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1,843 results on '"Fisher, A."'

1. Establishment of fetomaternal tolerance through glycan-mediated B cell suppression

Author

Rizzuto, G, Brooks, JF, Tuomivaara, ST, McIntyre, TI, Ma, S, Rideaux, D, Zikherman, J, Fisher, SJ, and Erlebacher, A

Subjects
Pediatric, Contraception/Reproduction, Autoimmune Disease, Aetiology, 2.1 Biological and endogenous factors, Underpinning research, 1.1 Normal biological development and functioning, Inflammatory and immune system, Good Health and Well Being, Animals, Antigens, Autoimmune Diseases, B-Lymphocytes, Female, Immune Tolerance, Mice, Placenta, Polysaccharides, Pregnancy, Trophoblasts, General Science & Technology
Abstract

Discrimination of self from non-self is fundamental to a wide range of immunological processes1. During pregnancy, the mother does not recognize the placenta as immunologically foreign because antigens expressed by trophoblasts, the placental cells that interface with the maternal immune system, do not activate maternal T cells2. Currently, these activation defects are thought to reflect suppression by regulatory T cells3. By contrast, mechanisms of B cell tolerance to trophoblast antigens have not been identified. Here we provide evidence that glycan-mediated B cell suppression has a key role in establishing fetomaternal tolerance in mice. B cells specific for a model trophoblast antigen are strongly suppressed through CD22-LYN inhibitory signalling, which in turn implicates the sialylated glycans of the antigen as key suppressive determinants. Moreover, B cells mediate the MHC-class-II-restricted presentation of antigens to CD4+ T cells, which leads to T cell suppression, and trophoblast-derived sialoglycoproteins are released into the maternal circulation during pregnancy in mice and humans. How protein glycosylation promotes non-immunogenic placental self-recognition may have relevance to immune-mediated pregnancy complications and to tumour immune evasion. We also anticipate that our findings will bolster efforts to harness glycan biology to control antigen-specific immune responses in autoimmune disease.

Published
2022

2. TDP-43 loss and ALS-risk SNPs drive mis-splicing and depletion of UNC13A

Author

Brown, Anna-Leigh, Wilkins, Oscar G, Keuss, Matthew J, Hill, Sarah E, Zanovello, Matteo, Lee, Weaverly Colleen, Bampton, Alexander, Lee, Flora CY, Masino, Laura, Qi, Yue A, Bryce-Smith, Sam, Gatt, Ariana, Hallegger, Martina, Fagegaltier, Delphine, Phatnani, Hemali, Newcombe, Jia, Gustavsson, Emil K, Seddighi, Sahba, Reyes, Joel F, Coon, Steven L, Ramos, Daniel, Schiavo, Giampietro, Fisher, Elizabeth MC, Raj, Towfique, Secrier, Maria, Lashley, Tammaryn, Ule, Jernej, Buratti, Emanuele, Humphrey, Jack, Ward, Michael E, and Fratta, Pietro

Subjects
Rare Diseases, Dementia, Prevention, ALS, Brain Disorders, Neurodegenerative, Neurosciences, Acquired Cognitive Impairment, Genetics, Clinical Research, 2.1 Biological and endogenous factors, Aetiology, Neurological, Alternative Splicing, Amyotrophic Lateral Sclerosis, Codon, Nonsense, DNA-Binding Proteins, Frontotemporal Dementia, Humans, Nerve Tissue Proteins, Polymorphism, Single Nucleotide, TDP-43 Proteinopathies, NYGC ALS Consortium, General Science & Technology
Abstract

Variants of UNC13A, a critical gene for synapse function, increase the risk of amyotrophic lateral sclerosis and frontotemporal dementia1-3, two related neurodegenerative diseases defined by mislocalization of the RNA-binding protein TDP-434,5. Here we show that TDP-43 depletion induces robust inclusion of a cryptic exon in UNC13A, resulting in nonsense-mediated decay and loss of UNC13A protein. Two common intronic UNC13A polymorphisms strongly associated with amyotrophic lateral sclerosis and frontotemporal dementia risk overlap with TDP-43 binding sites. These polymorphisms potentiate cryptic exon inclusion, both in cultured cells and in brains and spinal cords from patients with these conditions. Our findings, which demonstrate a genetic link between loss of nuclear TDP-43 function and disease, reveal the mechanism by which UNC13A variants exacerbate the effects of decreased TDP-43 function. They further provide a promising therapeutic target for TDP-43 proteinopathies.

Published
2022

3. Protect pollinators — reform pesticide regulations

Author

Fisher, Adrian

Subjects
Agriculture, Animals, Environmental Policy, Government Regulation, Neonicotinoids, Pesticides, Pollination, Risk Assessment, Ecology, Law, General Science & Technology
Published
2021

4. A virally encoded high-resolution screen of cytomegalovirus dependencies

Author

Finkel, Yaara, primary, Nachshon, Aharon, additional, Aharon, Einav, additional, Arazi, Tamar, additional, Simonovsky, Elena, additional, Dobešová, Martina, additional, Saud, Zack, additional, Gluck, Avi, additional, Fisher, Tal, additional, Stanton, Richard J., additional, Schwartz, Michal, additional, and Stern-Ginossar, Noam, additional

Published
2024
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5. SARS-CoV-2 uses a multipronged strategy to impede host protein synthesis

Author

Finkel, Yaara, Gluck, Avi, Nachshon, Aharon, Winkler, Roni, Fisher, Tal, Rozman, Batsheva, Mizrahi, Orel, Lubelsky, Yoav, Zuckerman, Binyamin, Slobodin, Boris, Yahalom-Ronen, Yfat, Tamir, Hadas, Ulitsky, Igor, Israely, Tomer, Paran, Nir, Schwartz, Michal, and Stern-Ginossar, Noam

Subjects
Messenger RNA -- Physiological aspects, Protein biosynthesis -- Observations, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

The coronavirus SARS-CoV-2 is the cause of the ongoing pandemic of COVID-19.sup.1. Coronaviruses have developed a variety of mechanisms to repress host mRNA translation to allow the translation of viral mRNA, and concomitantly block the cellular innate immune response.sup.2,3. Although several different proteins of SARS-CoV-2 have previously been implicated in shutting off host expression.sup.4-7, a comprehensive picture of the effects of SARS-CoV-2 infection on cellular gene expression is lacking. Here we combine RNA sequencing, ribosome profiling and metabolic labelling of newly synthesized RNA to comprehensively define the mechanisms that are used by SARS-CoV-2 to shut off cellular protein synthesis. We show that infection leads to a global reduction in translation, but that viral transcripts are not preferentially translated. Instead, we find that infection leads to the accelerated degradation of cytosolic cellular mRNAs, which facilitates viral takeover of the mRNA pool in infected cells. We reveal that the translation of transcripts that are induced in response to infection (including innate immune genes) is impaired. We demonstrate this impairment is probably mediated by inhibition of nuclear mRNA export, which prevents newly transcribed cellular mRNA from accessing ribosomes. Overall, our results uncover a multipronged strategy that is used by SARS-CoV-2 to take over the translation machinery and to suppress host defences. RNA sequencing, ribosome profiling and metabolic labelling of newly synthesized RNA reveal the strategy used by SARS-CoV-2 to shut off cellular protein synthesis in the host and allow the translation of viral transcripts., Author(s): Yaara Finkel [sup.1] , Avi Gluck [sup.1] , Aharon Nachshon [sup.1] , Roni Winkler [sup.1] , Tal Fisher [sup.1] , Batsheva Rozman [sup.1] , Orel Mizrahi [sup.1] , Yoav [...]

Published
2021
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6. A trade-off between plant and soil carbon storage under elevated CO.sub.2

Author

Terrer, C., Phillips, R. P., Hungate, B. A., Rosende, J., Pett-Ridge, J., Craig, M. E., van Groenigen, K. J., Keenan, T.F., Sulman, B.N., Stocker, B.D., Reich, P.B., Pellegrini, A.F.A., Pendall, E., Zhang, H., Evans, R.D., Carrillo, Y., and Fisher, J.B.

Subjects
Plants -- Environmental aspects, Soils -- Carbon content, Ecological research, Carbon dioxide -- Environmental aspects, Plant-soil relationships -- Research, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

Terrestrial ecosystems remove about 30 per cent of the carbon dioxide (CO.sub.2) emitted by human activities each year.sup.1, yet the persistence of this carbon sink depends partly on how plant biomass and soil organic carbon (SOC) stocks respond to future increases in atmospheric CO.sub.2 (refs. .sup.2,3). Although plant biomass often increases in elevated CO.sub.2 (eCO.sub.2) experiments.sup.4-6, SOC has been observed to increase, remain unchanged or even decline.sup.7. The mechanisms that drive this variation across experiments remain poorly understood, creating uncertainty in climate projections.sup.8,9. Here we synthesized data from 108 eCO.sub.2 experiments and found that the effect of eCO.sub.2 on SOC stocks is best explained by a negative relationship with plant biomass: when plant biomass is strongly stimulated by eCO.sub.2, SOC storage declines; conversely, when biomass is weakly stimulated, SOC storage increases. This trade-off appears to be related to plant nutrient acquisition, in which plants increase their biomass by mining the soil for nutrients, which decreases SOC storage. We found that, overall, SOC stocks increase with eCO.sub.2 in grasslands (8 [plus or minus] 2 per cent) but not in forests (0 [plus or minus] 2 per cent), even though plant biomass in grasslands increase less (9 [plus or minus] 3 per cent) than in forests (23 [plus or minus] 2 per cent). Ecosystem models do not reproduce this trade-off, which implies that projections of SOC may need to be revised. A synthesis of elevated carbon dioxide experiments reveals that when plant biomass is strongly stimulated by elevated carbon dioxide levels, soil carbon storage declines, and where biomass is weakly stimulated, soil carbon accumulates., Author(s): C. Terrer [sup.1] [sup.2] , R. P. Phillips [sup.3] , B. A. Hungate [sup.4] [sup.5] , J. Rosende [sup.6] , J. Pett-Ridge [sup.1] , M. E. Craig [sup.3] [sup.7] [...]

Published
2021
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7. Z-nucleic-acid sensing triggers ZBP1-dependent necroptosis and inflammation

Author

Jiao, Huipeng, Wachsmuth, Laurens, Kumari, Snehlata, Schwarzer, Robin, Lin, Juan, Eren, Remzi Onur, and Fisher, Amanda

Subjects
Binding proteins -- Research -- Physiological aspects -- Genetic aspects, Biological research -- Genetic aspects -- Research -- Physiological aspects, Biology, Experimental -- Genetic aspects -- Research -- Physiological aspects, Inflammation -- Causes of -- Physiological aspects -- Genetic aspects, Antisense nucleic acids -- Research -- Physiological aspects -- Genetic aspects, Necrosis -- Control -- Physiological aspects -- Genetic aspects -- Research, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

The biological function of Z-DNA and Z-RNA, nucleic acid structures with a left-handed double helix, is poorly understood.sup.1-3. Z-DNA-binding protein 1 (ZBP1; also known as DAI or DLM-1) is a nucleic acid sensor that contains two Z[alpha] domains that bind Z-DNA.sup.4,5 and Z-RNA.sup.6-8. ZBP1 mediates host defence against some viruses.sup.6,7,9-14 by sensing viral nucleic acids.sup.6,7,10. RIPK1 deficiency, or mutation of its RIP homotypic interaction motif (RHIM), triggers ZBP1-dependent necroptosis and inflammation in mice.sup.15,16. However, the mechanisms that induce ZBP1 activation in the absence of viral infection remain unknown. Here we show that Z[alpha]-dependent sensing of endogenous ligands induces ZBP1-mediated perinatal lethality in mice expressing RIPK1 with mutated RHIM (Ripk1.sup.mR/mR), skin inflammation in mice with epidermis-specific RIPK1 deficiency (RIPK1.sup.E-KO) and colitis in mice with intestinal epithelial-specific FADD deficiency (FADD.sup.IEC-KO). Consistently, functional Z[alpha] domains were required for ZBP1-induced necroptosis in fibroblasts that were treated with caspase inhibitors or express RIPK1 with mutated RHIM. Inhibition of nuclear export triggered the Z[alpha]-dependent activation of RIPK3 in the nucleus resulting in cell death, which suggests that ZBP1 may recognize nuclear Z-form nucleic acids. We found that ZBP1 constitutively bound cellular double-stranded RNA in a Z[alpha]-dependent manner. Complementary reads derived from endogenous retroelements were detected in epidermal RNA, which suggests that double-stranded RNA derived from these retroelements may act as a Z[alpha]-domain ligand that triggers the activation of ZBP1. Collectively, our results provide evidence that the sensing of endogenous Z-form nucleic acids by ZBP1 triggers RIPK3-dependent necroptosis and inflammation, which could underlie the development of chronic inflammatory conditions--particularly in individuals with mutations in RIPK1 and CASP8.sup.17-20. Analyses of mouse models of inflammation suggest some chronic inflammatory conditions may result from Z-DNA-binding protein 1 sensing endogenous Z-form nucleic acids--such as those of endogenous retroelements--through its Z[alpha] domains., Author(s): Huipeng Jiao [sup.1] [sup.2] , Laurens Wachsmuth [sup.1] [sup.2] , Snehlata Kumari [sup.1] [sup.2] , Robin Schwarzer [sup.1] [sup.2] , Juan Lin [sup.1] [sup.2] , Remzi Onur Eren [sup.1] [...]

Published
2020
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8. Sensorimotor experience remaps visual input to a heading-direction network

Author

Fisher, Yvette E., Lu, Jenny, D'Alessandro, Isabel, and Wilson, Rachel I.

Subjects
Directions (Geography) -- Psychological aspects -- Analysis, Animal navigation -- Psychological aspects -- Analysis, Neurons -- Analysis -- Physiological aspects, Scene perception -- Influence, Sensorimotor integration -- Influence, Drosophila -- Physiological aspects -- Mechanical properties -- Observations, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

In the Drosophila brain, 'compass' neurons track the orientation of the body and head (the fly's heading) during navigation .sup.1,2. In the absence of visual cues, the compass neuron network estimates heading by integrating self-movement signals over time.sup.3,4. When a visual cue is present, the estimate of the network is more accurate.sup.1,3. Visual inputs to compass neurons are thought to originate from inhibitory neurons called R neurons (also known as ring neurons); the receptive fields of R neurons tile visual space.sup.5. The axon of each R neuron overlaps with the dendrites of every compass neuron.sup.6, raising the question of how visual cues are integrated into the compass. Here, using in vivo whole-cell recordings, we show that a visual cue can evoke synaptic inhibition in compass neurons and that R neurons mediate this inhibition. Each compass neuron is inhibited only by specific visual cue positions, indicating that many potential connections from R neurons onto compass neurons are actually weak or silent. We also show that the pattern of visually evoked inhibition can reorganize over minutes as the fly explores an altered virtual-reality environment. Using ensemble calcium imaging, we demonstrate that this reorganization causes persistent changes in the compass coordinate frame. Taken together, our data suggest a model in which correlated pre- and postsynaptic activity triggers associative long-term synaptic depression of visually evoked inhibition in compass neurons. Our findings provide evidence for the theoretical proposal that associative plasticity of sensory inputs, when combined with attractor dynamics, can reconcile self-movement information with changing external cues to generate a coherent sense of direction.sup.7-12. Visual inputs to compass neurons can reorganize over minutes as a fly explores an altered virtual-reality environment., Author(s): Yvette E. Fisher [sup.1] , Jenny Lu [sup.1] , Isabel D'Alessandro [sup.1] , Rachel I. Wilson [sup.1] Author Affiliations: (1) Department of Neurobiology, Harvard Medical School, Boston, USA Main [...]

Published
2019
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9. Airborne DNA reveals predictable spatial and seasonal dynamics of fungi

Author

Abrego, Nerea, Furneaux, Brendan, Hardwick, Bess, Somervuo, Panu, Palorinne, Isabella, Aguilar-Trigueros, Carlos A., Andrew, Nigel R., Babiy, Ulyana V., Bao, Tan, Bazzano, Gisela, Bondarchuk, Svetlana N., Bonebrake, Timothy C., Brennan, Georgina L., Bret-Harte, Syndonia, Bässler, Claus, Cagnolo, Luciano, Cameron, Erin K., Chapurlat, Elodie, Creer, Simon, D’Acqui, Luigi P., de Vere, Natasha, Desprez-Loustau, Marie-Laure, Dongmo, Michel A. K., Jacobsen, Ida B. Dyrholm, Fisher, Brian L., Flores de Jesus, Miguel, Gilbert, Gregory S., Griffith, Gareth W., Gritsuk, Anna A., Gross, Andrin, Grudd, Håkan, Halme, Panu, Hanna, Rachid, Hansen, Jannik, Hansen, Lars Holst, Hegbe, Apollon D. M. T., Hill, Sarah, Hogg, Ian D., Hultman, Jenni, Hyde, Kevin D., Hynson, Nicole A., Ivanova, Natalia, Karisto, Petteri, Kerdraon, Deirdre, Knorre, Anastasia, Krisai-Greilhuber, Irmgard, Kurhinen, Juri, Kuzmina, Masha, Lecomte, Nicolas, Lecomte, Erin, Loaiza, Viviana, Lundin, Erik, Meire, Alexander, Mešić, Armin, Miettinen, Otto, Monkhouse, Norman, Mortimer, Peter, Müller, Jörg, Nilsson, R. Henrik, Nonti, Puani Yannick C., Nordén, Jenni, Nordén, Björn, Norros, Veera, Paz, Claudia, Pellikka, Petri, Pereira, Danilo, Petch, Geoff, Pitkänen, Juha-Matti, Popa, Flavius, Potter, Caitlin, Purhonen, Jenna, Pätsi, Sanna, Rafiq, Abdullah, Raharinjanahary, Dimby, Rakos, Niklas, Rathnayaka, Achala R., Raundrup, Katrine, Rebriev, Yury A., Rikkinen, Jouko, Rogers, Hanna M. K., Rogovsky, Andrey, Rozhkov, Yuri, Runnel, Kadri, Saarto, Annika, Savchenko, Anton, Schlegel, Markus, Schmidt, Niels Martin, Seibold, Sebastian, Skjøth, Carsten, Stengel, Elisa, Sutyrina, Svetlana V., Syvänperä, Ilkka, Tedersoo, Leho, Timm, Jebidiah, Tipton, Laura, Toju, Hirokazu, Uscka-Perzanowska, Maria, van der Bank, Michelle, van der Bank, F. Herman, Vandenbrink, Bryan, Ventura, Stefano, Vignisson, Solvi R., Wang, Xiaoyang, Weisser, Wolfgang W., Wijesinghe, Subodini N., Wright, S. Joseph, Yang, Chunyan, Yorou, Nourou S., Young, Amanda, Yu, Douglas W., Zakharov, Evgeny V., Hebert, Paul D. N., Roslin, Tomas, and Ovaskainen, Otso

Abstract

Fungi are among the most diverse and ecologically important kingdoms in life. However, the distributional ranges of fungi remain largely unknown as do the ecological mechanisms that shape their distributions1,2. To provide an integrated view of the spatial and seasonal dynamics of fungi, we implemented a globally distributed standardized aerial sampling of fungal spores3. The vast majority of operational taxonomic units were detected within only one climatic zone, and the spatiotemporal patterns of species richness and community composition were mostly explained by annual mean air temperature. Tropical regions hosted the highest fungal diversity except for lichenized, ericoid mycorrhizal and ectomycorrhizal fungi, which reached their peak diversity in temperate regions. The sensitivity in climatic responses was associated with phylogenetic relatedness, suggesting that large-scale distributions of some fungal groups are partially constrained by their ancestral niche. There was a strong phylogenetic signal in seasonal sensitivity, suggesting that some groups of fungi have retained their ancestral trait of sporulating for only a short period. Overall, our results show that the hyperdiverse kingdom of fungi follows globally highly predictable spatial and temporal dynamics, with seasonality in both species richness and community composition increasing with latitude. Our study reports patterns resembling those described for other major groups of organisms, thus making a major contribution to the long-standing debate on whether organisms with a microbial lifestyle follow the global biodiversity paradigms known for macroorganisms4,5.

Published
2024
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10. Comprehensive molecular characterization of gastric adenocarcinoma

Author

Bass, Adam J, Thorsson, Vesteinn, Shmulevich, Ilya, Reynolds, Sheila M, Miller, Michael, Bernard, Brady, Hinoue, Toshinori, Laird, Peter W, Curtis, Christina, Shen, Hui, Weisenberger, Daniel J, Schultz, Nikolaus, Shen, Ronglai, Weinhold, Nils, Kelsen, David P, Bowlby, Reanne, Chu, Andy, Kasaian, Katayoon, Mungall, Andrew J, Robertson, A Gordon, Sipahimalani, Payal, Cherniack, Andrew, Getz, Gad, Liu, Yingchun, Noble, Michael S, Pedamallu, Chandra, Sougnez, Carrie, Taylor-Weiner, Amaro, Akbani, Rehan, Lee, Ju-Seog, Liu, Wenbin, Mills, Gordon B, Yang, Da, Zhang, Wei, Pantazi, Angeliki, Parfenov, Michael, Gulley, Margaret, Piazuelo, M Blanca, Schneider, Barbara G, Kim, Jihun, Boussioutas, Alex, Sheth, Margi, Demchok, John A, Rabkin, Charles S, Willis, Joseph E, Ng, Sam, Garman, Katherine, Beer, David G, Pennathur, Arjun, Raphael, Benjamin J, Wu, Hsin-Ta, Odze, Robert, Kim, Hark K, Bowen, Jay, Leraas, Kristen M, Lichtenberg, Tara M, Weaver, Stephanie, McLellan, Michael, Wiznerowicz, Maciej, Sakai, Ryo, Lawrence, Michael S, Cibulskis, Kristian, Lichtenstein, Lee, Fisher, Sheila, Gabriel, Stacey B, Lander, Eric S, Ding, Li, Niu, Beifang, Ally, Adrian, Balasundaram, Miruna, Birol, Inanc, Brooks, Denise, Butterfield, Yaron SN, Carlsen, Rebecca, Chu, Justin, Chuah, Eric, Chun, Hye-Jung E, Clarke, Amanda, Dhalla, Noreen, Guin, Ranabir, Holt, Robert A, Jones, Steven JM, Lee, Darlene, Li, Haiyan A, Lim, Emilia, Ma, Yussanne, Marra, Marco A, Mayo, Michael, Moore, Richard A, Mungall, Karen L, Ming Nip, Ka, and Schein, Jacqueline E

Subjects
Genetics, Digestive Diseases, Genetic Testing, Human Genome, Rare Diseases, Cancer, Good Health and Well Being, Adenocarcinoma, Female, Gene Expression Regulation, Neoplastic, Genome, Human, Herpesvirus 4, Human, Humans, Male, Mutation, Proteome, Stomach Neoplasms, Cancer Genome Atlas Research Network, General Science & Technology
Abstract

Gastric cancer is a leading cause of cancer deaths, but analysis of its molecular and clinical characteristics has been complicated by histological and aetiological heterogeneity. Here we describe a comprehensive molecular evaluation of 295 primary gastric adenocarcinomas as part of The Cancer Genome Atlas (TCGA) project. We propose a molecular classification dividing gastric cancer into four subtypes: tumours positive for Epstein-Barr virus, which display recurrent PIK3CA mutations, extreme DNA hypermethylation, and amplification of JAK2, CD274 (also known as PD-L1) and PDCD1LG2 (also known as PD-L2); microsatellite unstable tumours, which show elevated mutation rates, including mutations of genes encoding targetable oncogenic signalling proteins; genomically stable tumours, which are enriched for the diffuse histological variant and mutations of RHOA or fusions involving RHO-family GTPase-activating proteins; and tumours with chromosomal instability, which show marked aneuploidy and focal amplification of receptor tyrosine kinases. Identification of these subtypes provides a roadmap for patient stratification and trials of targeted therapies.

Published
2014

13. Targeting TBK1 to overcome resistance to cancer immunotherapy

Author

Yi Sun, Or-yam Revach, Seth Anderson, Emily A. Kessler, Clara H. Wolfe, Anne Jenney, Caitlin E. Mills, Emily J. Robitschek, Thomas G. R. Davis, Sarah Kim, Amina Fu, Xiang Ma, Jia Gwee, Payal Tiwari, Peter P. Du, Princy Sindurakar, Jun Tian, Arnav Mehta, Alexis M. Schneider, Keren Yizhak, Moshe Sade-Feldman, Thomas LaSalle, Tatyana Sharova, Hongyan Xie, Shuming Liu, William A. Michaud, Rodrigo Saad-Beretta, Kathleen B. Yates, Arvin Iracheta-Vellve, Johan K. E. Spetz, Xingping Qin, Kristopher A. Sarosiek, Gao Zhang, Jong Wook Kim, Mack Y. Su, Angelina M. Cicerchia, Martin Q. Rasmussen, Samuel J. Klempner, Dejan Juric, Sara I. Pai, David M. Miller, Anita Giobbie-Hurder, Jonathan H. Chen, Karin Pelka, Dennie T. Frederick, Susanna Stinson, Elena Ivanova, Amir R. Aref, Cloud P. Paweletz, David A. Barbie, Debattama R. Sen, David E. Fisher, Ryan B. Corcoran, Nir Hacohen, Peter K. Sorger, Keith T. Flaherty, Genevieve M. Boland, Robert T. Manguso, and Russell W. Jenkins

Subjects
Multidisciplinary
Published
2023

14. Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes.

Author

Biankin, Andrew, Waddell, Nicola, Kassahn, Karin, Gingras, Marie-Claude, Muthuswamy, Lakshmi, Johns, Amber, Miller, David, Wilson, Peter, Patch, Ann-Marie, Wu, Jianmin, Chang, David, Cowley, Mark, Gardiner, Brooke, Song, Sarah, Harliwong, Ivon, Idrisoglu, Senel, Nourse, Craig, Nourbakhsh, Ehsan, Manning, Suzanne, Wani, Shivangi, Gongora, Milena, Pajic, Marina, Scarlett, Christopher, Gill, Anthony, Pinho, Andreia, Rooman, Ilse, Anderson, Matthew, Holmes, Oliver, Leonard, Conrad, Taylor, Darrin, Wood, Scott, Xu, Qinying, Nones, Katia, Fink, J, Christ, Angelika, Bruxner, Tim, Cloonan, Nicole, Kolle, Gabriel, Newell, Felicity, Pinese, Mark, Mead, R, Humphris, Jeremy, Kaplan, Warren, Jones, Marc, Colvin, Emily, Nagrial, Adnan, Humphrey, Emily, Chou, Angela, Chin, Venessa, Chantrill, Lorraine, Mawson, Amanda, Samra, Jaswinder, Kench, James, Lovell, Jessica, Daly, Roger, Merrett, Neil, Toon, Christopher, Epari, Krishna, Nguyen, Nam, Barbour, Andrew, Zeps, Nikolajs, Kakkar, Nipun, Zhao, Fengmei, Wu, Yuan, Wang, Min, Muzny, Donna, Fisher, William, Brunicardi, F, Hodges, Sally, Reid, Jeffrey, Drummond, Jennifer, Chang, Kyle, Han, Yi, Lewis, Lora, Dinh, Huyen, Buhay, Christian, Beck, Timothy, Timms, Lee, Sam, Michelle, Begley, Kimberly, Brown, Andrew, Pai, Deepa, Panchal, Ami, Buchner, Nicholas, De Borja, Richard, Denroche, Robert, Yung, Christina, Serra, Stefano, Onetto, Nicole, Mukhopadhyay, Debabrata, Tsao, Ming-Sound, Shaw, Patricia, Petersen, Gloria, Gallinger, Steven, Hruban, Ralph, Maitra, Anirban, Iacobuzio-Donahue, Christine, Schulick, Richard, Wolfgang, Christopher, and Morgan, Richard

Subjects
Animals, Axons, Carcinoma, Pancreatic Ductal, Gene Dosage, Gene Expression Regulation, Neoplastic, Genome, Humans, Kaplan-Meier Estimate, Mice, Mutation, Pancreatic Neoplasms, Proteins, Signal Transduction
Abstract

Pancreatic cancer is a highly lethal malignancy with few effective therapies. We performed exome sequencing and copy number analysis to define genomic aberrations in a prospectively accrued clinical cohort (n = 142) of early (stage I and II) sporadic pancreatic ductal adenocarcinoma. Detailed analysis of 99 informative tumours identified substantial heterogeneity with 2,016 non-silent mutations and 1,628 copy-number variations. We define 16 significantly mutated genes, reaffirming known mutations (KRAS, TP53, CDKN2A, SMAD4, MLL3, TGFBR2, ARID1A and SF3B1), and uncover novel mutated genes including additional genes involved in chromatin modification (EPC1 and ARID2), DNA damage repair (ATM) and other mechanisms (ZIM2, MAP2K4, NALCN, SLC16A4 and MAGEA6). Integrative analysis with in vitro functional data and animal models provided supportive evidence for potential roles for these genetic aberrations in carcinogenesis. Pathway-based analysis of recurrently mutated genes recapitulated clustering in core signalling pathways in pancreatic ductal adenocarcinoma, and identified new mutated genes in each pathway. We also identified frequent and diverse somatic aberrations in genes described traditionally as embryonic regulators of axon guidance, particularly SLIT/ROBO signalling, which was also evident in murine Sleeping Beauty transposon-mediated somatic mutagenesis models of pancreatic cancer, providing further supportive evidence for the potential involvement of axon guidance genes in pancreatic carcinogenesis.

Published
2012

15. A call for transparent reporting to optimize the predictive value of preclinical research

Author

Landis, Story C, Amara, Susan G, Asadullah, Khusru, Austin, Chris P, Blumenstein, Robi, Bradley, Eileen W, Crystal, Ronald G, Darnell, Robert B, Ferrante, Robert J, Fillit, Howard, Finkelstein, Robert, Fisher, Marc, Gendelman, Howard E, Golub, Robert M, Goudreau, John L, Gross, Robert A, Gubitz, Amelie K, Hesterlee, Sharon E, Howells, David W, Huguenard, John, Kelner, Katrina, Koroshetz, Walter, Krainc, Dimitri, Lazic, Stanley E, Levine, Michael S, Macleod, Malcolm R, McCall, John M, Moxley III, Richard T, Narasimhan, Kalyani, Noble, Linda J, Perrin, Steve, Porter, John D, Steward, Oswald, Unger, Ellis, Utz, Ursula, and Silberberg, Shai D

Subjects
Accounting, Auditing and Accountability, Biomedical and Clinical Sciences, Commerce, Management, Tourism and Services, Animals, Publishing, Random Allocation, Research Design, Sample Size, Statistics as Topic, General Science & Technology
Abstract

The US National Institute of Neurological Disorders and Stroke convened major stakeholders in June 2012 to discuss how to improve the methodological reporting of animal studies in grant applications and publications. The main workshop recommendation is that at a minimum studies should report on sample-size estimation, whether and how animals were randomized, whether investigators were blind to the treatment, and the handling of data. We recognize that achieving a meaningful improvement in the quality of reporting will require a concerted effort by investigators, reviewers, funding agencies and journal editors. Requiring better reporting of animal studies will raise awareness of the importance of rigorous study design to accelerate scientific progress.

Published
2012

16. FXR inhibition may protect from SARS-CoV-2 infection by reducing ACE2

Author

Teresa, Brevini, Mailis, Maes, Gwilym J, Webb, Binu V, John, Claudia D, Fuchs, Gustav, Buescher, Lu, Wang, Chelsea, Griffiths, Marnie L, Brown, William E, Scott, Pehuén, Pereyra-Gerber, William T H, Gelson, Stephanie, Brown, Scott, Dillon, Daniele, Muraro, Jo, Sharp, Megan, Neary, Helen, Box, Lee, Tatham, James, Stewart, Paul, Curley, Henry, Pertinez, Sally, Forrest, Petra, Mlcochova, Sagar S, Varankar, Mahnaz, Darvish-Damavandi, Victoria L, Mulcahy, Rhoda E, Kuc, Thomas L, Williams, James A, Heslop, Davide, Rossetti, Olivia C, Tysoe, Vasileios, Galanakis, Marta, Vila-Gonzalez, Thomas W M, Crozier, Johannes, Bargehr, Sanjay, Sinha, Sara S, Upponi, Corrina, Fear, Lisa, Swift, Kourosh, Saeb-Parsy, Susan E, Davies, Axel, Wester, Hannes, Hagström, Espen, Melum, Darran, Clements, Peter, Humphreys, Jo, Herriott, Edyta, Kijak, Helen, Cox, Chloe, Bramwell, Anthony, Valentijn, Christopher J R, Illingworth, Bassam, Dahman, Dustin R, Bastaich, Raphaella D, Ferreira, Thomas, Marjot, Eleanor, Barnes, Andrew M, Moon, Alfred S, Barritt, Ravindra K, Gupta, Stephen, Baker, Anthony P, Davenport, Gareth, Corbett, Vassilis G, Gorgoulis, Simon J A, Buczacki, Joo-Hyeon, Lee, Nicholas J, Matheson, Michael, Trauner, Andrew J, Fisher, Paul, Gibbs, Andrew J, Butler, Christopher J E, Watson, George F, Mells, Gordon, Dougan, Andrew, Owen, Ansgar W, Lohse, Ludovic, Vallier, Fotios, Sampaziotis, and consortium, UK-PBC research

Subjects
Multidisciplinary
Abstract

Preventing SARS-CoV-2 infection by modulating viral host receptors, such as angiotensin-converting enzyme 2 (ACE2)1, could represent a new chemoprophylactic approach for COVID-19 that complements vaccination2,3. However, the mechanisms that control the expression of ACE2 remain unclear. Here we show that the farnesoid X receptor (FXR) is a direct regulator of ACE2 transcription in several tissues affected by COVID-19, including the gastrointestinal and respiratory systems. We then use the over-the-counter compound z-guggulsterone and the off-patent drug ursodeoxycholic acid (UDCA) to reduce FXR signalling and downregulate ACE2 in human lung, cholangiocyte and intestinal organoids and in the corresponding tissues in mice and hamsters. We show that the UDCA-mediated downregulation of ACE2 reduces susceptibility to SARS-CoV-2 infection in vitro, in vivo and in human lungs and livers perfused ex situ. Furthermore, we reveal that UDCA reduces the expression of ACE2 in the nasal epithelium in humans. Finally, we identify a correlation between UDCA treatment and positive clinical outcomes after SARS-CoV-2 infection using retrospective registry data, and confirm these findings in an independent validation cohort of recipients of liver transplants. In conclusion, we show that FXR has a role in controlling ACE2 expression and provide evidence that modulation of this pathway could be beneficial for reducing SARS-CoV-2 infection, paving the way for future clinical trials.

Published
2022

17. Integrated genomic analyses of ovarian carcinoma

Author

Bell, D, Berchuck, A, Birrer, M, Chien, J, Cramer, DW, Dao, F, Dhir, R, DiSaia, P, Gabra, H, Glenn, P, Godwin, AK, Gross, J, Hartmann, L, Huang, M, Huntsman, DG, Iacocca, M, Imielinski, M, Kalloger, S, Karlan, BY, Levine, DA, Mills, GB, Morrison, C, Mutch, D, Olvera, N, Orsulic, S, Park, K, Petrelli, N, Rabeno, B, Rader, JS, Sikic, BI, Smith-McCune, K, Sood, AK, Bowtell, D, Penny, R, Testa, JR, Chang, K, Creighton, CJ, Dinh, HH, Drummond, JA, Fowler, G, Gunaratne, P, Hawes, AC, Kovar, CL, Lewis, LR, Morgan, MB, Newsham, IF, Santibanez, J, Reid, JG, Trevino, LR, Wu, Y-Q, Wang, M, Muzny, DM, Wheeler, DA, Gibbs, RA, Getz, G, Lawrence, MS, Cibulskis, K, Sivachenko, AY, Sougnez, C, Voet, D, Wilkinson, J, Bloom, T, Ardlie, K, Fennell, T, Baldwin, J, Nichol, R, Fisher, S, Gabriel, S, Lander, ES, Ding, L, Fulton, RS, Koboldt, DC, McLellan, MD, Wylie, T, Walker, J, O’Laughlin, M, Dooling, DJ, Fulton, L, Abbott, R, Dees, ND, Zhang, Q, Kandoth, C, Wendl, M, Schierding, W, Shen, D, Harris, CC, Schmidt, H, Kalicki, J, Delehaunty, KD, Fronick, CC, Demeter, R, Cook, L, Wallis, JW, Lin, L, Magrini, VJ, Hodges, JS, Eldred, JM, Smith, SM, Pohl, CS, and Vandin, F

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Genetics, Oncology and Carcinogenesis, Biotechnology, Rare Diseases, Human Genome, Ovarian Cancer, Cancer, Aged, Carcinoma, DNA Methylation, Female, Gene Dosage, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Genomics, Humans, MicroRNAs, Middle Aged, Mutation, Ovarian Neoplasms, RNA, Messenger, Cancer Genome Atlas Research Network, General Science & Technology
Abstract

A catalogue of molecular aberrations that cause ovarian cancer is critical for developing and deploying therapies that will improve patients' lives. The Cancer Genome Atlas project has analysed messenger RNA expression, microRNA expression, promoter methylation and DNA copy number in 489 high-grade serous ovarian adenocarcinomas and the DNA sequences of exons from coding genes in 316 of these tumours. Here we report that high-grade serous ovarian cancer is characterized by TP53 mutations in almost all tumours (96%); low prevalence but statistically recurrent somatic mutations in nine further genes including NF1, BRCA1, BRCA2, RB1 and CDK12; 113 significant focal DNA copy number aberrations; and promoter methylation events involving 168 genes. Analyses delineated four ovarian cancer transcriptional subtypes, three microRNA subtypes, four promoter methylation subtypes and a transcriptional signature associated with survival duration, and shed new light on the impact that tumours with BRCA1/2 (BRCA1 or BRCA2) and CCNE1 aberrations have on survival. Pathway analyses suggested that homologous recombination is defective in about half of the tumours analysed, and that NOTCH and FOXM1 signalling are involved in serous ovarian cancer pathophysiology.

Published
2011

18. Tropical forests are approaching critical temperature thresholds

Author

Doughty, Christopher E., primary, Keany, Jenna M., additional, Wiebe, Benjamin C., additional, Rey-Sanchez, Camilo, additional, Carter, Kelsey R., additional, Middleby, Kali B., additional, Cheesman, Alexander W., additional, Goulden, Michael L., additional, da Rocha, Humberto R., additional, Miller, Scott D., additional, Malhi, Yadvinder, additional, Fauset, Sophie, additional, Gloor, Emanuel, additional, Slot, Martijn, additional, Oliveras Menor, Imma, additional, Crous, Kristine Y., additional, Goldsmith, Gregory R., additional, and Fisher, Joshua B., additional

Published
2023
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19. Long-term organic carbon preservation enhanced by iron and manganese

Author

Moore, Oliver W., primary, Curti, Lisa, additional, Woulds, Clare, additional, Bradley, James A., additional, Babakhani, Peyman, additional, Mills, Benjamin J. W., additional, Homoky, William B., additional, Xiao, Ke-Qing, additional, Bray, Andrew W., additional, Fisher, Ben J., additional, Kazemian, Majid, additional, Kaulich, Burkhard, additional, Dale, Andrew W., additional, and Peacock, Caroline L., additional

Published
2023
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20. B-cell-specific checkpoint molecules that regulate anti-tumour immunity

Author

Bod, Lloyd, primary, Kye, Yoon-Chul, additional, Shi, Jingwen, additional, Torlai Triglia, Elena, additional, Schnell, Alexandra, additional, Fessler, Johannes, additional, Ostrowski, Stephen M., additional, Von-Franque, Max Y., additional, Kuchroo, Juhi R., additional, Barilla, Rocky M., additional, Zaghouani, Sarah, additional, Christian, Elena, additional, Delorey, Toni Marie, additional, Mohib, Kanishka, additional, Xiao, Sheng, additional, Slingerland, Nadine, additional, Giuliano, Christopher J., additional, Ashenberg, Orr, additional, Li, Zhaorong, additional, Rothstein, David M., additional, Fisher, David E., additional, Rozenblatt-Rosen, Orit, additional, Sharpe, Arlene H., additional, Quintana, Francisco J., additional, Apetoh, Lionel, additional, Regev, Aviv, additional, and Kuchroo, Vijay K., additional

Published
2023
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21. Novel antigen-presenting cell imparts Treg-dependent tolerance to gut microbiota

Author

Blossom Akagbosu, Zakieh Tayyebi, Gayathri Shibu, Yoselin A. Paucar Iza, Deeksha Deep, Yollanda Franco Parisotto, Logan Fisher, H. Amalia Pasolli, Valentin Thevin, Rasa Elmentaite, Maximilian Knott, Saskia Hemmers, Lorenz Jahn, Christin Friedrich, Jacob Verter, Zhong-Min Wang, Marcel van den Brink, Georg Gasteiger, Thomas G. P. Grünewald, Julien C. Marie, Christina Leslie, Alexander Y. Rudensky, and Chrysothemis C. Brown

Subjects
Multidisciplinary
Abstract

Establishing and maintaining tolerance to self-antigens or innocuous foreign antigens is vital for the preservation of organismal health. Within the thymus, medullary thymic epithelial cells (mTECs) expressing autoimmune regulator (AIRE) have a critical role in self-tolerance through deletion of autoreactive T cells and promotion of thymic regulatory T (Treg) cell development1–4. Within weeks of birth, a separate wave of Treg cell differentiation occurs in the periphery upon exposure to antigens derived from the diet and commensal microbiota5–8, yet the cell types responsible for the generation of peripheral Treg (pTreg) cells have not been identified. Here we describe the identification of a class of RORγt+ antigen-presenting cells called Thetis cells, with transcriptional features of both mTECs and dendritic cells, comprising four major sub-groups (TC I–TC IV). We uncover a developmental wave of Thetis cells within intestinal lymph nodes during a critical window in early life, coinciding with the wave of pTreg cell differentiation. Whereas TC I and TC III expressed the signature mTEC nuclear factor AIRE, TC IV lacked AIRE expression and was enriched for molecules required for pTreg generation, including the TGF-β-activating integrin αvβ8. Loss of either major histocompatibility complex class II (MHCII) or ITGB8 by Thetis cells led to a profound impairment in intestinal pTreg differentiation, with ensuing colitis. By contrast, MHCII expression by RORγt+ group 3 innate lymphoid cells (ILC3) and classical dendritic cells was neither sufficient nor required for pTreg generation, further implicating TC IV as the tolerogenic RORγt+ antigen-presenting cell with an essential function in early life. Our studies reveal parallel pathways for the establishment of tolerance to self and foreign antigens in the thymus and periphery, respectively, marked by the involvement of shared cellular and transcriptional programmes.

Published
2022

22. The unexpected surface of asteroid (101955) Bennu

Author

D. S. Lauretta, D. N. DellaGiustina, C. A. Bennett, D. R. Golish, K. J. Becker, S. S. Balram-Knutson, O. S. Barnouin, T. L. Becker, W. F. Bottke, W. V. Boynton, H. Campins, H. C. Connolly Jr, C. Y. Drouet d’Aubigny, J. P. Dworkin, J. P. Emery, H. L. Enos, V. E. Hamilton, C. W. Hergenrother, E. S. Howell, M. R. M. Izawa, H. H. Kaplan, M. C. Nolan, B. Rizk, H. L. Roper, D. J. Scheeres, P. H. Smith, K. J. Walsh, C. W. V. Wolner, D. E. Highsmith, J. Small, D. Vokrouhlický, N. E. Bowles, E. Brown, K. L. Donaldson Hanna, T. Warren, C. Brunet, R. A. Chicoine, S. Desjardins, D. Gaudreau, T. Haltigin, S. Millington-Veloza, A. Rubi, J. Aponte, N. Gorius, A. Lunsford, B. Allen, J. Grindlay, D. Guevel, D. Hoak, J. Hong, D. L. Schrader, J. Bayron, O. Golubov, P. Sánchez, J. Stromberg, M. Hirabayashi, C. M. Hartzell, S. Oliver, M. Rascon, A. Harch, J. Joseph, S. Squyres, D. Richardson, L. McGraw, R. Ghent, R. P. Binzel, M. M. Al Asad, C. L. Johnson, L. Philpott, H. C. M. Susorney, E. A. Cloutis, R. D. Hanna, F. Ciceri, A. R. Hildebrand, E.-M. Ibrahim, L. Breitenfeld, T. Glotch, A. D. Rogers, B. E. Clark, S. Ferrone, C. A. Thomas, Y. Fernandez, W. Chang, A. Cheuvront, D. Trang, S. Tachibana, H. Yurimoto, J. R. Brucato, G. Poggiali, M. Pajola, E. Dotto, E. Mazzotta Epifani, M. K. Crombie, C. Lantz, J. de Leon, J. Licandro, J. L. Rizos Garcia, S. Clemett, K. Thomas-Keprta, S. Van wal, M. Yoshikawa, J. Bellerose, S. Bhaskaran, C. Boyles, S. R. Chesley, C. M. Elder, D. Farnocchia, A. Harbison, B. Kennedy, A. Knight, N. Martinez-Vlasoff, N. Mastrodemos, T. McElrath, W. Owen, R. Park, B. Rush, L. Swanson, Y. Takahashi, D. Velez, K. Yetter, C. Thayer, C. Adam, P. Antreasian, J. Bauman, C. Bryan, B. Carcich, M. Corvin, J. Geeraert, J. Hoffman, J. M. Leonard, E. Lessac-Chenen, A. Levine, J. McAdams, L. McCarthy, D. Nelson, B. Page, J. Pelgrift, E. Sahr, K. Stakkestad, D. Stanbridge, D. Wibben, B. Williams, K. Williams, P. Wolff, P. Hayne, D. Kubitschek, M. A. Barucci, J. D. P. Deshapriya, S. Fornasier, M. Fulchignoni, P. Hasselmann, F. Merlin, A. Praet, E. B. Bierhaus, O. Billett, A. Boggs, B. Buck, S. Carlson-Kelly, J.Cerna, K. Chaffin, E. Church, M. Coltrin, J. Daly, A. Deguzman, R. Dubisher, D. Eckart, D. Ellis, P. Falkenstern, A. Fisher, M. E. Fisher, P. Fleming, K. Fortney, S. Francis, S. Freund, S. Gonzales, P. Haas, A. Hasten, D. Hauf, A. Hilbert, D. Howell, F. Jaen, N. Jayakody, M. Jenkins, K. Johnson, M. Lefevre, H. Ma, C. Mario, K. Martin, C. May, M. McGee, B. Miller, C. Miller, G. Miller, A. Mirfakhrai, E. Muhle, C. Norman, R. Olds, C. Parish, M. Ryle, M. Schmitzer, P. Sherman, M. Skeen, M. Susak, B. Sutter, Q. Tran, C. Welch, R. Witherspoon, J. Wood, J. Zareski, M. Arvizu-Jakubicki, E. Asphaug, E. Audi, R.-L. Ballouz, R. Bandrowski, S. Bendall, H. Bloomenthal, D. Blum, J. Brodbeck, K. N. Burke, M. Chojnacki, A. Colpo, J. Contreras, J. Cutts, D. Dean, B. Diallo, D. Drinnon, K. Drozd, R. Enos, C. Fellows, T. Ferro, M. R. Fisher, G. Fitzgibbon, M. Fitzgibbon, J. Forelli, T. Forrester, I. Galinsky, R. Garcia, A. Gardner, N. Habib, D. Hamara, D. Hammond, K. Hanley, K. Harshman, K. Herzog, D. Hill, C. Hoekenga, S. Hooven, E. Huettner, A. Janakus, J. Jones, T. R. Kareta, J. Kidd, K. Kingsbury, L. Koelbel, J. Kreiner, D. Lambert, C. Lewin, B. Lovelace, M. Loveridge, M. Lujan, C. K. Maleszewski, R. Malhotra, K. Marchese, E. McDonough, N. Mogk, V. Morrison, E. Morton, R. Munoz, J. Nelson, J. Padilla, R. Pennington, A. Polit, N. Ramos, V. Reddy, M. Riehl, S. Salazar, S. R. Schwartz, S. Selznick, N. Shultz, S. Stewart, S. Sutton, T. Swindle, Y. H. Tang, M. Westermann, D. Worden, T. Zega, Z. Zeszut, A. Bjurstrom, L. Bloomquist, C. Dickinson, E. Keates, J. Liang, V. Nifo, A. Taylor, F. Teti, M. Caplinger, H. Bowles, S. Carter, S. Dickenshied, D. Doerres, T. Fisher, W. Hagee, J. Hill, M. Miner, D. Noss, N. Piacentine, M. Smith, A. Toland, P. Wren, M. Bernacki, D. Pino Munoz, S.-i. Watanabe, S. A. Sandford, A. Aqueche, B. Ashman, M. Barker, A. Bartels, K. Berry, B. Bos, R. Burns, A. Calloway, R. Carpenter, N. Castro, R. Cosentino, J. Donaldson, J. Elsila Cook, C. Emr, D. Everett, D. Fennell, K. Fleshman, D. Folta, D. Gallagher, J. Garvin, K. Getzandanner, D. Glavin, S. Hull, K. Hyde, H. Ido, A. Ingegneri, N. Jones, P. Kaotira, L. F. Lim, A. Liounis, C. Lorentson, D. Lorenz, J. Lyzhoft, E. M. Mazarico, R. Mink, W. Moore, M. Moreau, S. Mullen, J. Nagy, G. Neumann, J. Nuth, D. Poland, D. C. Reuter, L. Rhoads, S. Rieger, D. Rowlands, D. Sallitt, A. Scroggins, G. Shaw, A. A. Simon, J. Swenson, P. Vasudeva, M. Wasser, R. Zellar, J. Grossman, G. Johnston, M. Morris, J. Wendel, A. Burton, L. P. Keller, L. Mcnamara, S. Messenger, K. Messenger, A. Nguyen, K. Righter, E. Queen, K. Bellamy, K. Dill, S. Gardner, M. Giuntini, B. Key, J. Kissell, D. Patterson, D. Vaughan, B. Wright, R. W. Gaskell, L. Le Corre, J.-Y. Li, J. L. Molaro, E. E. Palmer, M. A. Siegler, P. Tricarico, J. R. Weirich, X.-D. Zou, T. Ireland, K. Tait, P. Bland, S. Anwar, N. Bojorquez-Murphy, P. R. Christensen, C. W. Haberle, G. Mehall, K. Rios, I. Franchi, B. Rozitis, C. B. Beddingfield, J. Marshall, D. N. Brack, A. S. French, J. W. McMahon, E. R. Jawin, T. J. McCoy, S. Russell, M. Killgore, J. L. Bandfield, B. C. Clark, M. Chodas, M. Lambert, R. A. Masterson, M. G. Daly, J. Freemantle, J. A. Seabrook, K. Craft, R. T. Daly, C. Ernst, R. C. Espiritu, M. Holdridge, M. Jones, A. H. Nair, L. Nguyen, J. Peachey, M. E. Perry, J. Plescia, J. H. Roberts, R. Steele, R. Turner, J. Backer, K. Edmundson, J. Mapel, M. Milazzo, S. Sides, C. Manzoni, B. May, M. Delbo, G. Libourel, P. Michel, A. Ryan, F. Thuillet, and B. Marty

Subjects
Astronomy, Exobiology
Abstract

NASA’S Origins, Spectral Interpretation, Resource Identification and Security-Regolith Explorer (OSIRIS-REx) spacecraft recently arrived at the near-Earth asteroid (101955) Bennu, a primitive body that represents the objects that may have brought prebiotic molecules and volatiles such as water to Earth1. Bennu is a low-albedo B-type asteroid2 that has been linked to organic-rich hydrated carbonaceous chondrites3. Such meteorites are altered by ejection from their parent body and contaminated by atmospheric entry and terrestrial microbes. Therefore, the primary mission objective is to return a sample of Bennu to Earth that is pristine—that is, not affected by these processes4. The OSIRIS-REx spacecraft carries a sophisticated suite of instruments to characterize Bennu’s global properties, support the selection of a sampling site and document that site at a sub-centimetre scale5,6,7,8,9,10,11. Here we consider early OSIRIS-REx observations of Bennu to understand how the asteroid’s properties compare to pre-encounter expectations and to assess the prospects for sample return. The bulk composition of Bennu appears to be hydrated and volatile-rich, as expected. However, in contrast to pre-encounter modelling of Bennu’s thermal inertia12 and radar polarization ratios13—which indicated a generally smooth surface covered by centimetre-scale particles—resolved imaging reveals an unexpected surficial diversity. The albedo, texture, particle size and roughness are beyond the spacecraft design specifications. On the basis of our pre-encounter knowledge, we developed a sampling strategy to target 50-metre-diameter patches of loose regolith with grain sizes smaller than two centimetres4. We observe only a small number of apparently hazard-free regions, of the order of 5 to 20 metres in extent, the sampling of which poses a substantial challenge to mission success.

Published
2019
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23. A Cdk9-PP1 switch regulates the elongation-termination transition of RNA polymerase II

Author

Parua, Pabitra K., Booth, Gregory T., Sansó, Miriam, Benjamin, Bradley, Tanny, Jason C., Lis, John T., and Fisher, Robert P.

Subjects
RNA polymerases -- Physiological aspects, Chromatin, Messenger RNA, Phosphatases, Transcription (Genetics), Genetic testing, RNA, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

The end of the RNA polymerase II (Pol II) transcription cycle is strictly regulated to prevent interference between neighbouring genes and to safeguard transcriptome integrity.sup.1. The accumulation of Pol II downstream of the cleavage and polyadenylation signal can facilitate the recruitment of factors involved in mRNA 3'-end formation and termination.sup.2, but how this sequence is initiated remains unclear. In a chemical-genetic screen, human protein phosphatase 1 (PP1) isoforms were identified as substrates of positive transcription elongation factor b (P-TEFb), also known as the cyclin-dependent kinase 9 (Cdk9)-cyclin T1 (CycT1) complex.sup.3. Here we show that Cdk9 and PP1 govern phosphorylation of the conserved elongation factor Spt5 in the fission yeast Schizosaccharomyces pombe. Cdk9 phosphorylates both Spt5 and a negative regulatory site on the PP1 isoform Dis2.sup.4. Sites targeted by Cdk9 in the Spt5 carboxy-terminal domain can be dephosphorylated by Dis2 in vitro, and dis2 mutations retard Spt5 dephosphorylation after inhibition of Cdk9 in vivo. Chromatin immunoprecipitation and sequencing analysis indicates that Spt5 is dephosphorylated as transcription complexes traverse the cleavage and polyadenylation signal, concomitant with the accumulation of Pol II phosphorylated at residue Ser2 of the carboxy-terminal domain consensus heptad repeat.sup.5. A conditionally lethal Dis2-inactivating mutation attenuates the drop in Spt5 phosphorylation on chromatin, promotes transcription beyond the normal termination zone (as detected by precision run-on transcription and sequencing.sup.6) and is genetically suppressed by the ablation of Cdk9 target sites in Spt5. These results suggest that the transition of Pol II from elongation to termination coincides with a Dis2-dependent reversal of Cdk9 signalling--a switch that is analogous to a Cdk1-PP1 circuit that controls mitotic progression.sup.4.The kinase Cdk9 and the phosphatase Dis2 regulate the termination of transcription in fission yeast in part by controlling the phosphorylation state of the elongation factor Spt5., Author(s): Pabitra K. Parua [sup.1] , Gregory T. Booth [sup.2] , Miriam Sansó [sup.1] [sup.4] , Bradley Benjamin [sup.1] , Jason C. Tanny [sup.3] , John T. Lis [sup.2] , [...]

Published
2018
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24. Author Correction: Testosterone histories from tusks reveal woolly mammoth musth episodes

Author

Cherney, Michael D., primary, Fisher, Daniel C., additional, Auchus, Richard J., additional, Rountrey, Adam N., additional, Selcer, Perrin, additional, Shirley, Ethan A., additional, Beld, Scott G., additional, Buigues, Bernard, additional, Mol, Dick, additional, Boeskorov, Gennady G., additional, Vartanyan, Sergey L., additional, and Tikhonov, Alexei N., additional

Published
2023
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26. Testosterone histories from tusks reveal woolly mammoth musth episodes

Author

Cherney, Michael D., primary, Fisher, Daniel C., additional, Auchus, Richard J., additional, Rountrey, Adam N., additional, Selcer, Perrin, additional, Shirley, Ethan A., additional, Beld, Scott G., additional, Buigues, Bernard, additional, Mol, Dick, additional, Boeskorov, Gennady G., additional, Vartanyan, Sergey L., additional, and Tikhonov, Alexei N., additional

Published
2023
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27. Author Correction: Neoadjuvant relatlimab and nivolumab in resectable melanoma

Author

Amaria, Rodabe N., primary, Postow, Michael, additional, Burton, Elizabeth M., additional, Tetzlaff, Michael T., additional, Ross, Merrick I., additional, Torres-Cabala, Carlos, additional, Glitza, Isabella C., additional, Duan, Fei, additional, Milton, Denái R., additional, Busam, Klaus, additional, Simpson, Lauren, additional, McQuade, Jennifer L., additional, Wong, Michael K., additional, Gershenwald, Jeffrey E., additional, Lee, Jeffrey E., additional, Goepfert, Ryan P., additional, Keung, Emily Z., additional, Fisher, Sarah B., additional, Betof-Warner, Allison, additional, Shoushtari, Alexander N., additional, Callahan, Margaret, additional, Coit, Daniel, additional, Bartlett, Edmund K., additional, Bello, Danielle, additional, Momtaz, Parisa, additional, Nicholas, Courtney, additional, Gu, Aidi, additional, Zhang, Xuejun, additional, Korivi, Brinda Rao, additional, Patnana, Madhavi, additional, Patel, Sapna P., additional, Diab, Adi, additional, Lucci, Anthony, additional, Prieto, Victor G., additional, Davies, Michael A., additional, Allison, James P., additional, Sharma, Padmanee, additional, Wargo, Jennifer A., additional, Ariyan, Charlotte, additional, and Tawbi, Hussein A., additional

Published
2023
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30. Altered TMPRSS2 usage by SARS-CoV-2 Omicron impacts tropism and fusogenicity

Author

Meng, B., Abdullahi, A., Ferreira, I., Goonawardane, N., Saito, A., Kimura, I., Yamasoba, D., Gerber, P., Fatihi, S., Rathore, S., Zepeda, S., Papa, G., Kemp, S., Ikeda, T., Toyoda, M., Tan, T., Kuramochi, J., Mitsunaga, S., Ueno, T., Shirakawa, K., Takaori-Kondo, A., Brevini, T., Mallery, D., Charles, O., Collaboration, C., Japan, G., Consortium, E., Bowen, J., Joshi, A., Walls, A., Jackson, L., Martin, D., Smith, K., Bradley, J., Briggs, J., Choi, J., Madissoon, E., Meyer, K., Mlcochova, P., Ceron-Gutierrez, L., Doffinger, R., Teichmann, S., Fisher, A., Pizzuto, M., de Marco, A., Corti, D., Hosmillo, M., Lee, J., James, L., Thukral, L., Veesler, D., Sigal, A., Sampaziotis, F., Goodfellow, I., Matheson, N., Sato, K., and Gupta, R.

Subjects
Immune evasion, SARS-CoV-2
Abstract

The SARS-CoV-2 Omicron BA.1 variant emerged in 20211 and bears multiple spike mutations2. Here we show that Omicron spike has higher affinity for ACE2 compared to Delta as well as a marked change of antigenicity conferring significant evasion of therapeutic monoclonal and vaccine-elicited polyclonal neutralising antibodies after two doses. mRNA vaccination as a third vaccine dose rescues and broadens neutralisation. Importantly, antiviral drugs remdesivir and molnupiravir retain efficacy against Omicron BA.1. Replication was similar for Omicron and Delta virus isolates in human nasal epithelial cultures. However, in lower airway organoids, lung cells and gut cells, Omicron demonstrated lower replication. Omicron spike protein was less efficiently cleaved compared to Delta. Replication differences mapped to entry efficiency using spike pseudotyped virus (PV) assays. The defect for Omicron PV to enter specific cell types effectively correlated with higher cellular RNA expression of TMPRSS2, and knock down of TMPRSS2 impacted Delta entry to a greater extent than Omicron. Furthermore, drug inhibitors targeting specific entry pathways3 demonstrated that the Omicron spike inefficiently utilises the cellular protease TMPRSS2 that promotes cell entry via plasma membrane fusion, with greater dependency on cell entry via the endocytic pathway. Consistent with suboptimal S1/S2 cleavage and inability to utilise TMPRSS2, syncytium formation by the Omicron spike was markedly impaired compared to the Delta spike. Omicron’s less efficient spike cleavage at S1/S2 is associated with shift in cellular tropism away from TMPRSS2 expressing cells, with implications for altered pathogenesis., SARS-CoV-2オミクロン株による中和抗体回避と感染指向性の変化. 京都大学プレスリリース. 2022-02-03.

Published
2022

31. Intravenous and intracranial GD2-CAR T cells for H3K27M+diffuse midline gliomas

Author

Monje, Michelle, Mahdi, Jasia, Majzner, Robbie, Yeom, Kristen W., Schultz, Liora M., Richards, Rebecca M., Barsan, Valentin, Song, Kun-Wei, Kamens, Jen, Baggott, Christina, Kunicki, Michael, Rietberg, Skyler P., Lim, Alexandria Sung, Reschke, Agnes, Mavroukakis, Sharon, Egeler, Emily, Moon, Jennifer, Patel, Shabnum, Chinnasamy, Harshini, Erickson, Courtney, Jacobs, Ashley, Duh, Allison K., Tunuguntla, Ramya, Klysz, Dorota Danuta, Fowler, Carley, Green, Sean, Beebe, Barbara, Carr, Casey, Fujimoto, Michelle, Brown, Annie Kathleen, Petersen, Ann-Louise G., McIntyre, Catherine, Siddiqui, Aman, Lepori-Bui, Nadia, Villar, Katlin, Pham, Kymhuynh, Bove, Rachel, Musa, Eric, Reynolds, Warren D., Kuo, Adam, Prabhu, Snehit, Rasmussen, Lindsey, Cornell, Timothy T., Partap, Sonia, Fisher, Paul G., Campen, Cynthia J., Grant, Gerald, Prolo, Laura, Ye, Xiaobu, Sahaf, Bita, Davis, Kara L., Feldman, Steven A., Ramakrishna, Sneha, and Mackall, Crystal

Abstract

H3K27M-mutant diffuse midline gliomas (DMGs) express high levels of the disialoganglioside GD2 (ref. 1). Chimeric antigen receptor-modified T cells targeting GD2 (GD2-CART) eradicated DMGs in preclinical models2. Arm A of Phase I trial no. NCT04196413(ref. 3) administered one intravenous (IV) dose of autologous GD2-CART to patients with H3K27M-mutant pontine (DIPG) or spinal DMG (sDMG) at two dose levels (DL1, 1 × 106kg−1; DL2, 3 × 106kg−1) following lymphodepleting chemotherapy. Patients with clinical or imaging benefit were eligible for subsequent intracerebroventricular (ICV) intracranial infusions (10–30 × 106GD2-CART). Primary objectives were manufacturing feasibility, tolerability and the identification of maximally tolerated IV dose. Secondary objectives included preliminary assessments of benefit. Thirteen patients enroled, with 11 receiving IV GD2-CART on study (n= 3 DL1 (3 DIPG); n= 8 DL2 (6 DIPG, 2 sDMG)). GD2-CART manufacture was successful for all patients. No dose-limiting toxicities occurred on DL1, but three patients experienced dose-limiting cytokine release syndrome on DL2, establishing DL1 as the maximally tolerated IV dose. Nine patients received ICV infusions, with no dose-limiting toxicities. All patients exhibited tumour inflammation-associated neurotoxicity, safely managed with intensive monitoring and care. Four patients demonstrated major volumetric tumour reductions (52, 54, 91 and 100%), with a further three patients exhibiting smaller reductions. One patient exhibited a complete response ongoing for over 30 months since enrolment. Nine patients demonstrated neurological benefit, as measured by a protocol-directed clinical improvement score. Sequential IV, followed by ICV GD2-CART, induced tumour regressions and neurological improvements in patients with DIPG and those with sDMG.

Published
2024
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32. Targeting TBK1 to overcome resistance to cancer immunotherapy

Author

Sun, Yi, primary, Revach, Or-yam, additional, Anderson, Seth, additional, Kessler, Emily A., additional, Wolfe, Clara H., additional, Jenney, Anne, additional, Mills, Caitlin E., additional, Robitschek, Emily J., additional, Davis, Thomas G. R., additional, Kim, Sarah, additional, Fu, Amina, additional, Ma, Xiang, additional, Gwee, Jia, additional, Tiwari, Payal, additional, Du, Peter P., additional, Sindurakar, Princy, additional, Tian, Jun, additional, Mehta, Arnav, additional, Schneider, Alexis M., additional, Yizhak, Keren, additional, Sade-Feldman, Moshe, additional, LaSalle, Thomas, additional, Sharova, Tatyana, additional, Xie, Hongyan, additional, Liu, Shuming, additional, Michaud, William A., additional, Saad-Beretta, Rodrigo, additional, Yates, Kathleen B., additional, Iracheta-Vellve, Arvin, additional, Spetz, Johan K. E., additional, Qin, Xingping, additional, Sarosiek, Kristopher A., additional, Zhang, Gao, additional, Kim, Jong Wook, additional, Su, Mack Y., additional, Cicerchia, Angelina M., additional, Rasmussen, Martin Q., additional, Klempner, Samuel J., additional, Juric, Dejan, additional, Pai, Sara I., additional, Miller, David M., additional, Giobbie-Hurder, Anita, additional, Chen, Jonathan H., additional, Pelka, Karin, additional, Frederick, Dennie T., additional, Stinson, Susanna, additional, Ivanova, Elena, additional, Aref, Amir R., additional, Paweletz, Cloud P., additional, Barbie, David A., additional, Sen, Debattama R., additional, Fisher, David E., additional, Corcoran, Ryan B., additional, Hacohen, Nir, additional, Sorger, Peter K., additional, Flaherty, Keith T., additional, Boland, Genevieve M., additional, Manguso, Robert T., additional, and Jenkins, Russell W., additional

Published
2023
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33. A DNA methylation atlas of normal human cell types

Author

Loyfer, Netanel, primary, Magenheim, Judith, additional, Peretz, Ayelet, additional, Cann, Gordon, additional, Bredno, Joerg, additional, Klochendler, Agnes, additional, Fox-Fisher, Ilana, additional, Shabi-Porat, Sapir, additional, Hecht, Merav, additional, Pelet, Tsuria, additional, Moss, Joshua, additional, Drawshy, Zeina, additional, Amini, Hamed, additional, Moradi, Patriss, additional, Nagaraju, Sudharani, additional, Bauman, Dvora, additional, Shveiky, David, additional, Porat, Shay, additional, Dior, Uri, additional, Rivkin, Gurion, additional, Or, Omer, additional, Hirshoren, Nir, additional, Carmon, Einat, additional, Pikarsky, Alon, additional, Khalaileh, Abed, additional, Zamir, Gideon, additional, Grinbaum, Ronit, additional, Abu Gazala, Machmud, additional, Mizrahi, Ido, additional, Shussman, Noam, additional, Korach, Amit, additional, Wald, Ori, additional, Izhar, Uzi, additional, Erez, Eldad, additional, Yutkin, Vladimir, additional, Samet, Yaacov, additional, Rotnemer Golinkin, Devorah, additional, Spalding, Kirsty L., additional, Druid, Henrik, additional, Arner, Peter, additional, Shapiro, A. M. James, additional, Grompe, Markus, additional, Aravanis, Alex, additional, Venn, Oliver, additional, Jamshidi, Arash, additional, Shemer, Ruth, additional, Dor, Yuval, additional, Glaser, Benjamin, additional, and Kaplan, Tommy, additional

Published
2023
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34. A gravitational-wave standard siren measurement of the Hubble constant

Author

Abbott, B. P., Abbott, R., Abbott, T. D., Acernese, F., Ackley, K., Adams, C., Adams, T., Addesso, P., Adhikari, R. X., Adya, V. B., Affeldt, C., Afrough, M., Agarwal, B., Agathos, M., Agatsuma, K., Aggarwal, N., Aguiar, O. D., Aiello, L., Ain, A., Ajith, P., Allen, B., Allen, G., Allocca, A., Altin, P. A., Amato, A., Ananyeva, A., Anderson, S. B., Anderson, W. G., Angelova, S. V., Antier, S., Appert, S., Arai, K., Araya, M. C., Areeda, J. S., Arnaud, N., Arun, K. G., Ascenzi, S., Ashton, G., Ast, M., Aston, S. M., Astone, P., Atallah, D. V., Aufmuth, P., Aulbert, C., AultONeal, K., Austin, C., Avila-Alvarez, A., Babak, S., Bacon, P., Bader, M. K. M., Bae, S., Baker, P. T., Baldaccini, F., Ballardin, G., Ballmer, S. W., Banagiri, S., Barayoga, J. C., Barclay, S. E., Barish, B. C., Barker, D., Barkett, K., Barone, F., Barr, B., Barsotti, L., Barsuglia, M., Barta, D., Bartlett, J., Bartos, I., Bassiri, R., Basti, A., Batch, J. C., Bawaj, M., Bayley, J. C., Bazzan, M., Bcsy, B., Beer, C., Bejger, M., Belahcene, I., Bell, A. S., Berger, B. K., Bergmann, G., Bero, J. J., Berry, C. P. L., Bersanetti, D., Bertolini, A., Betzwieser, J., Bhagwat, S., Bhandare, R., Bilenko, I. A., Billingsley, G., Billman, C. R., Birch, J., Birney, R., Birnholtz, O., Biscans, S., Biscoveanu, S., Bisht, A., Bitossi, M., Biwer, C., Bizouard, M. A., Blackburn, J. K., Blackman, J., Blair, C. D., Blair, D. G., Blair, R. M., Bloemen, S., Bock, O., Bode, N., Boer, M., Bogaert, G., Bohe, A., Bondu, F., Bonilla, E., Bonnand, R., Boom, B. A., Bork, R., Boschi, V., Bose, S., Bossie, K., Bouffanais, Y., Bozzi, A., Bradaschia, C., Brady, P. R., Branchesi, M., Brau, J. E., Briant, T., Brillet, A., Brinkmann, M., Brisson, V., Brockill, P., Broida, J. E., Brooks, A. F., Brown, D. A., Brown, D. D., Brunett, S., Buchanan, C. C., Buikema, A., Bulik, T., Bulten, H. J., Buonanno, A., Buskulic, D., Buy, C., Byer, R. L., Cabero, M., Cadonati, L., Cagnoli, G., Cahillane, C., Bustillo, J. Caldern, Callister, T. A., Calloni, E., Camp, J. B., Canepa, M., Canizares, P., Cannon, K. C., Cao, H., Cao, J., Capano, C. D., Capocasa, E., Carbognani, F., Caride, S., Carney, M. F., Diaz, J. Casanueva, Casentini, C., Caudill, S., Cavagli, M., Cavalier, F., Cavalieri, R., Cella, G., Cepeda, C. B., Cerd-Durn, P., Cerretani, G., Cesarini, E., Chamberlin, S. J., Chan, M., Chao, S., Charlton, P., Chase, E., Chassande-Mottin, E., Chatterjee, D., Chatziioannou, K., Cheeseboro, B. D., Chen, H. Y., Chen, X., Chen, Y., Cheng, H.-P., Chia, H., Chincarini, A., Chiummo, A., Chmiel, T., Cho, H. S., Cho, M., Chow, J. H., Christensen, N., Chu, Q., Chua, A. J. K., Chua, S., Chung, A. K. W., Chung, S., Ciani, G., Ciolfi, R., Cirelli, C. E., Cirone, A., Clara, F., Clark, J. A., Clearwater, P., Cleva, F., Cocchieri, C., Coccia, E., Cohadon, P.-F., Cohen, D., Colla, A., Collette, C. G., Cominsky, L. R., Constancio, M., Jr., Conti, L., Cooper, S. J., Corban, P., Corbitt, T. R., Cordero-Carrin, I., Corley, K. R., Cornish, N., Corsi, A., Cortese, S., Costa, C. A., Coughlin, M. W., Coughlin, S. B., Coulon, J.-P., Countryman, S. T., Couvares, P., Covas, P. B., Cowan, E. E., Coward, D. M., Cowart, M. J., Coyne, D. C., Coyne, R., Creighton, J. D. E., Creighton, T. D., Cripe, J., Crowder, S. G., Cullen, T. J., Cumming, A., Cunningham, L., Cuoco, E., Dal Canton, T., Dlya, G., Danilishin, S. L., DAntonio, S., Danzmann, K., Dasgupta, A., Da Silva Costa, C. F., Datrier, L. E. H., Dattilo, V., Dave, I., Davier, M., Davis, D., Daw, E. J., Day, B., De, S., DeBra, D., Degallaix, J., De Laurentis, M., Delglise, S., Del Pozzo, W., Demos, N., Denker, T., Dent, T., De Pietri, R., Dergachev, V., De Rosa, R., DeRosa, R. T., De Rossi, C., DeSalvo, R., de Varona, O., Devenson, J., Dhurandhar, S., Daz, M. C., Di Fiore, L., Di Giovanni, M., Di Girolamo, T., Di Lieto, A., Di Pace, S., Di Palma, I., Di Renzo, F., Doctor, Z., Dolique, V., Donovan, F., Dooley, K. L., Doravari, S., Dorrington, I., Douglas, R., Dovale lvarez, M., Downes, T. P., Drago, M., Dreissigacker, C., Driggers, J. C., Du, Z., Ducrot, M., Dupej, P., Dwyer, S. E., Edo, T. B., Edwards, M. C., Effler, A., Eggenstein, H.-B., Ehrens, P., Eichholz, J., Eikenberry, S. S., Eisenstein, R. A., Essick, R. C., Estevez, D., Etienne, Z. B., Etzel, T., Evans, M., Evans, T. M., Factourovich, M., Fafone, V., Fair, H., Fairhurst, S., Fan, X., Farinon, S., Farr, B., Farr, W. M., Fauchon-Jones, E. J., Favata, M., Fays, M., Fee, C., Fehrmann, H., Feicht, J., Fejer, M. M., Fernandez-Galiana, A., Ferrante, I., Ferreira, E. C., Ferrini, F., Fidecaro, F., Finstad, D., Fiori, I., Fiorucci, D., Fishbach, M., Fisher, R. P., Fitz-Axen, M., Flaminio, R., Fletcher, M., Fong, H., Font, J. A., Forsyth, P. W. F., Forsyth, S. S., Fournier, J.-D., Frasca, S., Frasconi, F., Frei, Z., Freise, A., Frey, R., Frey, V., Fries, E. M., Fritschel, P., Frolov, V. V., Fulda, P., Fyffe, M., Gabbard, H., Gadre, B. U., Gaebel, S. M., Gair, J. R., Gammaitoni, L., Ganija, M. R., Gaonkar, S. G., Garcia-Quiros, C., Garufi, F., Gateley, B., Gaudio, S., Gaur, G., Gayathri, V., Gehrels, N., Gemme, G., Genin, E., Gennai, A., George, D., George, J., Gergely, L., Germain, V., Ghonge, S., Ghosh, Abhirup, Ghosh, Archisman, Ghosh, S., Giaime, J. A., Giardina, K. D., Giazotto, A., Gill, K., Glover, L., Goetz, E., Goetz, R., Gomes, S., Goncharov, B., Gonzlez, G., Castro, J. M. Gonzalez, Gopakumar, A., Gorodetsky, M. L., Gossan, S. E., Gosselin, M., Gouaty, R., Grado, A., Graef, C., Granata, M., Grant, A., Gras, S., Gray, C., Greco, G., Green, A. C., Gretarsson, E. M., Groot, P., Grote, H., Grunewald, S., Gruning, P., Guidi, G. M., Guo, X., Gupta, A., Gupta, M. K., Gushwa, K. E., Gustafson, E. K., Gustafson, R., Halim, O., Hall, B. R., Hall, E. D., Hamilton, E. Z., Hammond, G., Haney, M., Hanke, M. M., Hanks, J., Hanna, C., Hannam, M. D., Hannuksela, O. A., Hanson, J., Hardwick, T., Harms, J., Harry, G. M., Harry, I. W., Hart, M. J., Haster, C.-J., Haughian, K., Healy, J., Heidmann, A., Heintze, M. C., Heitmann, H., Hello, P., Hemming, G., Hendry, M., Heng, I. S., Hennig, J., Heptonstall, A. W., Heurs, M., Hild, S., Hinderer, T., Hoak, D., Hofman, D., Holt, K., Holz, D. E., Hopkins, P., Horst, C., Hough, J., Houston, E. A., Howell, E. J., Hreibi, A., Hu, Y. M., Huerta, E. A., Huet, D., Hughey, B., Husa, S., Huttner, S. H., Huynh-Dinh, T., Indik, N., Inta, R., Intini, G., Isa, H. N., Isac, J.-M., Isi, M., Iyer, B. R., Izumi, K., Jacqmin, T., Jani, K., Jaranowski, P., Jawahar, S., Jimnez-Forteza, F., Johnson, W. W., Jones, D. I., Jones, R., Jonker, R. J. G., Ju, L., Junker, J., Kalaghatgi, C. V., Kalogera, V., Kamai, B., Kandhasamy, S., Kang, G., Kanner, J. B., Kapadia, S. J., Karki, S., Karvinen, K. S., Kasprzack, M., Katolik, M., Katsavounidis, E., Katzman, W., Kaufer, S., Kawabe, K., Kflian, F., Keitel, D., Kemball, A. J., Kennedy, R., Kent, C., Key, J. S., Khalili, F. Y., Khan, I., Khan, S., Khan, Z., Khazanov, E. A., Kijbunchoo, N., Kim, Chunglee, Kim, J. C., Kim, K., Kim, W., Kim, W. S., Kim, Y.-M., Kimbrell, S. J., King, E. J., King, P. J., Kinley-Hanlon, M., Kirchhoff, R., Kissel, J. S., Kleybolte, L., Klimenko, S., Knowles, T. D., Koch, P., Koehlenbeck, S. M., Koley, S., Kondrashov, V., Kontos, A., Korobko, M., Korth, W. Z., Kowalska, I., Kozak, D. B., Krmer, C., Kringel, V., Krishnan, B., Krlak, A., Kuehn, G., Kumar, P., Kumar, R., Kumar, S., Kuo, L., Kutynia, A., Kwang, S., Lackey, B. D., Lai, K. H., Landry, M., Lang, R. N., Lange, J., Lantz, B., Lanza, R. K., Lartaux-Vollard, A., Lasky, P. D., Laxen, M., Lazzarini, A., Lazzaro, C., Leaci, P., Leavey, S., Lee, C. H., Lee, H. K., Lee, H. M., Lee, H. W., Lee, K., Lehmann, J., Lenon, A., Leonardi, M., Leroy, N., Letendre, N., Levin, Y., Li, T. G. F., Linker, S. D., Littenberg, T. B., Liu, J., Liu, X., Lo, R. K. L., Lockerbie, N. A., London, L. T., Lord, J. E., Lorenzini, M., Loriette, V., Lormand, M., Losurdo, G., Lough, J. D., Lousto, C. O., Lovelace, G., Lck, H., Lumaca, D., Lundgren, A. P., Lynch, R., Ma, Y., Macas, R., Macfoy, S., Machenschalk, B., MacInnis, M., Macleod, D. M., Hernandez, I. Magaa, Magaa-Sandoval, F., Zertuche, L. Magaa, Magee, R. M., Majorana, E., Maksimovic, I., Man, N., Mandic, V., Mangano, V., Mansell, G. L., Manske, M., Mantovani, M., Marchesoni, F., Marion, F., Mrka, S., Mrka, Z., Markakis, C., Markosyan, A. S., Markowitz, A., Maros, E., Marquina, A., Martelli, F., Martellini, L., Martin, I. W., Martin, R. M., Martynov, D. V., Mason, K., Massera, E., Masserot, A., Massinger, T. J., Masso-Reid, M., Mastrogiovanni, S., Matas, A., Matichard, F., Matone, L., Mavalvala, N., Mazumder, N., McCarthy, R., McClelland, D. E., McCormick, S., McCuller, L., McGuire, S. C., McIntyre, G., McIver, J., McManus, D. J., McNeill, L., McRae, T., McWilliams, S. T., Meacher, D., Meadors, G. D., Mehmet, M., Meidam, J., Mejuto-Villa, E., Melatos, A., Mendell, G., Mercer, R. A., Merilh, E. L., Merzougui, M., Meshkov, S., Messenger, C., Messick, C., Metzdorff, R., Meyers, P. M., Miao, H., Michel, C., Middleton, H., Mikhailov, E. E., Milano, L., Miller, A. L., Miller, B. B., Miller, J., Millhouse, M., Milovich-Goff, M. C., Minazzoli, O., Minenkov, Y., Ming, J., Mishra, C., Mitra, S., Mitrofanov, V. P., Mitselmakher, G., Mittleman, R., Moffa, D., Moggi, A., Mogushi, K., Mohan, M., Mohapatra, S. R. P., Montani, M., Moore, C. J., Moraru, D., Moreno, G., Morriss, S. R., Mours, B., Mow-Lowry, C. M., Mueller, G., Muir, A. W., Mukherjee, Arunava, Mukherjee, D., Mukherjee, S., Mukund, N., Mullavey, A., Munch, J., Muiz, E. A., Muratore, M., Murray, P. G., Napier, K., Nardecchia, I., Naticchioni, L., Nayak, R. K., Neilson, J., Nelemans, G., Nelson, T. J. N., Nery, M., Neunzert, A., Nevin, L., Newport, J. M., Newton, G., Ng, K. K. Y., Nguyen, T. T., Nichols, D., Nielsen, A. B., Nissanke, S., Nitz, A., Noack, A., Nocera, F., Nolting, D., North, C., Nuttall, L. K., Oberling, J., ODea, G. D., Ogin, G. H., Oh, J. J., Oh, S. H., Ohme, F., Okada, M. A., Oliver, M., Oppermann, P., Oram, Richard J., OReilly, B., Ormiston, R., Ortega, L. F., OShaughnessy, R., Ossokine, S., Ottaway, D. J., Overmier, H., Owen, B. J., Pace, A. E., Page, J., Page, M. A., Pai, A., Pai, S. A., Palamos, J. R., Palashov, O., Palomba, C., Pal-Singh, A., Pan, Howard, Pan, Huang-Wei, Pang, B., Pang, P. T. H., Pankow, C., Pannarale, F., Pant, B. C., Paoletti, F., Paoli, A., Papa, M. A., Parida, A., Parker, W., Pascucci, D., Pasqualetti, A., Passaquieti, R., Passuello, D., Patil, M., Patricelli, B., Pearlstone, B. L., Pedraza, M., Pedurand, R., Pekowsky, L., Pele, A., Penn, S., Perez, C. J., Perreca, A., Perri, L. M., Pfeiffer, H. P., Phelps, M., Piccinni, O. J., Pichot, M., Piergiovanni, F., Pierro, V., Pillant, G., Pinard, L., Pinto, I. M., Pirello, M., Pitkin, M., Poe, M., Poggiani, R., Popolizio, P., Porter, E. K., Post, A., Powell, J., Prasad, J., Pratt, J. W. W., Pratten, G., Predoi, V., Prestegard, T., Prijatelj, M., Principe, M., Privitera, S., Prodi, G. A., Prokhorov, L. G., Puncken, O., Punturo, M., Puppo, P., Prrer, M., Qi, H., Quetschke, V., Quintero, E. A., Quitzow-James, R., Raab, F. J., Rabeling, D. S., Radkins, H., Raffai, P., Raja, S., Rajan, C., Rajbhandari, B., Rakhmanov, M., Ramirez, K. E., Ramos-Buades, A., Rapagnani, P., Raymond, V., Razzano, M., Read, J., Regimbau, T., Rei, L., Reid, S., Reitze, D. H., Ren, W., Reyes, S. D., Ricci, F., Ricker, P. M., Rieger, S., Riles, K., Rizzo, M., Robertson, N. A., Robie, R., Robinet, F., Rocchi, A., Rolland, L., Rollins, J. G., Roma, V. J., Romano, J. D., Romano, R., Romel, C. L., Romie, J. H., Rosiska, D., Ross, M. P., Rowan, S., Rdiger, A., Ruggi, P., Rutins, G., Ryan, K., Sachdev, S., Sadecki, T., Sadeghian, L., Sakellariadou, M., Salconi, L., Saleem, M., Salemi, F., Samajdar, A., Sammut, L., Sampson, L. M., Sanchez, E. J., Sanchez, L. E., Sanchis-Gual, N., Sandberg, V., Sanders, J. R., Sassolas, B., Sathyaprakash, B. S., Saulson, P. R., Sauter, O., Savage, R. L., Sawadsky, A., Schale, P., Scheel, M., Scheuer, J., Schmidt, J., Schmidt, P., Schnabel, R., Schofield, R. M. S., Schnbeck, A., Schreiber, E., Schuette, D., Schulte, B. W., Schutz, B. F., Schwalbe, S. G., Scott, J., Scott, S. M., Seidel, E., Sellers, D., Sengupta, A. S., Sentenac, D., Sequino, V., Sergeev, A., Shaddock, D. A., Shaffer, T. J., Shah, A. A., Shahriar, M. S., Shaner, M. B., Shao, L., Shapiro, B., Shawhan, P., Sheperd, A., Shoemaker, D. H., Shoemaker, D. M., Siellez, K., Siemens, X., Sieniawska, M., Sigg, D., Silva, A. D., Singer, L. P., Singh, A., Singhal, A., Sintes, A. M., Slagmolen, B. J. J., Smith, B., Smith, J. R., Smith, R. J. E., Somala, S., Son, E. J., Sonnenberg, J. A., Sorazu, B., Sorrentino, F., Souradeep, T., Spencer, A. P., Srivastava, A. K., Staats, K., Staley, A., Steer, D., Steinke, M., Steinlechner, J., Steinlechner, S., Steinmeyer, D., Stevenson, S. P., Stone, R., Stops, D. J., Strain, K. A., Stratta, G., Strigin, S. E., Strunk, A., Sturani, R., Stuver, A. L., Summerscales, T. Z., Sun, L., Sunil, S., Suresh, J., Sutton, P. J., Swinkels, B. L., Szczepaczyk, M. J., Tacca, M., Tait, S. C., Talbot, C., Talukder, D., Tanner, D. B., Tpai, M., Taracchini, A., Tasson, J. D., Taylor, J. A., Taylor, R., Tewari, S. V., Theeg, T., Thies, F., Thomas, E. G., Thomas, M., Thomas, P., Thorne, K. A., Thrane, E., Tiwari, S., Tiwari, V., Tokmakov, K. V., Toland, K., Tonelli, M., Tornasi, Z., Torres-Forn, A., Torrie, C. I., Tyr, D., Travasso, F., Traylor, G., Trinastic, J., Tringali, M. C., Trozzo, L., Tsang, K. W., Tse, M., Tso, R., Tsukada, L., Tsuna, D., Tuyenbayev, D., Ueno, K., Ugolini, D., Unnikrishnan, C. S., Urban, A. L., Usman, S. A., Vahlbruch, H., Vajente, G., Valdes, G., van Bakel, N., van Beuzekom, M., van den Brand, J. F. J., Van Den Broeck, C., Vander-Hyde, D. C., van der Schaaf, L., van Heijningen, J. V., van Veggel, A. A., Vardaro, M., Varma, V., Vass, S., Vasth, M., Vecchio, A., Vedovato, G., Veitch, J., Veitch, P. J., Venkateswara, K., Venugopalan, G., Verkindt, D., Vetrano, F., Vicer, A., Viets, A. D., Vinciguerra, S., Vine, D. J., Vinet, J.-Y., Vitale, S., Vo, T., Vocca, H., Vorvick, C., Vyatchanin, S. P., Wade, A. R., Wade, L. E., Wade, M., Walet, R., Walker, M., Wallace, L., Walsh, S., Wang, G., Wang, H., Wang, J. Z., Wang, W. H., Wang, Y. F., Ward, R. L., Warner, J., Was, M., Watchi, J., Weaver, B., Wei, L.-W., Weinert, M., Weinstein, A. J., Weiss, R., Wen, L., Wessel, E. K., Weels, P., Westerweck, J., Westphal, T., Wette, K., Whelan, J. T., Whitcomb, S. E., Whiting, B. F., Whittle, C., Wilken, D., Williams, D., Williams, R. D., Williamson, A. R., Willis, J. L., Willke, B., Wimmer, M. H., Winkler, W., Wipf, C. C., Wittel, H., Woan, G., Woehler, J., Wofford, J., Wong, K. W. K., Worden, J., Wright, J. L., Wu, D. S., Wysocki, D. M., Xiao, S., Yamamoto, H., Yancey, C. C., Yang, L., Yap, M. J., Yazback, M., Yu, Hang, Yu, Haocun, Yvert, M., Zadrony, A., Zanolin, M., Zelenova, T., Zendri, J.-P., Zevin, M., Zhang, L., Zhang, M., Zhang, T., Zhang, Y.-H., Zhao, C., Zhou, M., Zhou, Z., Zhu, S. J., Zhu, X. J., Zimmerman, A. B., Zucker, M. E., Zweizig, J., Foley, R. J., Coulter, D. A., Drout, M. R., Kasen, D., Kilpatrick, C. D., Madore, B. F., Murguia-Berthier, A., Pan, Y.-C., Piro, A. L., Prochaska, J. X., Ramirez-Ruiz, E., Rest, A., Rojas-Bravo, C., Shappee, B. J., Siebert, M. R., Simon, J. D., Ulloa, N., Annis, J., Soares-Santos, M., Brout, D., Scolnic, D., Diehl, H. T., Frieman, J., Berger, E., Alexander, K. D., Allam, S., Balbinot, E., Blanchard, P., Butler, R. E., Chornock, R., Cook, E. R., Cowperthwaite, P., Drlica-Wagner, A., Durret, F., Eftekhari, T., Finley, D. A., Fong, W., Fryer, C. L., Garca-Bellido, J., Gill, M. S. S., Gruendl, R. A., Hartley, W., Herner, K., Huterer, D., Kessler, R., Li, T. S., Lin, H., Lopes, P. A. A., Loureno, A. C. C., Margutti, R., Marriner, J., Marshall, J. L., Matheson, T., Medina, G. E., Metzger, B. D., Muoz, R. R., Muir, J., Nicholl, M., Nugent, P., Palmese, A., Paz-Chinchn, F., Quataert, E., Sako, M., Sauseda, M., Schlegel, D. J., Secco, L. F., Smith, N., Sobreira, F., Stebbins, A., Villar, V. A., Vivas, A. K., Wester, W., Williams, P. K. G., Yanny, B., Zenteno, A., Abbott, T. M. C., Abdalla, F. B., Bechtol, K., Benoit-Lvy, A., Bertin, E., Bridle, S. L., Brooks, D., Buckley-Geer, E., Burke, D. L., Rosell, A. Carnero, Kind, M. Carrasco, Carretero, J., Castander, F. J., Cunha, C. E., DAndrea, C. B., da Costa, L. N., Davis, C., DePoy, D. L., Desai, S., Dietrich, J. P., Estrada, J., Fernandez, E., Flaugher, B., Fosalba, P., Gaztanaga, E., Gerdes, D. W., Giannantonio, T., Goldstein, D. A., Gruen, D., Gutierrez, G., Hartley, W. G., Honscheid, K., Jain, B., James, D. J., Jeltema, T., Johnson, M. W. G., Kent, S., Krause, E., Kron, R., Kuehn, K., Kuhlmann, S., Kuropatkin, N., Lahav, O., Lima, M., Maia, M. A. G., March, M., Miller, C. J., Miquel, R., Neilsen, E., Nord, B., Ogando, R. L. C., Plazas, A. A., Romer, A. K., Roodman, A., Rykoff, E. S., Sanchez, E., Scarpine, V., Schubnell, M., Sevilla-Noarbe, I., Smith, M., Smith, R. C., Suchyta, E., Tarle, G., Thomas, D., Thomas, R. C., Troxel, M. A., Tucker, D. L., Vikram, V., Walker, A. R., Weller, J., Zhang, Y., Haislip, J. B., Kouprianov, V. V., Reichart, D. E., Tartaglia, L., Sand, D. J., Valenti, S., Yang, S., Arcavi, Iair, Hosseinzadeh, Griffin, Howell, D. Andrew, McCully, Curtis, Poznanski, Dovi, Vasylyev, Sergiy, Tanvir, N. R., Levan, A. J., Hjorth, J., Cano, Z., Copperwheat, C., de Ugarte-Postigo, A., Evans, P. A., Fynbo, J. P. U., Gonzlez-Fernndez, C., Greiner, J., Irwin, M., Lyman, J., Mandel, I., McMahon, R., Milvang-Jensen, B., OBrien, P., Osborne, J. P., Perley, D. A., Pian, E., Palazzi, E., Rol, E., Rosetti, S., Rosswog, S., Rowlinson, A., Schulze, S., Steeghs, D. T. H., Thne, C. C., Ulaczyk, K., Watson, D., Wiersema, K., Lipunov, V. M., Gorbovskoy, E., Kornilov, V. G., Tyurina, N., Balanutsa, P., Vlasenko, D., Gorbunov, I., Podesta, R., Levato, H., Saffe, C., Buckley, D. A. H., Budnev, N. M., Gress, O., Yurkov, V., Rebolo, R., and Serra-Ricart, M.

Subjects
Gravitational waves -- Measurement, Hubble constant -- Measurement, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

Author(s): The LIGO Scientific Collaboration and The Virgo Collaboration; B. P. Abbott [1]; R. Abbott [1]; T. D. Abbott [2]; F. Acernese [3, 4]; K. Ackley [5, 6]; C. Adams [...]

Published
2017
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35. Altered TMPRSS2 usage by SARS-CoV-2 Omicron impacts infectivity and fusogenicity

Author

Meng, B., Abdullahi, A., Ferreira, I. A. T. M., Goonawardane, N., Saito, A., Kimura, I., Yamasoba, D., Gerber, P. P., Fatihi, S., Rathore, S., Zepeda, S. K., Papa, G., Kemp, S. A., Ikeda, T., Toyoda, M., Tan, T. S., Kuramochi, J., Mitsunaga, S., Ueno, T., Shirakawa, K., Takaori-Kondo, A., Brevini, T., Mallery, D. L., Charles, O. J., Baker, S., Dougan, G., Hess, C., Kingston, N., Lehner, P. J., Lyons, P. A., Matheson, N. J., Ouwehand, W. H., Saunders, C., Summers, C., Thaventhiran, J. E. D., Toshner, M., Weekes, M. P., Maxwell, P., Shaw, A., Bucke, A., Calder, J., Canna, L., Domingo, J., Elmer, A., Fuller, S., Harris, J., Hewitt, S., Kennet, J., Jose, S., Kourampa, J., Meadows, A., O'Brien, C., Price, J., Publico, C., Rastall, R., Ribeiro, C., Rowlands, J., Ruffolo, V., Tordesillas, H., Bullman, B., Dunmore, B. J., Graf, S., Hodgson, J., Huang, C., Hunter, K., Jones, E., Legchenko, E., Matara, C., Martin, J., Mescia, F., O'Donnell, C., Pointon, L., Shih, J., Sutcliffe, R., Tilly, T., Treacy, C., Tong, Z., Wood, J., Wylot, M., Betancourt, A., Bower, G., Cossetti, C., De Sa, A., Epping, M., Fawke, S., Gleadall, N., Grenfell, R., Hinch, A., Jackson, S., Jarvis, I., Krishna, B., Nice, F., Omarjee, O., Perera, M., Potts, M., Richoz, N., Romashova, V., Stefanucci, L., Strezlecki, M., Turner, L., De Bie, E. M. D. D., Bunclark, K., Josipovic, M., Mackay, M., Butcher, H., Caputo, D., Chandler, M., Chinnery, P., Clapham-Riley, D., Dewhurst, E., Fernandez, C., Furlong, A., Graves, B., Gray, J., Hein, S., Ivers, T., Le Gresley, E., Linger, R., Kasanicki, M., King, R., Meloy, S., Moulton, A., Muldoon, F., Ovington, N., Papadia, S., Penkett, C. J., Phelan, I., Ranganath, V., Paraschiv, R., Sage, A., Sambrook, J., Scholtes, I., Schon, K., Stark, H., Stirrups, K. E., Townsend, P., Walker, N., Webster, J., Butlertanaka, E. P., Tanaka, Y. L., Ito, J., Uriu, K., Kosugi, Y., Suganami, M., Oide, A., Yokoyama, M., Chiba, M., Motozono, C., Nasser, H., Shimizu, R., Kitazato, K., Hasebe, H., Irie, T., Nakagawa, S., Wu, J., Takahashi, M., Fukuhara, T., Shimizu, K., Tsushima, K., Kubo, H., Kazuma, Y., Nomura, R., Horisawa, Y., Nagata, K., Kawai, Y., Yanagida, Y., Tashiro, Y., Tokunaga, K., Ozono, S., Kawabata, R., Morizako, N., Sadamasu, K., Asakura, H., Nagashima, M., Yoshimura, K., Cardenas, P., Munoz, E., Barragan, V., Marquez, S., Prado-Vivar, B., Becerra-Wong, M., Caravajal, M., Trueba, G., Rojas-Silva, P., Grunauer, M., Gutierrez, B., Guadalupe, J. J., Fernandez-Cadena, J. C., Andrade-Molina, D., Baldeon, M., Pinos, A., Bowen, J. E., Joshi, A., Walls, A. C., Jackson, L., Martin, D., Smith, K. G. C., Bradley, J., Briggs, J. A. G., Choi, J., Madissoon, E., Meyer, K. B., Mlcochova, P., Ceron-Gutierrez, L., Doffinger, R., Teichmann, S. A., Fisher, A. J., Pizzuto, M. S., de Marco, A., Corti, D., Hosmillo, M., Lee, J. H., James, L. C., Thukral, L., Veesler, D., Sigal, A., Sampaziotis, F., Goodfellow, I. G., Sato, K., and Gupta, R. K.

Subjects
Adult, Male, COVID-19 Vaccines, Virus Replication, Membrane Fusion, Antibodies, Cell Line, Tissue Culture Techniques, Chlorocebus aethiops, 80 and over, Animals, Humans, Viral, Neutralizing, Lung, Aged, Multidisciplinary, Virulence, SARS-CoV-2, Immune Sera, Cell Membrane, Serine Endopeptidases, COVID-19, Convalescence, Middle Aged, Virus Internalization, Spike Glycoprotein, Intestines, Coronavirus, Nasal Mucosa, Mutation, Female, Angiotensin-Converting Enzyme 2, Aged, 80 and over, Antibodies, Neutralizing, Antibodies, Viral, Spike Glycoprotein, Coronavirus
Abstract

The SARS-CoV-2 Omicron BA.1 variant emerged in 20211 and has multiple mutations in its spike protein2. Here we show that the spike protein of Omicron has a higher affinity for ACE2 compared with Delta, and a marked change in its antigenicity increases Omicron’s evasion of therapeutic monoclonal and vaccine-elicited polyclonal neutralizing antibodies after two doses. mRNA vaccination as a third vaccine dose rescues and broadens neutralization. Importantly, the antiviral drugs remdesivir and molnupiravir retain efficacy against Omicron BA.1. Replication was similar for Omicron and Delta virus isolates in human nasal epithelial cultures. However, in lung cells and gut cells, Omicron demonstrated lower replication. Omicron spike protein was less efficiently cleaved compared with Delta. The differences in replication were mapped to the entry efficiency of the virus on the basis of spike-pseudotyped virus assays. The defect in entry of Omicron pseudotyped virus to specific cell types effectively correlated with higher cellular RNA expression of TMPRSS2, and deletion of TMPRSS2 affected Delta entry to a greater extent than Omicron. Furthermore, drug inhibitors targeting specific entry pathways3 demonstrated that the Omicron spike inefficiently uses the cellular protease TMPRSS2, which promotes cell entry through plasma membrane fusion, with greater dependency on cell entry through the endocytic pathway. Consistent with suboptimal S1/S2 cleavage and inability to use TMPRSS2, syncytium formation by the Omicron spike was substantially impaired compared with the Delta spike. The less efficient spike cleavage of Omicron at S1/S2 is associated with a shift in cellular tropism away from TMPRSS2-expressing cells, with implications for altered pathogenesis.

Published
2022

36. Global patterns of drought recovery

Author

Schwalm, Christopher R., Anderegg, William R. L., Michalak, Anna M., Fisher, Joshua B., Biondi, Franco, Koch, George, Litvak, Marcy, Ogle, Kiona, Shaw, John D., Wolf, Adam, Huntzinger, Deborah N., Schaefer, Kevin, Cook, Robert, Wei, Yaxing, Fang, Yuanyuan, Hayes, Daniel, Huang, Maoyi, Jain, Atul, and Tian, Hanqin

Subjects
Droughts -- Environmental aspects, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

Author(s): Christopher R. Schwalm (corresponding author) [1, 2]; William R. L. Anderegg [3]; Anna M. Michalak [4]; Joshua B. Fisher [5]; Franco Biondi [6]; George Koch [2]; Marcy Litvak [7]; [...]

Published
2017
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37. Phylogenetic ctDNA analysis depicts early-stage lung cancer evolution

Author

Abbosh, Christopher, Birkbak, Nicolai J., Wilson, Gareth A., Jamal-Hanjani, Mariam, Constantin, Tudor, Salari, Raheleh, Le Quesne, John, Moore, David A., Veeriah, Selvaraju, Rosenthal, Rachel, Marafioti, Teresa, Kirkizlar, Eser, Watkins, Thomas B. K., McGranahan, Nicholas, Ward, Sophia, Martinson, Luke, Riley, Joan, Fraioli, Francesco, Al Bakir, Maise, Grnroos, Eva, Zambrana, Francisco, Endozo, Raymondo, Bi, Wenya Linda, Fennessy, Fiona M., Sponer, Nicole, Johnson, Diana, Laycock, Joanne, Shafi, Seema, Czyzewska-Khan, Justyna, Rowan, Andrew, Chambers, Tim, Matthews, Nik, Turajlic, Samra, Hiley, Crispin, Lee, Siow Ming, Forster, Martin D., Ahmad, Tanya, Falzon, Mary, Borg, Elaine, Lawrence, David, Hayward, Martin, Kolvekar, Shyam, Panagiotopoulos, Nikolaos, Janes, Sam M., Thakrar, Ricky, Ahmed, Asia, Blackhall, Fiona, Summers, Yvonne, Hafez, Dina, Naik, Ashwini, Ganguly, Apratim, Kareht, Stephanie, Shah, Rajesh, Joseph, Leena, Marie Quinn, Anne, Crosbie, Phil A., Naidu, Babu, Middleton, Gary, Langman, Gerald, Trotter, Simon, Nicolson, Marianne, Remmen, Hardy, Kerr, Keith, Chetty, Mahendran, Gomersall, Lesley, Fennell, Dean A., Nakas, Apostolos, Rathinam, Sridhar, Anand, Girija, Khan, Sajid, Russell, Peter, Ezhil, Veni, Ismail, Babikir, Irvin-Sellers, Melanie, Prakash, Vineet, Lester, Jason F., Kornaszewska, Malgorzata, Attanoos, Richard, Adams, Haydn, Davies, Helen, Oukrif, Dahmane, Akarca, Ayse U., Hartley, John A., Lowe, Helen L., Lock, Sara, Iles, Natasha, Bell, Harriet, Ngai, Yenting, Elgar, Greg, Szallasi, Zoltan, Schwarz, Roland F., Herrero, Javier, Stewart, Aengus, Quezada, Sergio A., Peggs, Karl S., Van Loo, Peter, Dive, Caroline, Lin, C. Jimmy, Rabinowitz, Matthew, Aerts, Hugo J. W. L., Hackshaw, Allan, Shaw, Jacqui A., Zimmermann, Bernhard G., Swanton, Charles, Bosshard-Carter, Leticia, Goh, Gerald, Gorman, Pat, Murugaesu, Nirupa, Hynds, Robert E., Horswell, Stuart, Bakir, Maise Al, Mitter, Richard, Escudero, Mickael, Xu, Hang, Goldman, Jacki, Stone, Richard Kevin, Denner, Tamara, Biggs, Jennifer, Costa, Marta, Begum, Sharmin, Phillimore, Ben, Nye, Emma, Graca, Sofia, Joshi, Kroopa, Furness, Andrew, Ben Aissa, Assma, Wong, Yien Ning Sophia, Georgiou, Andy, Simeon, Celia, Hector, Gemma, Smith, Amy, Aranda, Marie, Novelli, Marco, Papadatos-Pastos, Dionysis, Carnell, Dawn, Mendes, Ruheena, George, Jeremy, Navani, Neal, Taylor, Magali, Choudhary, Junaid, Califano, Raffaele, Taylor, Paul, Krysiak, Piotr, Rammohan, Kendadai, Fontaine, Eustace, Booton, Richard, Evison, Matthew, Moss, Stuart, Idries, Faiza, Bishop, Paul, Chaturvedi, Anshuman, Quinn, Anne Marie, Doran, Helen, Leek, Angela, Harrison, Phil, Moore, Katrina, Waddington, Rachael, Novasio, Juliette, Rogan, Jane, Smith, Elaine, Tugwood, Jonathan, Brady, Ged, Rothwell, Dominic G., Chemi, Francesca, Pierce, Jackie, Gulati, Sakshi, Bellamy, Mary, Bancroft, Hollie, Kerr, Amy, Kadiri, Salma, Webb, Joanne, Djearaman, Madava, Quesne, John Le, Thomas, Anne, Walter, Harriet, Monteiro, William, Marshall, Hilary, Nelson, Louise, Bennett, Jonathan, Primrose, Lindsay, Amadi, Anita, Palmer, Shirley, Miller, Joy, Buchan, Keith, Edwards, Alison, Morgan, Fiona, Verjee, Azmina, MacKenzie, Mairead, Wilcox, Maggie, Smith, Sean, Gower, Nicole, Ottensmeier, Christian, Chee, Serena, Johnson, Benjamin, Alzetani, Aiman, Shaw, Emily, Lim, Eric, De Sousa, Paulo, Barbosa, Monica Tavares, Bowman, Alex, Jordan, Simon, Rice, Alexandra, Raubenheimer, Hilgardt, Proli, Chiara, Cufari, Maria Elena, Ronquillo, John Carlo, Kwayie, Angela, Bhayani, Harshil, Hamilton, Morag, Bakar, Yusura, Mensah, Natalie, Ambrose, Lyn, Devaraj, Anand, Buderi, Silviu, Finch, Jonathan, Azcarate, Leire, Chavan, Hema, Green, Sophie, Mashinga, Hillaria, Nicholson, Andrew G., Lau, Kelvin, Sheaff, Michael, Schmid, Peter, Conibear, John, Light, Teresa, Horey, Tracey, Danson, Sarah, Bury, Jonathan, Edwards, John, Hill, Jennifer, Matthews, Sue, Kitsanta, Yota, Suvarna, Kim, Fisher, Patricia, Keerio, Allah Dino, Shackcloth, Michael, Gosney, John, Postmus, Pieter, Feeney, Sarah, Asante-Siaw, Julius, Dentro, Stefan, and Dessimoz, Christophe

Subjects
Lung cancer -- Genetic aspects -- Development and progression, DNA sequencing -- Methods, Phylogeny -- Observations, Cancer metastasis -- Genetic aspects, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

The early detection of relapse following primary surgery for non-small-cell lung cancer and the characterization of emerging subclones, which seed metastatic sites, might offer new therapeutic approaches for limiting tumour recurrence. The ability to track the evolutionary dynamics of early-stage lung cancer non-invasively in circulating tumour DNA (ctDNA) has not yet been demonstrated. Here we use a tumour-specific phylogenetic approach to profile the ctDNA of the first 100 TRACERx (Tracking Non-Small-Cell Lung Cancer Evolution Through Therapy (Rx)) study participants, including one patient who was also recruited to the PEACE (Posthumous Evaluation of Advanced Cancer Environment) post-mortem study. We identify independent predictors of ctDNA release and analyse the tumour-volume detection limit. Through blinded profiling of postoperative plasma, we observe evidence of adjuvant chemotherapy resistance and identify patients who are very likely to experience recurrence of their lung cancer. Finally, we show that phylogenetic ctDNA profiling tracks the subclonal nature of lung cancer relapse and metastasis, providing a new approach for ctDNA-driven therapeutic studies., Author(s): Christopher Abbosh [1]; Nicolai J. Birkbak [1, 2]; Gareth A. Wilson [1, 2]; Mariam Jamal-Hanjani [1]; Tudor Constantin [3]; Raheleh Salari [3]; John Le Quesne [4]; David A. Moore [...]

Published
2017
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38. Genetic mechanisms of critical illness in COVID-19

Author

Pairo-Castineira, Erola, Clohisey, Sara, Klaric, Lucija, Bretherick, Andrew D, Rawlik, Konrad, Pasko, Dorota, Walker, Susan, Parkinson, Nick, Fourman, Max Head, Russell, Clark D, Furniss, James, Richmond, Anne, Gountouna, Elvina, Wrobel, Nicola, Harrison, David, Wang, Bo, Yang, Wu, Meynert, Alison, Griffiths, Fiona, Oosthuyzen, Wilna, Kousathanas, Athanasios, Moutsianas, Loukas, Yang, Zhijian, Zhai, Ranran, Zheng, Chenqing, Grimes, Graeme, Beale, Rupert, Millar, Jonathan, Shih, Barbara, Keating, Sean, Zechner, Marie, Haley, Chris, Porteous, David J, Hayward, Caroline, Yang, Jian, Knight, Julian, Summers, Charlotte, Shankar-Hari, Manu, Klenerman, Paul, Turtle, Lance, Antonia, Ho, Moore, Shona C, Hinds, Charles, Horby, Peter, Nichol, Alistair, Maslove, David, Ling, Lowell, Mcauley, Danny, Montgomery, Hugh, Walsh, Timothy, Pereira, Alexandre C, Renieri, Johnny, Millar, Alistair, Nichol, Tim, Walsh, Manu, Shankar-Hari, Chris, Ponting, Jen, Meikle, Paul, Finernan, Ellie, Mcmaster, Andy, Law, J Kenneth Baillie, Trevor, Paterson, Tony, Wackett, Ruth, Armstrong, Richard, Clark, Audrey, Coutts, Lorna, Donnelly, Tammy, Gilchrist, Katarzyna, Hafezi, Louise, Macgillivray, Alan, Maclean, Sarah, Mccafferty, Kirstie, Morrice, Jane, Weaver, Ceilia, Boz, Ailsa, Golightly, Mari, Ward, Hanning, Mal, Helen, Szoor-McElhinney, Adam, Brown, Ross, Hendry, Andrew, Stenhouse, Louise, Cullum, Dawn, Law, Sarah, Law, Rachel, Law, Maaike, Swets, Nicky, Day, Filip, Taneski, Esther, Duncan, Nicholas, Parkinson, Collier, D, Wood, S, Zak, A, Borra, C, Matharu, M, May, P, Alldis, Z, Mitchelmore, O, Bowles, R, Easthope, A, Bibi, F, Lancoma-Malcolm, I, Gurasashvili, J, Pheby, J, Shiel, J, Bolton, M, Patel, M, Taylor, M, Zongo, O, Ebano, P, Harding, P, Astin-Chamberlain, R, Choudhury, Y, Cox, A, Kallon, D, Burton, M, Hall, R, Blowes, S, Prime, Z, Biddle, J, Prysyazhna, O, Newman, T, Tierney, C, Kassam, J, Shankar-Hari, M, Ostermann, M, Campos, S, Bociek, A, Lim, R, Grau, N, O Jones, T, Whitton, C, 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Konrad [0000-0002-0010-370X], Walker, Susan [0000-0002-5016-6426], Fourman, Max Head [0000-0001-7381-2278], Russell, Clark D [0000-0002-9873-8243], Gountouna, Elvina [0000-0001-7870-2780], Wang, Bo [0000-0002-1580-797X], Wu, Yang [0000-0002-0128-7280], Kousathanas, Athanasios [0000-0001-6265-6521], Moutsianas, Loukas [0000-0001-5453-345X], Zhai, Ranran [0000-0002-5834-9120], Beale, Rupert [0000-0002-6705-8560], Keating, Sean [0000-0001-8552-5604], Haley, Chris [0000-0002-9811-0210], Porteous, David J [0000-0003-1249-6106], Hayward, Caroline [0000-0002-9405-9550], Yang, Jian [0000-0003-2001-2474], Knight, Julian [0000-0002-0377-5536], Summers, Charlotte [0000-0002-7269-2873], Shankar-Hari, Manu [0000-0002-5338-2538], Turtle, Lance [0000-0002-0778-1693], Moore, Shona C [0000-0001-8610-2806], Hinds, Charles [0000-0001-5094-8324], McAuley, Danny [0000-0002-3283-1947], Montgomery, Hugh [0000-0001-8797-5019], Renieri, Alessandra [0000-0002-0846-9220], Shen, Xia [0000-0003-4390-1979], 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T., Massey, E., Croston, G., Reschreiter, H., Camsooksai, J., Patch, S., Jenkins, S., Humphrey, C., Wadams, B., Msiska, M., Adanini, O., Attwood, B., Parsons, P., Tatham, K., Jhanji, S., Black, E., Dela Rosa, A., Howle, R., Thomas, B., Bemand, T., Raobaikady, R., Saha, R., Staines, N., Daniel, A., Finn, J., Hutter, J., Doble, P., Shovelton, C., Pawley, C., Kannan, T., Hill, M., Combes, E., Monnery, S., Joefield, T., Popescu, M., Thankachen, M., Oblak, M., Little, J., Mcivor, S., Brady, A., Whittle, H., Prady, H., Chan, R., Ahmed, A., Morris, A., Gibson, C., Gordon, E., Keenan, S., Quinn, H., Benyon, S., Marriott, S., Zitter, L., Park, L., Baines, K., Lyons, M., Holland, M., Keenan, N., Young, M., Garrioch, S., Dawson, J., Tolson, M., Scholefield, B., Bi, R., Richardson, N., Schumacher, N., Cosier, T., Millen, G., Higham, A., Turki, S., Allen, L., Crisp, N., Hazleton, T., Knight, A., Deery, J., Price, C., Turney, S., Tilbey, S., Beranova, E., Wright, D., George, L., Twiss, S., Wadd, S., Postlethwaite, K., Gondo, P., Masunda, B., Kayani, A., Hadebe, B., Whiteside, J., Clarke, N., Donnison, P., Trim, F., Leadbitter, I., Butcher, D., O'Sullivan, S., Purewal, B., Bell, S., Rivers, V., O'Leary, R., Birch, J., Collins, E., Anderson, S., Hammerton, K., Andrews, E., Burns, K., Edmond, I., Todd, A., Donnachie, J., Turner, P., Prentice, L., Symon, L., Runciman, N., Auld, F., Halkes, M., Mercer, P., Thornton, L., Debreceni, G., Wilkins, J., Crickmore, V., Subramanian, G., Marshall, R., Jennings, C., Latif, M., Bunni, L., Spivey, M., Bean, S., Burt, K., Linnett, V., Ritzema, J., Sanderson, A., Mccormick, W., Bokhari, M., Kapoor, R., Loader, D., Ayers, A., Harrison, W., North, J., Belagodu, Z., Paramsothy, R., Olufuwa, O., Gherman, A., Fuller, B., Stuart, C., Kelsall, O., Davis, C., Wild, L., Wood, H., Thrush, J., Durie, A., Austin, K., Archer, K., Anderson, P., Vigurs, C., Thorpe, C., Knights, E., Boyle, N., Price, A., Kubisz-Pudelko, A., Wood, D., Lewis, A., Board, S., Pippard, L., Perry, J., Beesley, K., Rattray, A., Lee, E., Lennon, L., Douglas, K., Bell, D., Boyle, R., Glass, L., Nauman Akhtar, M., Dent, K., Potoczna, D., Pearson, S., Horsley, E., Spencer, S., Mullan, D., Skinner, D., Gaylard, J., Barber, R., Hewitt, C., Hilldrith, A., Shepardson, S., Wills, M., Jackson-Lawrence, K., Gupta, A., Timlick, E., Gorman, C., Otahal, I., Gales, A., Coetzee, S., Sell, C., Raj, M., Peiu, M., Quaid, S., Watson, E., Elliott, K., Mallinson, J., Chandler, B., Turnbull, A., Finch, C., Holl, C., Cooper, J., Evans, A., Khaliq, W., Collins, A., Gude, E. T., Love, N., van Koutrik, L., Hunt, J., Kaye, D., Fisher, E., Brayne, A., Tuckey, V., Jackson, P., Parkin, J., Tariq, A., Houlden, H., Tucci, A., Hardy, J., Moncur, E., Highgate, J., Cowley, A., Mitra, A., Stead, R., Behan, T., Burnett, C., Newton, M., Heeney, E., Pollard, R., Hatton, J., Patel, A., Kasipandian, V., Allibone, S., Genetu, R. M., O'Brien, L., Omar, Z., Perkins, E., Davies, K., Tetla, D., Shelley, B., Irvine, V., Williams, S., Williams, P., Goodsell, J., Tutton, R., Bough, L., Winter-Goodwin, B., Kitson, R., Pinnell, J., Wilson, A., Nortcliffe, T., Wood, T., Home, M., Holdroyd, K., Robinson, M., Shaw, R., Greig, J., Brady, M., Haigh, A., Matupe, L., Usher, M., Mellor, S., Dale, S., Gledhill, L., Shaw, L., Turner, G., Kelly, D., Anwar, B., Riley, H., Sturgeon, H., Ali, A., Thomis, L., Melia, D., Dance, A., Humphreys, S., Frost, I., Gopal, V., Godden, J., Holden, A., Swann, S., Smith, T., Clapham, M., Poultney, U., Harper, R., Rice, P., Reece-Anthony, R., Gurung, B., Moultrie, S., Odam, M., Mayer, A., Bellini, A., Pickard, A., Bryant, J., Roe, N., Sowter, J., Lang, K., Taylor, J., Barry, P., Hobrok, M., Tench, H., Wolf-Roberts, R., Mcguinness, H., Loosley, R., Hawcutt, D., Rad, L., O'Malley, L., Saunderson, P., Seddon, G., Anderson, T., Rogers, N., Ruddy, J., Harkins, M., Beith, C., Mcalpine, A., Ferguson, L., Grant, P., Macfadyen, S., Mclaughlin, M., Baird, T., Rundell, S., Welsh, B., Hamill, R., Fisher, F., Gregory, J., Campbell, A., Smuts, S., Kenneth Baillie, J., Carson, G., Alex, B., Bach, B., Barclay, W. S., Bogaert, D., Chand, M., Cooke, G. S., Docherty, A. B., Dunning, J., da Silva Filipe, A., Fletcher, T., Green, C. A., Harrison, E. M., Hiscox, J. A., Ho, A. Y. W., Horby, P. W., Ijaz, S., Khoo, S., Lim, W. S., Mentzer, A. J., Merson, L., Meynert, A. M., Noursadeghi, M., Palmarini, M., Paxton, W. A., Pollakis, G., Price, N., Rambaut, A., Robertson, D. L., Sancho-Shimizu, V., Scott, J. T., de Silva, T., Sigfrid, L., Solomon, T., Sriskandan, S., Stuart, D., Tedder, R. S., Thomson, E. C., Thompson, A. A. R., Thwaites, R. S., Turtle, L. C. W., Zambon, M., Hardwick, H., Donohue, C., Lyons, R., Norman, L., Pius, R., Drake, T. M., Fairfield, C. J., Knight, S. R., Mclean, K. A., Murphy, D., Shaw, C. A., Dalton, J., Girvan, M., Saviciute, E., Roberts, S., Harrison, J., Marsh, L., Connor, M., Halpin, S., Gamble, C., Leeming, G., Wham, M., Greenhalf, W., Shaw, V., Mcdonald, S., Ganna, A., Sulem, P., van Heel, D. A., Cordioli, M., Sveinbjornsson, G., Niemi, M. E. K., Shelton, J. F., Shastri, A. J., Ye, C., Weldon, C. H., Filshtein-Sonmez, T., Coker, D., Symons, A., Esparza-Gordillo, J., Aslibekyan, S., Auton, A., Krieger, J. E., Marques, E., Jannes, C. E., Mari, F., Daga, S., Baldassarri, M., Benetti, E., Furini, S., Fallerini, C., Fava, F., Valentino, F., Doddato, G., Giliberti, A., Tita, R., Amitrano, S., Bruttini, M., Croci, S., Meloni, I., Pinto, A. M., Frullanti, E., Mencarelli, M. A., Rizzo, C. L., Montagnani, F., Di Sarno, L., Tommasi, A., Palmieri, M., Emiliozzi, A., Fabbiani, M., Rossetti, B., Zanelli, G., Bargagli, E., Bergantini, L., D'Alessandro, M., Cameli, P., Bennet, D., Anedda, F., Marcantonio, S., Scolletta, S., Franchi, F., Mazzei, M. A., Guerrini, S., Conticini, E., Cantarini, L., Frediani, B., Tacconi, D., Spertilli, C., Feri, M., Donati, A., Scala, R., Guidelli, L., Spargi, G., Corridi, M., Nencioni, C., Croci, L., Caldarelli, G. P., Spagnesi, M., Piacentini, P., Bandini, M., Desanctis, E., Cappelli, S., Canaccini, A., Verzuri, A., Anemoli, V., Ognibene, A., Vaghi, M., D'Arminio Monforte, A., Merlini, E., Mondelli, M. U., Mantovani, S., Ludovisi, S., Girardis, M., Venturelli, S., Sita, M., Cossarizza, A., Antinori, A., Vergori, A., Rusconi, S., Siano, M., Gabrieli, A., Riva, A., Francisci, D., Schiaroli, E., Scotton, P. G., Andretta, F., Panese, S., Scaggiante, R., Gatti, F., Parisi, S. G., Castelli, F., Quiros-Roldan, M. E., Magro, P., Zanella, I., Della Monica, M., Piscopo, C., Capasso, M., Russo, R., Andolfo, I., Iolascon, A., Fiorentino, G., Carella, M., Castori, M., Merla, G., Aucella, F., Raggi, P., Marciano, C., Perna, R., Bassetti, M., Di Biagio, A., Sanguinetti, M., Masucci, L., Valente, S., Mandala, M., Giorli, A., Salerni, L., Zucchi, P., Parravicini, P., Menatti, E., Baratti, S., Trotta, T., Giannattasio, F., Coiro, G., Lena, F., Coviello, D. A., Mussini, C., Bosio, G., Martinelli, E., Mancarella, S., Tavecchia, L., Crotti, L., Picchiotti, N., Gori, M., Gabbi, C., Sanarico, M., Ceri, S., Pinoli, P., Raimondi, F., Biscarini, F., Stella, A., Shen, X., Ponting, C. P., Fawkes, A., Tenesa, A., Caulfield, M., Scott, R., Rowan, K., Murphy, L., Openshaw, P. J. M., Semple, M. G., Vitart, V., and Wilson, J. F.

Subjects
0301 basic medicine, Male, CCR2, Chromosomes, Human, Pair 21, Genome-wide association study, Receptor, Interferon alpha-beta, Disease, Bioinformatics, Genome-wide association studies, 23andMe Investigators, Interferon alpha-beta, 0302 clinical medicine, Receptors, 2',5'-Oligoadenylate Synthetase, Pair 12, genetics, Lung, BRACOVID Investigators, Multidisciplinary, GenOMICC Investigators, Tyrosine kinase 2, 030220 oncology & carcinogenesis, Multigene Family, Medical genetics, Female, Dipeptidyl-Peptidases and Tripeptidyl-Peptidase, 5'-Oligoadenylate Synthetase, Human, Receptor, medicine.medical_specialty, Critical Care, Receptors, CCR2, General Science & Technology, Critical Illness, Chromosomes, 03 medical and health sciences, Intensive care, Mendelian randomization, Immunogenetics, medicine, Humans, Dipeptidyl-Peptidases and Tripeptidyl-Peptidases, Gen-COVID Investigators, Inflammation, TYK2 Kinase, Chromosomes, Human, Pair 12, Pair 19, SARS-CoV-2, business.industry, Drug Repositioning, COVID-19, United Kingdom, COVID-19 Human Genetics Initiative, 030104 developmental biology, Viral infection, Chromosomes, Human, Pair 19, Genome-Wide Association Study, Pharmacogenomics, ISARICC Investigators, Pair 21, 2', business
Abstract

Host-mediated lung inflammation is present1, and drives mortality2, in the critical illness caused by coronavirus disease 2019 (COVID-19). Host genetic variants associated with critical illness may identify mechanistic targets for therapeutic development3. Here we report the results of the GenOMICC (Genetics Of Mortality In Critical Care) genome-wide association study in 2,244 critically ill patients with COVID-19 from 208 UK intensive care units. We have identified and replicated the following new genome-wide significant associations: on chromosome 12q24.13 (rs10735079,P=1.65×10−8) in a gene cluster that encodes antiviral restriction enzyme activators (OAS1,OAS2andOAS3); on chromosome 19p13.2 (rs74956615,P=2.3×10−8) near the gene that encodes tyrosine kinase 2 (TYK2); on chromosome 19p13.3 (rs2109069,P=3.98× 10−12) within the gene that encodes dipeptidyl peptidase 9 (DPP9); and on chromosome 21q22.1 (rs2236757,P=4.99×10−8) in the interferon receptor geneIFNAR2. We identified potential targets for repurposing of licensed medications: using Mendelian randomization, we found evidence that low expression ofIFNAR2, or high expression ofTYK2, are associated with life-threatening disease; and transcriptome-wide association in lung tissue revealed that high expression of the monocyte–macrophage chemotactic receptorCCR2is associated with severe COVID-19. Our results identify robust genetic signals relating to key host antiviral defence mechanisms and mediators of inflammatory organ damage in COVID-19. Both mechanisms may be amenable to targeted treatment with existing drugs. However, large-scale randomized clinical trials will be essential before any change to clinical practice.

Published
2020
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40. Neoadjuvant relatlimab and nivolumab in resectable melanoma

Author

Amaria, Rodabe N., primary, Postow, Michael, additional, Burton, Elizabeth M., additional, Tezlaff, Michael T., additional, Ross, Merrick I., additional, Torres-Cabala, Carlos, additional, Glitza, Isabella C., additional, Duan, Fei, additional, Milton, Denái R., additional, Busam, Klaus, additional, Simpson, Lauren, additional, McQuade, Jennifer L., additional, Wong, Michael K., additional, Gershenwald, Jeffrey E., additional, Lee, Jeffrey E., additional, Goepfert, Ryan P., additional, Keung, Emily Z., additional, Fisher, Sarah B., additional, Betof-Warner, Allison, additional, Shoushtari, Alexander N., additional, Callahan, Margaret, additional, Coit, Daniel, additional, Bartlett, Edmund K., additional, Bello, Danielle, additional, Momtaz, Parisa, additional, Nicholas, Courtney, additional, Gu, Aidi, additional, Zhang, Xuejun, additional, Korivi, Brinda Rao, additional, Patnana, Madhavi, additional, Patel, Sapna P., additional, Diab, Adi, additional, Lucci, Anthony, additional, Prieto, Victor G., additional, Davies, Michael A., additional, Allison, James P., additional, Sharma, Padmanee, additional, Wargo, Jennifer A., additional, Ariyan, Charlotte, additional, and Tawbi, Hussein A., additional

Published
2022
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41. Novel antigen-presenting cell imparts Treg-dependent tolerance to gut microbiota

Author

Akagbosu, Blossom, primary, Tayyebi, Zakieh, additional, Shibu, Gayathri, additional, Paucar Iza, Yoselin A., additional, Deep, Deeksha, additional, Parisotto, Yollanda Franco, additional, Fisher, Logan, additional, Pasolli, H. Amalia, additional, Thevin, Valentin, additional, Elmentaite, Rasa, additional, Knott, Maximilian, additional, Hemmers, Saskia, additional, Jahn, Lorenz, additional, Friedrich, Christin, additional, Verter, Jacob, additional, Wang, Zhong-Min, additional, van den Brink, Marcel, additional, Gasteiger, Georg, additional, Grünewald, Thomas G. P., additional, Marie, Julien C., additional, Leslie, Christina, additional, Rudensky, Alexander Y., additional, and Brown, Chrysothemis C., additional

Published
2022
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42. SARS-CoV-2 uses a multipronged strategy to impede host protein synthesis

Author

Aharon Nachshon, Michal Schwartz, Yoav Lubelsky, Hadas Tamir, Tal Fisher, Roni Winkler, Batsheva Rozman, Orel Mizrahi, Yfat Yahalom-Ronen, Nir Paran, Igor Ulitsky, Yaara Finkel, Boris Slobodin, Binyamin Zuckerman, Noam Stern-Ginossar, Tomer Israely, and Avi Gluck

Subjects
RNA Stability, viruses, Viral Nonstructural Proteins, Biology, Ribosome, Cell Line, 03 medical and health sciences, 0302 clinical medicine, Gene expression, Protein biosynthesis, Humans, RNA, Messenger, Ribosome profiling, 030304 developmental biology, 0303 health sciences, Messenger RNA, Multidisciplinary, Innate immune system, SARS-CoV-2, COVID-19, RNA, Translation (biology), Immunity, Innate, Cell biology, Protein Biosynthesis, Host-Pathogen Interactions, RNA, Viral, 5' Untranslated Regions, Ribosomes, 030217 neurology & neurosurgery
Abstract

The coronavirus SARS-CoV-2 is the cause of the ongoing pandemic of COVID-191. Coronaviruses have developed a variety of mechanisms to repress host mRNA translation to allow the translation of viral mRNA, and concomitantly block the cellular innate immune response2,3. Although several different proteins of SARS-CoV-2 have previously been implicated in shutting off host expression4-7, a comprehensive picture of the effects of SARS-CoV-2 infection on cellular gene expression is lacking. Here we combine RNA sequencing, ribosome profiling and metabolic labelling of newly synthesized RNA to comprehensively define the mechanisms that are used by SARS-CoV-2 to shut off cellular protein synthesis. We show that infection leads to a global reduction in translation, but that viral transcripts are not preferentially translated. Instead, we find that infection leads to the accelerated degradation of cytosolic cellular mRNAs, which facilitates viral takeover of the mRNA pool in infected cells. We reveal that the translation of transcripts that are induced in response to infection (including innate immune genes) is impaired. We demonstrate this impairment is probably mediated by inhibition of nuclear mRNA export, which prevents newly transcribed cellular mRNA from accessing ribosomes. Overall, our results uncover a multipronged strategy that is used by SARS-CoV-2 to take over the translation machinery and to suppress host defences.

Published
2021

43. A trade-off between plant and soil carbon storage under elevated CO2

Author

Robert B. Jackson, J. Rosende, Peter B. Reich, J. Fisher, Yolima Carrillo, Elise Pendall, K. Van Sundert, Richard P. Phillips, Jennifer Pett-Ridge, Benjamin N. Sulman, K. J. van Groenigen, R. D. Evans, Sara Vicca, Trevor F. Keenan, Adam F. A. Pellegrini, Bruce A. Hungate, Haicheng Zhang, Matthew E. Craig, Benjamin D. Stocker, and César Terrer

Subjects
0106 biological sciences, Carbon dioxide in Earth's atmosphere, Multidisciplinary, 010504 meteorology & atmospheric sciences, food and beverages, Carbon sink, Biomass, Soil carbon, complex mixtures, 010603 evolutionary biology, 01 natural sciences, chemistry.chemical_compound, Nutrient, Agronomy, chemistry, Carbon dioxide, Environmental science, Terrestrial ecosystem, Ecosystem, 0105 earth and related environmental sciences
Abstract

Terrestrial ecosystems remove about 30 per cent of the carbon dioxide (CO2) emitted by human activities each year1, yet the persistence of this carbon sink depends partly on how plant biomass and soil organic carbon (SOC) stocks respond to future increases in atmospheric CO2 (refs. 2,3). Although plant biomass often increases in elevated CO2 (eCO2) experiments4–6, SOC has been observed to increase, remain unchanged or even decline7. The mechanisms that drive this variation across experiments remain poorly understood, creating uncertainty in climate projections8,9. Here we synthesized data from 108 eCO2 experiments and found that the effect of eCO2 on SOC stocks is best explained by a negative relationship with plant biomass: when plant biomass is strongly stimulated by eCO2, SOC storage declines; conversely, when biomass is weakly stimulated, SOC storage increases. This trade-off appears to be related to plant nutrient acquisition, in which plants increase their biomass by mining the soil for nutrients, which decreases SOC storage. We found that, overall, SOC stocks increase with eCO2 in grasslands (8 ± 2 per cent) but not in forests (0 ± 2 per cent), even though plant biomass in grasslands increase less (9 ± 3 per cent) than in forests (23 ± 2 per cent). Ecosystem models do not reproduce this trade-off, which implies that projections of SOC may need to be revised. A synthesis of elevated carbon dioxide experiments reveals that when plant biomass is strongly stimulated by elevated carbon dioxide levels, soil carbon storage declines, and where biomass is weakly stimulated, soil carbon accumulates.

Published
2021

44. Author Correction: Neoadjuvant relatlimab and nivolumab in resectable melanoma

Author

Rodabe N. Amaria, Michael Postow, Elizabeth M. Burton, Michael T. Tetzlaff, Merrick I. Ross, Carlos Torres-Cabala, Isabella C. Glitza, Fei Duan, Denái R. Milton, Klaus Busam, Lauren Simpson, Jennifer L. McQuade, Michael K. Wong, Jeffrey E. Gershenwald, Jeffrey E. Lee, Ryan P. Goepfert, Emily Z. Keung, Sarah B. Fisher, Allison Betof-Warner, Alexander N. Shoushtari, Margaret Callahan, Daniel Coit, Edmund K. Bartlett, Danielle Bello, Parisa Momtaz, Courtney Nicholas, Aidi Gu, Xuejun Zhang, Brinda Rao Korivi, Madhavi Patnana, Sapna P. Patel, Adi Diab, Anthony Lucci, Victor G. Prieto, Michael A. Davies, James P. Allison, Padmanee Sharma, Jennifer A. Wargo, Charlotte Ariyan, and Hussein A. Tawbi

Subjects
Multidisciplinary
Published
2023

45. SARS-CoV-2 evolution during treatment of chronic infection

Author

Kemp, S. A., Collier, D. A., Datir, R. P., Ferreira, I. A. T. M., Gayed, S., Jahun, A., Hosmillo, M., Rees-Spear, C., Mlcochova, P., Lumb, I. U., Roberts, D. J., Chandra, A., Temperton, N., Baker, S., Dougan, G., Hess, C., Kingston, N., Lehner, P. J., Lyons, P. A., Matheson, N. J., Owehand, W. H., Saunders, C., Summers, C., Thaventhiran, J. E. D., Toshner, M., Weekes, M. P., Bucke, A., Calder, J., Canna, L., Domingo, J., Elmer, A., Fuller, S., Harris, J., Hewitt, S., Kennet, J., Jose, S., Kourampa, J., Meadows, A., O'Brien, C., Price, J., Publico, C., Rastall, R., Ribeiro, C., Rowlands, J., Ruffolo, V., Tordesillas, H., Bullman, B., Dunmore, B. J., Fawke, S., Graf, S., Hodgson, J., Huang, C., Hunter, K., Jones, E., Legchenko, E., Matara, C., Martin, J., Mescia, F., O'Donnell, C., Pointon, L., Pond, N., Shih, J., Sutcliffe, R., Tilly, T., Treacy, C., Tong, Z., Wood, J., Wylot, M., Bergamaschi, L., Betancourt, A., Bower, G., Cossetti, C., De Sa, A., Epping, M., Gleadall, N., Grenfell, R., Hinch, A., Huhn, O., Jackson, S., Jarvis, I., Lewis, D., Marsden, J., Nice, F., Okecha, G., Omarjee, O., Perera, M., Richoz, N., Romashova, V., Yarkoni, N. S., Sharma, R., Stefanucci, L., Stephens, J., Strezlecki, M., Turner, L., De Bie, E. M. D. D., Bunclark, K., Josipovic, M., Mackay, M., Rossi, S., Selvan, M., Spencer, S., Yong, C., Ansaripour, A., Michael, A., Mwaura, L., Patterson, C., Polwarth, G., Polgarova, P., di Stefano, G., Fahey, C., Michel, R., Bong, S. -H., Coudert, J. D., Holmes, E., Allison, J., Butcher, H., Caputo, D., Clapham-Riley, D., Dewhurst, E., Furlong, A., Graves, B., Gray, J., Ivers, T., Kasanicki, M., Le Gresley, E., Linger, R., Meloy, S., Muldoon, F., Ovington, N., Papadia, S., Phelan, I., Stark, H., Stirrups, K. E., Townsend, P., Walker, N., Webster, J., Robson, S. C., Loman, N. J., Connor, T. R., Golubchik, T., Martinez Nunez, R. T., Ludden, C., Corden, S., Johnston, I., Bonsall, D., Smith, C. P., Awan, A. R., Bucca, G., Estee Torok, M., Saeed, K., Prieto, J. A., Jackson, D. K., Hamilton, W. L., Snell, L. B., Moore, C., Harrison, E. M., Goncalves, S., Fairley, D. J., Loose, M. W., Watkins, J., Livett, R., Moses, S., Amato, R., Nicholls, S., Bull, M., Smith, D. L., Barrett, J., Aanensen, D. M., Curran, M. D., Parmar, S., Aggarwal, D., Shepherd, J. G., Parker, M. D., Glaysher, S., Bashton, M., Underwood, A. P., Pacchiarini, N., Loveson, K. F., Carabelli, A. M., Templeton, K. E., Langford, C. F., Sillitoe, J., de Silva, T. I., Wang, D., Kwiatkowski, D., Rambaut, A., O'Grady, J., Cottrell, S., Holden, M. T. G., Thomson, E. C., Osman, H., Andersson, M., Chauhan, A. J., Hassan-Ibrahim, M. O., Lawniczak, M., Alderton, A., Chand, M., Constantinidou, C., Unnikrishnan, M., Darby, A. C., Hiscox, J. A., Paterson, S., Martincorena, I., Robertson, D. L., Volz, E. M., Page, A. J., Pybus, O. G., Bassett, A. R., Ariani, C. V., Spencer Chapman, M. H., K. K., Li, Shah, R. N., Jesudason, N. G., Taha, Y., Mchugh, M. P., Dewar, R., Jahun, A. S., Mcmurray, C., Pandey, S., Mckenna, J. P., Nelson, A., Young, G. R., Mccann, C. M., Elliott, S., Lowe, H., Temperton, B., Roy, S., Price, A., Rey, S., Wyles, M., Rooke, S., Shaaban, S., de Cesare, M., Letchford, L., Silveira, S., Pelosi, E., Wilson-Davies, E., O'Toole, A., Hesketh, A. R., Stark, R., du Plessis, L., Ruis, C., Adams, H., Bourgeois, Y., Michell, S. L., Gramatopoulos, D., Edgeworth, J., Breuer, J., Todd, J. A., Fraser, C., Buck, D., John, M., Kay, G. L., Palmer, S., Peacock, S. J., Heyburn, D., Weldon, D., Robinson, E., Mcnally, A., Muir, P., Vipond, I. B., Boyes, J., Sivaprakasam, V., Salluja, T., Dervisevic, S., Meader, E. J., Park, N. R., Oliver, K., Jeffries, A. R., Ott, S., da Silva Filipe, A., Simpson, D. A., Williams, C., Masoli, J. A. H., Knight, B. A., Jones, C. R., Koshy, C., Ash, A., Casey, A., Bosworth, A., Ratcliffe, L., Xu-McCrae, L., Pymont, H. M., Hutchings, S., Berry, L., Jones, K., Halstead, F., Davis, T., Holmes, C., Iturriza-Gomara, M., Lucaci, A. O., Randell, P. A., Cox, A., Madona, P., Harris, K. A., Brown, J. R., Mahungu, T. W., Irish-Tavares, D., Haque, T., Hart, J., Witele, E., Fenton, M. L., Liggett, S., Graham, C., Swindells, E., Collins, J., Eltringham, G., Campbell, S., Mcclure, P. C., Clark, G., Sloan, T. J., Jones, C., Lynch, J., Warne, B., Leonard, S., Durham, J., Williams, T., Haldenby, S. T., Storey, N., Alikhan, N. -F., Holmes, N., Carlile, M., Perry, M., Craine, N., Lyons, R. A., Beckett, A. H., Goudarzi, S., Fearn, C., Cook, K., Dent, H., Paul, H., Davies, R., Blane, B., Girgis, S. T., Beale, M. A., Bellis, K. L., Dorman, M. J., Drury, E., Kane, L., Kay, S., Mcguigan, S., Nelson, R., Prestwood, L., Rajatileka, S., Batra, R., Williams, R. J., Kristiansen, M., Green, A., Justice, A., Mahanama, A. I. K., Samaraweera, B., Hadjirin, N. F., Quick, J., Poplawski, R., Kermack, L. M., Reynolds, N., Hall, G., Chaudhry, Y., Pinckert, M. L., Georgana, I., Moll, R. J., Thornton, A., Myers, R., Stockton, J., Williams, C. A., Yew, W. C., Trotter, A. J., Trebes, A., MacIntyre-Cockett, G., Birchley, A., Adams, A., Plimmer, A., Gatica-Wilcox, B., Mckerr, C., Hilvers, E., Jones, H., Asad, H., Coombes, J., Evans, J. M., Fina, L., Gilbert, L., Graham, L., Cronin, M., Kumziene-Summerhayes, S., Taylor, S., Jones, S., Groves, D. C., Zhang, P., Gallis, M., Louka, S. F., Starinskij, I., Jackson, C., Gourtovaia, M., Tonkin-Hill, G., Lewis, K., Tovar-Corona, J. M., James, K., Baxter, L., Alam, M. 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L., Karamani, A., Ensell, L., Chatterton, W., Pusok, M., Dadrah, A., Symmonds, A., Sluga, G., Molnar, Z., Baker, P., Bonner, S., Essex, S., Barton, E., Padgett, D., Scott, G., Greenaway, J., Payne, B. A. I., Burton-Fanning, S., Waugh, S., Raviprakash, V., Sheriff, N., Blakey, V., Williams, L. -A., Moore, J., Stonehouse, S., Smith, L., Davidson, R. K., Bedford, L., Coupland, L., Wright, V., Chappell, J. G., Tsoleridis, T., Ball, J., Khakh, M., Fleming, V. M., Lister, M. M., Howson-Wells, H. C., Boswell, T., Joseph, A., Willingham, I., Duckworth, N., Walsh, S., Wise, E., Moore, N., Mori, M., Cortes, N., Kidd, S., Williams, R., Gifford, L., Bicknell, K., Wyllie, S., Lloyd, A., Impey, R., Malone, C. S., Cogger, B. J., Levene, N., Monaghan, L., Keeley, A. J., Partridge, D. G., Raza, M., Evans, C., Johnson, K., Abnizova, I., Aigrain, L., Ali, M., Allen, L., Anderson, R., Ariani, C., Austin-Guest, S., Bala, S., Bassett, A., Battleday, K., Beal, J., Beale, M., Bellany, S., Bellerby, T., Bellis, K., Berger, D., Berriman, M., Betteridge, E., Bevan, P., Binley, S., Bishop, J., Blackburn, K., Bonfield, J., Boughton, N., Bowker, S., Brendler-Spaeth, T., Bronner, I., Brooklyn, T., Buddenborg, S. K., Bush, R., Caetano, C., Cagan, A., Carter, N., Cartwright, J., Monteiro, T. C., Chapman, L., Chillingworth, T. -J., Clapham, P., Clark, R., Clarke, A., Clarke, C., Cole, D., Cook, E., Coppola, M., Cornell, L., Cornwell, C., Corton, C., Crackett, A., Cranage, A., Craven, H., Craw, S., Crawford, M., Cutts, T., Dabrowska, M., Davies, M., Dawson, J., Day, C., Densem, A., Dibling, T., Dockree, C., Dodd, D., Dogga, S., Dougherty, M., Dove, A., Drummond, L., Dudek, M., Durrant, L., Easthope, E., Eckert, S., Ellis, P., Farr, B., Fenton, M., Ferrero, M., Flack, N., Fordham, H., Forsythe, G., Francis, M., Fraser, A., Freeman, A., Galvin, A., Garcia-Casado, M., Gedny, A., Girgis, S., Glover, J., Goodwin, S., Gould, O., Gray, A., Gray, E., Griffiths, C., Gu, Y., Guerin, F., Hamilton, W., Hanks, H., Harrison, E., Harrott, A., Harry, E., Harvison, J., Heath, P., Hernandez-Koutoucheva, A., Hobbs, R., Holland, D., Holmes, S., Hornett, G., Hough, N., Huckle, L., Hughes-Hallet, L., Hunter, A., Inglis, S., Iqbal, S., Jackson, A., Jackson, D., Verdejo, C. J., Jones, M., Kallepally, K., Kay, K., Keatley, J., Keith, A., King, A., Kitchin, L., Kleanthous, M., Klimekova, M., Korlevic, P., Krasheninnkova, K., Lane, G., Langford, C., Laverack, A., Law, K., Lensing, S., Lewis-Wade, A., Liddle, J., Lin, Q., Lindsay, S., Linsdell, S., Long, R., Lovell, J., Mack, J., Maddison, M., Makunin, A., Mamun, I., Mansfield, J., Marriott, N., Martin, M., Mayho, M., Mccarthy, S., Mcclintock, J., Mchugh, S., Mcminn, L., Meadows, C., Mobley, E., Moll, R., Morra, M., Morrow, L., Murie, K., Nash, S., Nathwani, C., Naydenova, P., Neaverson, A., Nerou, E., Nicholson, J., Nimz, T., Noell, G. G., O'Meara, S., Ohan, V., Olney, C., Ormond, D., Oszlanczi, A., Pang, Y. F., Pardubska, B., Park, N., Parmar, A., Patel, G., Payne, M., Peacock, S., Petersen, A., Plowman, D., Preston, T., Puethe, C., Quail, M., Rajan, D., Rance, R., Rawlings, S., Redshaw, N., Reynolds, J., Reynolds, M., Rice, S., Richardson, M., Roberts, C., Robinson, K., Robinson, M., Robinson, D., Rogers, H., Rojo, E. M., Roopra, D., Rose, M., Rudd, L., Sadri, R., Salmon, N., Saul, D., Schwach, F., Scott, C., Seekings, P., Shirley, L., Simms, A., Sinnott, M., Sivadasan, S., Siwek, B., Sizer, D., Skeldon, K., Skelton, J., Slater-Tunstill, J., Sloper, L., Smerdon, N., Smith, C., Smith, J., Smith, K., Smith, M., Smith, S., Smith, T., Sneade, L., Soria, C. D., Sousa, C., Souster, E., Sparkes, A., Spencer-Chapman, M., Squares, J., Steed, C., Stickland, T., Still, I., Stratton, M., Strickland, M., Swann, A., Swiatkowska, A., Sycamore, N., Swift, E., Symons, E., Szluha, S., Taluy, E., Tao, N., Taylor, K., Thompson, S., Thompson, M., Thomson, M., Thomson, N., Thurston, S., Toombs, D., Topping, B., Tovar-Corona, J., Ungureanu, D., Uphill, J., Urbanova, J., Jansen Van, P., Vancollie, V., Voak, P., Walker, D., Walker, M., Waller, M., Ward, G., Weatherhogg, C., Webb, N., Wells, A., Wells, E., Westwood, L., Whipp, T., Whiteley, T., Whitton, G., Whitwham, A., Widaa, S., Williams, M., Wilson, M., Wright, S., Farr, B. W., Quail, M. A., Thurston, S. A. J., Bronner, I. F., Redshaw, N. M., Lensing, S. V., Balcazar, C. E., Gallagher, M. D., Williamson, K. A., Stanton, T. D., Michelsen, M. L., Warwick-Dugdale, J., Manley, R., Farbos, A., Harrison, J. W., Sambles, C. M., Studholme, D. 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E., Gutierrez, B., Marchbank, A., Maksimovic, J., Spellman, K., Mccluggage, K., Morgan, M., Beer, R., Afifi, S., Workman, T., Fuller, W., Bresner, C., Angyal, A., Green, L. R., Parsons, P. J., Tucker, R. M., Brown, R., Whiteley, M., Rowe, W., Siveroni, I., Le-Viet, T., Gaskin, A., Johnson, R., Sharrocks, K., Blane, E., Modis, Y., Leigh, K. E., Briggs, J. A. G., van Gils, M. J., Smith, K. G. C., Bradley, J. R., Doffinger, R., Ceron-Gutierrez, L., Barcenas-Morales, G., Pollock, D. D., Goldstein, R. A., Smielewska, A., Skittrall, J. P., Gouliouris, T., Goodfellow, I. G., Gkrania-Klotsas, E., Illingworth, C. J. R., Mccoy, L. E., Gupta, R. K., Medical Microbiology and Infection Prevention, AII - Infectious diseases, Collier, Dami A [0000-0001-5446-4423], Jahun, Aminu [0000-0002-4585-1701], Temperton, Nigel [0000-0002-7978-3815], Modis, Yorgo [0000-0002-6084-0429], Briggs, John AG [0000-0003-3990-6910], Goldstein, Richard A [0000-0001-5148-4672], Skittrall, Jordan P [0000-0002-8228-3758], Gkrania-Klotsas, Effrossyni [0000-0002-0930-8330], McCoy, Laura E [0000-0001-9503-7946], Gupta, Ravindra K [0000-0001-9751-1808], and Apollo - University of Cambridge Repository

Subjects
0301 basic medicine, Male, Time Factors, viruses, Passive, Antibodies, Viral, CITIID-NIHR BioResource COVID-19 Collaboration, 2.1 Biological and endogenous factors, Viral, Aetiology, Neutralizing, Lung, Phylogeny, neutralising antibodies, Infectivity, education.field_of_study, Genome, Multidisciplinary, Alanine, biology, High-Throughput Nucleotide Sequencing, Viral Load, Spike Glycoprotein, Virus Shedding, Adenosine Monophosphate, Aged, Antibodies, Neutralizing, COVID-19, Chronic Disease, Genome, Viral, Humans, Immune Evasion, Immune Tolerance, Immunization, Passive, Immunosuppression Therapy, Mutagenesis, Mutant Proteins, Mutation, SARS-CoV-2, Spike Glycoprotein, Coronavirus, Evolution, Molecular, Infectious Diseases, Pneumonia & Influenza, Antibody, Infection, Viral load, Biotechnology, Evolution, General Science & Technology, antibody escape, Convalescent plasma, 030106 microbiology, Population, evasion, Antibodies, Virus, Article, Vaccine Related, resistance, 03 medical and health sciences, Immune system, COVID-19 Genomics UK (COG-UK) Consortium, Biodefense, Genetics, Viral shedding, education, COVID-19 Serotherapy, QR355, Prevention, Wild type, Molecular, Pneumonia, Virology, COVID-19 Drug Treatment, Coronavirus, Emerging Infectious Diseases, Good Health and Well Being, 030104 developmental biology, biology.protein, Immunization, immune suppression, mutation
Abstract

The spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is critical for virus infection through the engagement of the human ACE2 protein1 and is a major antibody target. Here we show that chronic infection with SARS-CoV-2 leads to viral evolution and reduced sensitivity to neutralizing antibodies in an immunosuppressed individual treated with convalescent plasma, by generating whole-genome ultra-deep sequences for 23 time points that span 101 days and using in vitro techniques to characterize the mutations revealed by sequencing. There was little change in the overall structure of the viral population after two courses of remdesivir during the first 57 days. However, after convalescent plasma therapy, we observed large, dynamic shifts in the viral population, with the emergence of a dominant viral strain that contained a substitution (D796H) in the S2 subunit and a deletion (ΔH69/ΔV70) in the S1 N-terminal domain of the spike protein. As passively transferred serum antibodies diminished, viruses with the escape genotype were reduced in frequency, before returning during a final, unsuccessful course of convalescent plasma treatment. In vitro, the spike double mutant bearing both ΔH69/ΔV70 and D796H conferred modestly decreased sensitivity to convalescent plasma, while maintaining infectivity levels that were similar to the wild-type virus.The spike substitution mutant D796H appeared to be the main contributor to the decreased susceptibility to neutralizing antibodies, but this mutation resulted in an infectivity defect. The spike deletion mutant ΔH69/ΔV70 had a twofold higher level of infectivity than wild-type SARS-CoV-2, possibly compensating for the reduced infectivity of the D796H mutation. These data reveal strong selection on SARS-CoV-2 during convalescent plasma therapy, which is associated with the emergence of viral variants that show evidence of reduced susceptibility to neutralizing antibodies in immunosuppressed individuals.

Published
2021

46. Neoadjuvant relatlimab and nivolumab in resectable melanoma

Author

Rodabe N. Amaria, Michael Postow, Elizabeth M. Burton, Michael T. Tetzlaff, Merrick I. Ross, Carlos Torres-Cabala, Isabella C. Glitza, Fei Duan, Denái R. Milton, Klaus Busam, Lauren Simpson, Jennifer L. McQuade, Michael K. Wong, Jeffrey E. Gershenwald, Jeffrey E. Lee, Ryan P. Goepfert, Emily Z. Keung, Sarah B. Fisher, Allison Betof-Warner, Alexander N. Shoushtari, Margaret Callahan, Daniel Coit, Edmund K. Bartlett, Danielle Bello, Parisa Momtaz, Courtney Nicholas, Aidi Gu, Xuejun Zhang, Brinda Rao Korivi, Madhavi Patnana, Sapna P. Patel, Adi Diab, Anthony Lucci, Victor G. Prieto, Michael A. Davies, James P. Allison, Padmanee Sharma, Jennifer A. Wargo, Charlotte Ariyan, and Hussein A. Tawbi

Subjects
Survival Rate, Multidisciplinary, Nivolumab, Macrophages, Humans, Antibodies, Monoclonal, Drug Therapy, Combination, Immune Checkpoint Inhibitors, Melanoma, Neoadjuvant Therapy, Neoplasm Staging
Abstract

Relatlimab and nivolumab combination immunotherapy improves progression-free survival over nivolumab monotherapy in patients with unresectable advanced melanoma1. We investigated this regimen in patients with resectable clinical stage III or oligometastatic stage IV melanoma (NCT02519322). Patients received two neoadjuvant doses (nivolumab 480 mg and relatlimab 160 mg intravenously every 4 weeks) followed by surgery, and then ten doses of adjuvant combination therapy. The primary end point was pathologic complete response (pCR) rate2. The combination resulted in 57% pCR rate and 70% overall pathologic response rate among 30 patients treated. The radiographic response rate using Response Evaluation Criteria in Solid Tumors 1.1 was 57%. No grade 3–4 immune-related adverse events were observed in the neoadjuvant setting. The 1- and 2-year recurrence-free survival rate was 100% and 92% for patients with any pathologic response, compared to 88% and 55% for patients who did not have a pathologic response (P = 0.005). Increased immune cell infiltration at baseline, and decrease in M2 macrophages during treatment, were associated with pathologic response. Our results indicate that neoadjuvant relatlimab and nivolumab induces a high pCR rate. Safety during neoadjuvant therapy is favourable compared to other combination immunotherapy regimens. These data, in combination with the results of the RELATIVITY-047 trial1, provide further confirmation of the efficacy and safety of this new immunotherapy regimen.

Published
2022

47. Corrigendum: Whole-genome landscape of pancreatic neuroendocrine tumours

Author

Scarpa, Aldo, Chang, David K., Nones, Katia, Corbo, Vincenzo, Patch, Ann-Marie, Bailey, Peter, Lawlor, Rita T., Johns, Amber L., Miller, David K., Mafficini, Andrea, Rusev, Borislav, Scardoni, Maria, Antonello, Davide, Barbi, Stefano, Sikora, Katarzyna O., Cingarlini, Sara, Vicentini, Caterina, McKay, Skye, Quinn, Michael C. J., Bruxner, Timothy J. C., Christ, Angelika N., Harliwong, Ivon, Idrisoglu, Senel, McLean, Suzanne, Nourse, Craig, Nourbakhsh, Ehsan, Wilson, Peter J., Anderson, Matthew J., Fink, Lynn J., Newell, Felicity, Waddell, Nick, Holmes, Oliver, Kazakoff, Stephen H., Leonard, Conrad, Wood, Scott, Xu, Qinying, Nagaraj, Shivashankar Hiriyur, Amato, Eliana, Dalai, Irene, Bersani, Samantha, Cataldo, Ivana, Dei Tos, Angelo P., Capelli, Paola, Davì, Maria Vittoria, Landoni, Luca, Malpaga, Anna, Miotto, Marco, Whitehall, Vicki L. J., Leggett, Barbara A., Harris, Janelle L., Harris, Jonathan, Jones, Marc D., Humphris, Jeremy, Chantrill, Lorraine A., Chin, Venessa, Nagrial, Adnan M., Pajic, Marina, Scarlett, Christopher J., Pinho, Andreia, Rooman, Ilse, Toon, Christopher, Wu, Jianmin, Pinese, Mark, Cowley, Mark, Barbour, Andrew, Mawson, Amanda, Humphrey, Emily S., Colvin, Emily K., Chou, Angela, Lovell, Jessica A., Jamieson, Nigel B., Duthie, Fraser, Gingras, Marie-Claude, Fisher, William E., Dagg, Rebecca A., Lau, Loretta M. S., Lee, Michael, Pickett, Hilda A., Reddel, Roger R., Samra, Jaswinder S., Kench, James G., Merrett, Neil D., Epari, Krishna, Nguyen, Nam Q., Zeps, Nikolajs, Falconi, Massimo, Simbolo, Michele, Butturini, Giovanni, Van Buren, George, Partelli, Stefano, Fassan, Matteo, Khanna, Kum Kum, Gill, Anthony J., Wheeler, David A., Gibbs, Richard A., Musgrove, Elizabeth A., Bassi, Claudio, Tortora, Giampaolo, Pederzoli, Paolo, Pearson, John V., Waddell, Nicola, Biankin, Andrew V., and Grimmond, Sean M.

Published
2017
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48. Whole-genome landscape of pancreatic neuroendocrine tumours

Author

Scarpa, Aldo, Chang, David K., Nones, Katia, Corbo, Vincenzo, Patch, Ann-Marie, Bailey, Peter, Lawlor, Rita T., Johns, Amber L., Miller, David K., Mafficini, Andrea, Rusev, Borislav, Scardoni, Maria, Antonello, Davide, Barbi, Stefano, Sikora, Katarzyna O., Cingarlini, Sara, Vicentini, Caterina, McKay, Skye, Quinn, Michael C. J., Bruxner, Timothy J. C., Christ, Angelika N., Harliwong, Ivon, Idrisoglu, Senel, McLean, Suzanne, Nourse, Craig, Nourbakhsh, Ehsan, Wilson, Peter J., Anderson, Matthew J., Fink, Lynn J., Newell, Felicity, Waddell, Nick, Holmes, Oliver, Kazakoff, Stephen H., Leonard, Conrad, Wood, Scott, Xu, Qinying, Nagaraj, Shivashankar Hiriyur, Amato, Eliana, Dalai, Irene, Bersani, Samantha, Cataldo, Ivana, Dei Tos, Angelo P., Capelli, Paola, Davì, Maria Vittoria, Landoni, Luca, Malpaga, Anna, Miotto, Marco, Whitehall, Vicki L. J., Leggett, Barbara A., Harris, Janelle L., Harris, Jonathan, Jones, Marc D., Humphris, Jeremy, Chantrill, Lorraine A., Chin, Venessa, Nagrial, Adnan M., Pajic, Marina, Scarlett, Christopher J., Pinho, Andreia, Rooman, Ilse, Toon, Christopher, Wu, Jianmin, Pinese, Mark, Cowley, Mark, Barbour, Andrew, Mawson, Amanda, Humphrey, Emily S., Colvin, Emily K., Chou, Angela, Lovell, Jessica A., Jamieson, Nigel B., Duthie, Fraser, Gingras, Marie-Claude, Fisher, William E., Dagg, Rebecca A., Lau, Loretta M. S., Lee, Michael, Pickett, Hilda A., Reddel, Roger R., Samra, Jaswinder S., Kench, James G., Merrett, Neil D., Epari, Krishna, Nguyen, Nam Q., Zeps, Nikolajs, Falconi, Massimo, Simbolo, Michele, Butturini, Giovanni, Van Buren, George, Partelli, Stefano, Fassan, Matteo, Khanna, Kum Kum, Gill, Anthony J., Wheeler, David A., Gibbs, Richard A., Musgrove, Elizabeth A., Bassi, Claudio, Tortora, Giampaolo, Pederzoli, Paolo, Pearson, John V., Waddell, Nicola, Biankin, Andrew V., and Grimmond, Sean M.

Published
2017
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49. Prevalence and architecture of de novo mutations in developmental disorders

Author

McRae, Jeremy F., Clayton, Stephen, Fitzgerald, Tomas W., Kaplanis, Joanna, Prigmore, Elena, Rajan, Diana, Sifrim, Alejandro, Aitken, Stuart, Akawi, Nadia, Alvi, Mohsan, Ambridge, Kirsty, Barrett, Daniel M., Bayzetinova, Tanya, Jones, Philip, Jones, Wendy D., King, Daniel, Krishnappa, Netravathi, Mason, Laura E., Singh, Tarjinder, Tivey, Adrian R., Ahmed, Munaza, Anjum, Uruj, Archer, Hayley, Armstrong, Ruth, Awada, Jana, Balasubramanian, Meena, Banka, Siddharth, Baralle, Diana, Barnicoat, Angela, Batstone, Paul, Baty, David, Bennett, Chris, Berg, Jonathan, Bernhard, Birgitta, Bevan, Paul A., Bitner-Glindzicz, Maria, Blair, Edward, Blyth, Moira, Bohanna, David, Bourdon, Louise, Bourn, David, Bradley, Lisa, Brady, Angela, Brent, Simon, Brewer, Carole, Brunstrom, Kate, Bunyan, David J., Burn, John, Canham, Natalie, Castle, Bruce, Chandler, Kate, Chatzimichali, Elena, Cilliers, Deirdre, Clarke, Angus, Clasper, Susan, Clayton-Smith, Jill, Clowes, Virginia, Coates, Andrea, Cole, Trevor, Colgiu, Irina, Collins, Amanda, Collinson, Morag N., Connell, Fiona, Cooper, Nicola, Cox, Helen, Cresswell, Lara, Cross, Gareth, Crow, Yanick, D’Alessandro, Mariella, Dabir, Tabib, Davidson, Rosemarie, Davies, Sally, de Vries, Dylan, Dean, John, Deshpande, Charu, Devlin, Gemma, Dixit, Abhijit, Dobbie, Angus, Donaldson, Alan, Donnai, Dian, Donnelly, Deirdre, Donnelly, Carina, Douglas, Angela, Douzgou, Sofia, Duncan, Alexis, Eason, Jacqueline, Ellard, Sian, Ellis, Ian, Elmslie, Frances, Evans, Karenza, Everest, Sarah, Fendick, Tina, Fisher, Richard, Flinter, Frances, Foulds, Nicola, Fry, Andrew, Fryer, Alan, Gardiner, Carol, Gaunt, Lorraine, Ghali, Neeti, Gibbons, Richard, Gill, Harinder, Goodship, Judith, Goudie, David, Gray, Emma, Green, Andrew, Greene, Philip, Greenhalgh, Lynn, Gribble, Susan, Harrison, Rachel, Harrison, Lucy, Harrison, Victoria, Hawkins, Rose, He, Liu, Hellens, Stephen, Henderson, Alex, Hewitt, Sarah, Hildyard, Lucy, Hobson, Emma, Holden, Simon, Holder, Muriel, Holder, Susan, Hollingsworth, Georgina, Homfray, Tessa, Humphreys, Mervyn, Hurst, Jane, Hutton, Ben, Ingram, Stuart, Irving, Melita, Islam, Lily, Jackson, Andrew, Jarvis, Joanna, Jenkins, Lucy, Johnson, Diana, Jones, Elizabeth, Josifova, Dragana, Joss, Shelagh, Kaemba, Beckie, Kazembe, Sandra, Kelsell, Rosemary, Kerr, Bronwyn, Kingston, Helen, Kini, Usha, Kinning, Esther, Kirby, Gail, Kirk, Claire, Kivuva, Emma, Kraus, Alison, Kumar, Dhavendra, Ajith Kumar, V. K., Lachlan, Katherine, Lam, Wayne, Lampe, Anne, Langman, Caroline, Lees, Melissa, Lim, Derek, Longman, Cheryl, Lowther, Gordon, Lynch, Sally A., Magee, Alex, Maher, Eddy, Male, Alison, Mansour, Sahar, Marks, Karen, Martin, Katherine, Maye, Una, McCann, Emma, McConnell, Vivienne, McEntagart, Meriel, McGowan, Ruth, McKay, Kirsten, McKee, Shane, McMullan, Dominic J., McNerlan, Susan, McWilliam, Catherine, Mehta, Sarju, Metcalfe, Kay, Middleton, Anna, Miedzybrodzka, Zosia, Miles, Emma, Mohammed, Shehla, Montgomery, Tara, Moore, David, Morgan, Sian, Morton, Jenny, Mugalaasi, Hood, Murday, Victoria, Murphy, Helen, Naik, Swati, Nemeth, Andrea, Nevitt, Louise, Newbury-Ecob, Ruth, Norman, Andrew, O’Shea, Rosie, Ogilvie, Caroline, Ong, Kai-Ren, Park, Soo-Mi, Parker, Michael J., Patel, Chirag, Paterson, Joan, Payne, Stewart, Perrett, Daniel, Phipps, Julie, Pilz, Daniela T., Pollard, Martin, Pottinger, Caroline, Poulton, Joanna, Pratt, Norman, Prescott, Katrina, Price, Sue, Pridham, Abigail, Procter, Annie, Purnell, Hellen, Quarrell, Oliver, Ragge, Nicola, Rahbari, Raheleh, Randall, Josh, Rankin, Julia, Raymond, Lucy, Rice, Debbie, Robert, Leema, Roberts, Eileen, Roberts, Jonathan, Roberts, Paul, Roberts, Gillian, Ross, Alison, Rosser, Elisabeth, Saggar, Anand, Samant, Shalaka, Sampson, Julian, Sandford, Richard, Sarkar, Ajoy, Schweiger, Susann, Scott, Richard, Scurr, Ingrid, Selby, Ann, Seller, Anneke, Sequeira, Cheryl, Shannon, Nora, Sharif, Saba, Shaw-Smith, Charles, Shearing, Emma, Shears, Debbie, Sheridan, Eamonn, Simonic, Ingrid, Singzon, Roldan, Skitt, Zara, Smith, Audrey, Smith, Kath, Smithson, Sarah, Sneddon, Linda, Splitt, Miranda, Squires, Miranda, Stewart, Fiona, Stewart, Helen, Straub, Volker, Suri, Mohnish, Sutton, Vivienne, Swaminathan, Ganesh Jawahar, Sweeney, Elizabeth, Tatton-Brown, Kate, Taylor, Cat, Taylor, Rohan, Tein, Mark, Temple, Karen I., Thomson, Jenny, Tischkowitz, Marc, Tomkins, Susan, Torokwa, Audrey, Treacy, Becky, Turner, Claire, Turnpenny, Peter, Tysoe, Carolyn, Vandersteen, Anthony, Varghese, Vinod, Vasudevan, Pradeep, Vijayarangakannan, Parthiban, Vogt, Julie, Wakeling, Emma, Wallwark, Sarah, Waters, Jonathon, Weber, Astrid, Wellesley, Diana, Whiteford, Margo, Widaa, Sara, Wilcox, Sarah, Wilkinson, Emily, Williams, Denise, Williams, Nicola, Wilson, Louise, Woods, Geoff, Wragg, Christopher, Wright, Michael, Yates, Laura, Yau, Michael, Nellåker, Chris, Parker, Michael, Firth, Helen V., Wright, Caroline F., FitzPatrick, David R., Barrett, Jeffrey C., and Hurles, Matthew E.

Published
2017
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50. Quantitative evolutionary dynamics using high-resolution lineage tracking

Author

Levy, Sasha F., Blundell, Jamie R., Venkataram, Sandeep, Petrov, Dmitri A., Fisher, Daniel S., and Sherlock, Gavin

Subjects
Gene mutations -- Identification and classification, Medical research -- Methods, Medicine, Experimental -- Methods, Gene expression -- Identification and classification, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

Evolution of large asexual cell populations underlies ~30% of deaths worldwide, including those caused by bacteria, fungi, parasites, and cancer. However, the dynamics underlying these evolutionary processes remain poorly understood because they involve many competing beneficial lineages, most of which never rise above extremely low frequencies in the population. To observe these normally hidden evolutionary dynamics, we constructed a sequencing-based ultra high-resolution lineage tracking system in Saccharomyces cerevisiae that allowed us to monitor the relative frequencies of ~500,000 lineages simultaneously. In contrast to some expectations, we found that the spectrum of fitness effects of beneficial mutations is neither exponential nor monotonic. Early adaptation is a predictable consequence of this spectrum and is strikingly reproducible, but the initial small-effect mutations are soon outcompeted by rarer large-effect mutations that result in variability between replicates. These results suggest that early evolutionary dynamics may be deterministic for a period of time before stochastic effects become important., A major focus of biomedical research has been to identify mutations responsible for increased pathogenicity, cancer progression, or drug resistance in large evolving asexual cell populations (1-12). Yet, even characterizing [...]

Published
2015
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