Arao, Karl, Colvin, Andy, Hoogland, Frits, Osborne, Kerry, Johnson, Randy, Poder, Tanel, Bach, Martin, Arao, Karl, Colvin, Andy, Hoogland, Frits, Osborne, Kerry, Johnson, Randy, and Poder, Tanel

Published
2015
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48. Exadata Performance Metrics

Author

Bach, Martin, Arao, Karl, Colvin, Andy, Hoogland, Frits, Osborne, Kerry, Johnson, Randy, Poder, Tanel, Bach, Martin, Arao, Karl, Colvin, Andy, Hoogland, Frits, Osborne, Kerry, Johnson, Randy, and Poder, Tanel

Published
2015
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49. Monitoring Exadata Performance

Author

Bach, Martin, Arao, Karl, Colvin, Andy, Hoogland, Frits, Osborne, Kerry, Johnson, Randy, Poder, Tanel, Bach, Martin, Arao, Karl, Colvin, Andy, Hoogland, Frits, Osborne, Kerry, Johnson, Randy, and Poder, Tanel

Published
2015
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50. Bile Acids Activate YAP to Promote Liver Carcinogenesis

Author

Anakk, Sayeepriyadarshini, Bhosale, Manoj, Schmidt, Valentina A, Johnson, Randy L, Finegold, Milton J, and Moore, David D

Subjects
Biochemistry and Cell Biology, Biological Sciences, Cancer, Rare Diseases, Liver Cancer, Chronic Liver Disease and Cirrhosis, Digestive Diseases, Stem Cell Research, Liver Disease, Aetiology, 2.1 Biological and endogenous factors, Oral and gastrointestinal, Adaptor Proteins, Signal Transducing, Adolescent, Animals, Bile Acids and Salts, Carcinogenesis, Carcinoma, Hepatocellular, Cell Cycle Proteins, Cells, Cultured, Child, Child, Preschool, Enzyme Activation, Hepatocyte Growth Factor, Hippo Signaling Pathway, Humans, Infant, Infant, Newborn, Liver Neoplasms, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Phosphoproteins, Protein Serine-Threonine Kinases, Proto-Oncogene Proteins, Receptors, Cytoplasmic and Nuclear, Serine-Threonine Kinase 3, Transcription Factors, YAP-Signaling Proteins, ras GTPase-Activating Proteins, Protein-Serine-Threonine Kinases, Medical Physiology, Biological sciences
Abstract

Elevated bile acid levels increase hepatocellular carcinoma by unknown mechanisms. Here, we show that mice with a severe defect in bile acid homeostasis due to the loss of the nuclear receptors FXR and SHP have enlarged livers, progenitor cell proliferation, and Yes-associated protein (YAP) activation and develop spontaneous liver tumorigenesis. This phenotype mirrors mice with loss of hippo kinases or overexpression of their downstream target, YAP. Bile acids act as upstream regulators of YAP via a pathway dependent on the induction of the scaffold protein IQGAP1. Patients with diverse biliary dysfunctions exhibit enhanced IQGAP1 and nuclear YAP expression. Our findings reveal an unexpected mechanism for bile acid regulation of liver growth and tumorigenesis via the Hippo pathway.

Published
2013

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