Sebastian Günther, Patrick Y A Reinke, Yaiza Fernández-García, Julia Lieske, Thomas J Lane, Helen M Ginn, Faisal H M Koua, Christiane Ehrt, Wiebke Ewert, Dominik Oberthuer, Oleksandr Yefanov, Susanne Meier, Kristina Lorenzen, Boris Krichel, Janine-Denise Kopicki, Luca Gelisio, Wolfgang Brehm, Ilona Dunkel, Brandon Seychell, Henry Gieseler, Brenna Norton-Baker, Beatriz Escudero-Pérez, Martin Domaracky, Sofiane Saouane, Alexandra Tolstikova, Thomas A White, Anna Hänle, Michael Groessler, Holger Fleckenstein, Fabian Trost, Marina Galchenkova, Yaroslav Gevorkov, Chufeng Li, Salah Awel, Ariana Peck, Miriam Barthelmess, Frank Schluenzen, Paulraj Lourdu Xavier, Nadine Werner, Hina Andaleeb, Najeeb Ullah, Sven Falke, Vasundara Srinivasan, Bruno Alves França, Martin Schwinzer, Hévila Brognaro, Cromarte Rogers, Diogo Melo, Joanna J Zaitseva-Doyle, Juraj Knoska, Gisel E Peña-Murillo, Aida Rahmani Mashhour, Vincent Hennicke, Pontus Fischer, Johanna Hakanpää, Jan Meyer, Philip Gribbon, Bernhard Ellinger, Maria Kuzikov, Markus Wolf, Andrea R Beccari, Gleb Bourenkov, David von Stetten, Guillaume Pompidor, Isabel Bento, Saravanan Panneerselvam, Ivars Karpics, Thomas R Schneider, Maria Marta Garcia-Alai, Stephan Niebling, Christian Günther, Christina Schmidt, Robin Schubert, Huijong Han, Juliane Boger, Diana C F Monteiro, Linlin Zhang, Xinyuanyuan Sun, Jonathan Pletzer-Zelgert, Jan Wollenhaupt, Christian G Feiler, Manfred S Weiss, Eike-Christian Schulz, Pedram Mehrabi, Katarina Karničar, Aleksandra Usenik, Jure Loboda, Henning Tidow, Ashwin Chari, Rolf Hilgenfeld, Charlotte Uetrecht, Russell Cox, Andrea Zaliani, Tobias Beck, Matthias Rarey, Stephan Günther, Dusan Turk, Winfried Hinrichs, Henry N Chapman, Arwen R Pearson, Christian Betzel, Alke Meents
The coronavirus disease (COVID-19) caused by SARS-CoV-2 is creating tremendous human suffering. To date, no effective drug is available to directly treat the disease. In a search for a drug against COVID-19, we have performed a high-throughput X-ray crystallographic screen of two repurposing drug libraries against the SARS-CoV-2 main protease (Mpro ), which is essential for viral replication. In contrast to commonly applied X-ray fragment screening experiments with molecules of low complexity, our screen tested already approved drugs and drugs in clinical trials...
April 2, 2021: Science
Xizi Chen, Yilun Qi, Zihan Wu, Xinxin Wang, Jiabei Li, Dan Zhao, Haifeng Hou, Yan Li, Zishuo Yu, Weida Liu, Mo Wang, Yulei Ren, Ze Li, Huirong Yang, Yanhui Xu
Transcription factor IID (TFIID) recognizes core promoters and supports preinitiation complex (PIC) assembly for RNA polymerase (Pol) II-mediated eukaryotic transcription. Here, we determined the structures of human TFIID-based PIC in three stepwise assembly states and revealed two-track PIC assembly: stepwise promoter deposition to Pol II and extensive modular reorganization on track I (on TATA-DBE promoters) versus direct promoter deposition on track II (on TATA-only and TATA-less promoters). The two tracks converge at ~50-subunit holo-PIC in identical conformation, whereby TFIID stabilizes PIC organization and supports loading (CDK)-activating kinase (CAK) onto Pol II and CAK-mediated phosphorylation of Pol II C-terminal domain...
April 1, 2021: Science
Leonidas Stamatatos, Julie Czartoski, Yu-Hsin Wan, Leah J Homad, Vanessa Rubin, Hayley Glantz, Moni Neradilek, Emilie Seydoux, Madeleine F Jennewein, Anna J MacCamy, Junli Feng, Gregory Mize, Stephen C De Rosa, Andrés Finzi, Maria P Lemos, Kristen W Cohen, Zoe Moodie, M Juliana McElrath, Andrew T McGuire
Emerging SARS-CoV-2 variants have raised concerns about resistance to neutralizing antibodies elicited by previous infection or vaccination. We examined whether sera from recovered and naïve donors collected prior to, and following immunizations with existing mRNA vaccines, could neutralize the Wuhan-Hu-1 and B.1.351 variants. Pre-vaccination sera from recovered donors neutralized Wuhan-Hu-1 and sporadically neutralized B.1.351, but a single immunization boosted neutralizing titers against all variants and SARS-CoV-1 by up to 1000-fold...
March 25, 2021: Science
Jennifer Lee, Tiffany Huang
No abstract text is available yet for this article.
March 25, 2021: Science
Doron Levin, Neta Raab, Yishay Pinto, Daphna Rothschild, Gal Zanir, Anastasia Godneva, Nadav Mellul, David Futorian, Doran Gal, Sigal Leviatan, David Zeevi, Ido Bachelet, Eran Segal
Animals in the wild are able to subsist on pathogen-infected and poisonous food and show immunity to various diseases. These may be due to their microbiota, yet we have a poor understanding of animal microbial diversity and function. We used metagenomics to analyze the gut microbiota of over 180 species in the wild, covering diverse classes, feeding behaviors, geographies, and traits. Using de novo metagenome assembly, we constructed and functionally annotated a database of over 5,000 genomes, comprising 1,209 bacterial species of which 75% are unknown...
March 25, 2021: Science
Marieke Verweij, Scott G Hansen, Ravi Iyer, Nessy John, Daniel Malouli, David Morrow, Isabel Scholz, Jennie Womack, Shaheed Abdulhaqq, Roxanne M Gilbride, Colette M Hughes, Abigail B Ventura, Julia C Ford, Andrea N Selseth, Kelli Oswald, Rebecca Shoemaker, Brian Berkemeier, William J Bosche, Michael Hull, Jason Shao, Jonah B Sacha, Michael K Axthelm, Paul T Edlefsen, Jeffrey D Lifson, Louis J Picker, Klaus Früh
Strain 68-1 rhesus cytomegalovirus (RhCMV) vectors expressing simian immunodeficiency virus (SIV) antigens elicit CD8+ T cells recognizing epitopes presented by major histocompatibility complex (MHC)-II and MHC-E, not MHC-Ia. These immune responses mediate replication arrest of SIV in 50 to 60% of monkeys. We show that the peptide VMAPRTLLL (VL9) embedded within the RhCMV protein Rh67 promotes intracellular MHC-E transport and recognition of RhCMV-infected fibroblasts by MHC-E-restricted CD8+ T cells. Deletion or mutation of viral VL9 abrogated MHC-E-restricted CD8+ T cell priming, resulting in CD8+ T cell responses exclusively targeting MHC-II-restricted epitopes...
March 25, 2021: Science
Martin Pavelka, Kevin Van-Zandvoort, Sam Abbott, Katharine Sherratt, Marek Majdan, Inštitút Zdravotných Analýz, Pavol Jarčuška, Marek Krajčí, Stefan Flasche, Sebastian Funk
Slovakia conducted multiple rounds of population-wide rapid antigen testing for SARS-CoV-2 in late 2020, combined with a period of additional contact restrictions. Observed prevalence decreased by 58% (95% CI: 57-58%) within one week in the 45 counties that were subject to two rounds of mass testing, an estimate that remained robust when adjusting for multiple potential confounders. Adjusting for epidemic growth of 4.4% (1.1-6.9%) per day preceding the mass testing campaign, the estimated decrease in prevalence compared to a scenario of unmitigated growth was 70% (67-73%)...
March 23, 2021: Science
Jonathan Pekar, Michael Worobey, Niema Moshiri, Konrad Scheffler, Joel O Wertheim
Understanding when SARS-CoV-2 emerged is critical to evaluating our current approach to monitoring novel zoonotic pathogens and understanding the failure of early containment and mitigation efforts for COVID-19. We employed a coalescent framework to combine retrospective molecular clock inference with forward epidemiological simulations to determine how long SARS-CoV-2 could have circulated prior to the time of the most recent common ancestor. Our results define the period between mid-October and mid-November 2019 as the plausible interval when the first case of SARS-CoV-2 emerged in Hubei province...
March 18, 2021: Science
Yuji Nakagawa, Yuichi Kasahara, Takuya Nomoto, Ryotaro Arita, Tsutomu Nojima, Yoshihiro Iwasa
Bardeen-Cooper-Schrieffer (BCS) superfluidity and Bose-Einstein condensation (BEC) are the two extreme limits of the ground state of the paired fermion systems. We report crossover behavior from the BCS limit to the BEC limit realized by varying carrier density in a two-dimensional (2D) superconductor, electron-doped layered material ZrNCl. The phase diagram, established by simultaneous measurements of resistivity and tunneling spectra under ionic gating, demonstrates a pseudogap phase in the low doping regime...
March 18, 2021: Science
Jun Zhang, Yongfei Cai, Tianshu Xiao, Jianming Lu, Hanqin Peng, Sarah M Sterling, Richard M Walsh, Sophia Rits-Volloch, Haisun Zhu, Alec N Woosley, Wei Yang, Piotr Sliz, Bing Chen
Substitution for aspartic acid by glycine at position 614 in the spike (S) protein of severe acute respiratory syndrome coronavirus 2 appears to facilitate rapid viral spread. The G614 strain and its recent variants are now the dominant circulating forms. We report here cryo-EM structures of a full-length G614 S trimer, which adopts three distinct prefusion conformations differing primarily by the position of one receptor-binding domain. A loop disordered in the D614 S trimer wedges between domains within a protomer in the G614 spike...
March 16, 2021: Science
H Holden Thorp
No abstract text is available yet for this article.
March 11, 2021: Science
R Abdella, A Talyzina, S Chen, C J Inouye, R Tjian, Y He
Eukaryotic transcription requires the assembly of a multi-subunit preinitiation complex (PIC) comprised of RNA polymerase II (Pol II) and the general transcription factors. The co-activator Mediator is recruited by transcription factors, facilitates the assembly of the PIC, and stimulates phosphorylation of the Pol II C-terminal domain (CTD) by the TFIIH subunit CDK7. Here, we present the cryo-electron microscopy structure of the human Mediator-bound PIC at sub-4 Å. Transcription factor binding sites within Mediator are primarily flexibly tethered to the tail module...
March 11, 2021: Science
Katrina A Lythgoe, Matthew Hall, Luca Ferretti, Mariateresa de Cesare, George MacIntyre-Cockett, Amy Trebes, Monique Andersson, Newton Otecko, Emma L Wise, Nathan Moore, Jessica Lynch, Stephen Kidd, Nicholas Cortes, Matilde Mori, Rebecca Williams, Gabrielle Vernet, Anita Justice, Angie Green, Samuel M Nicholls, M Azim Ansari, Lucie Abeler-Dörner, Catrin E Moore, Timothy E A Peto, David W Eyre, Robert Shaw, Peter Simmonds, David Buck, John A Todd, Thomas R Connor, Shirin Ashraf, Ana da Silva Filipe, James Shepherd, Emma C Thomson, David Bonsall, Christophe Fraser, Tanya Golubchik
Extensive global sampling and sequencing of the pandemic virus SARS-CoV-2 have enabled researchers to monitor its spread, and to identify concerning new variants. Two important determinants of variant spread are how frequently they arise within individuals, and how likely they are to be transmitted. To characterize within-host diversity and transmission we deep-sequenced 1313 clinical samples from the UK. SARS-CoV-2 infections are characterized by low levels of within-host diversity when viral loads are high, and a narrow bottleneck at transmission...
March 9, 2021: Science
Chadi M Saad-Roy, Sinead E Morris, C Jessica E Metcalf, Michael J Mina, Rachel E Baker, Jeremy Farrar, Edward C Holmes, Oliver G Pybus, Andrea L Graham, Simon A Levin, Bryan T Grenfell, Caroline E Wagner
In the face of vaccine dose shortages and logistical challenges, various deployment strategies are being proposed to increase population immunity levels to SARS-CoV-2. Two critical issues arise: how will the timing of delivery of the second dose affect both infection dynamics and prospects for the evolution of viral immune escape via a build-up of partially immune individuals. Both hinge on the robustness of the immune response elicited by a single dose, compared to natural and two-dose immunity. Building on an existing immuno-epidemiological model, we find that in the short-term, focusing on one dose generally decreases infections, but longer-term outcomes depend on this relative immune robustness...
March 9, 2021: Science
You-Jie Yu, Feng-Lian Zhang, Tian-Yu Peng, Chang-Ling Wang, Jie Cheng, Chen Chen, Kendall N Houk, Yi-Feng Wang
Defluorinative functionalization of readily accessible trifluoromethyl groups constitutes an economical route to partially fluorinated molecules. However, controllable replacement of one or two fluorine atoms while maintaining high chemoselectivity remains a formidable challenge. Here we describe a general strategy for sequential C-F bond functionalizations of trifluoroacetamides and trifluoroacetates. The reaction begins with activation of a carbonyl oxygen atom by a 4-dimethylaminopyridine-boryl radical, followed by a spin-center shift to trigger the C-F bond scission...
March 4, 2021: Science
Nicholas G Davies, Sam Abbott, Rosanna C Barnard, Christopher I Jarvis, Adam J Kucharski, James D Munday, Carl A B Pearson, Timothy W Russell, Damien C Tully, Alex D Washburne, Tom Wenseleers, Amy Gimma, William Waites, Kerry L M Wong, Kevin van Zandvoort, Justin D Silverman, Karla Diaz-Ordaz, Ruth Keogh, Rosalind M Eggo, Sebastian Funk, Mark Jit, Katherine E Atkins, W John Edmunds
A severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variant, VOC 202012/01 (lineage B.1.1.7), emerged in southeast England in September 2020 and is rapidly spreading toward fixation. Using a variety of statistical and dynamic modeling approaches, we estimate that this variant has a 43 to 90% (range of 95% credible intervals, 38 to 130%) higher reproduction number than preexisting variants. A fitted two-strain dynamic transmission model shows that VOC 202012/01 will lead to large resurgences of COVID-19 cases...
April 9, 2021: Science
M Florencia Sánchez, Sylvia Els-Heindl, Annette G Beck-Sickinger, Ralph Wieneke, Robert Tampé
Cell-cell communication relies on the assembly of receptor-ligand complexes at the plasma membrane. The spatiotemporal receptor organization has a pivotal role in evoking cellular responses. We studied the clustering of heterotrimeric guanine nucleotide-binding protein (G protein)-coupled receptors (GPCRs) and established a photo-instructive matrix with ultra-small lock-and-key interaction pairs to control lateral membrane organization of hormone neuropeptide Y2 receptors in living cells by light. Within seconds, receptor clustering was modulated in size, location, and density...
February 25, 2021: Science
Peter Ebert, Peter A Audano, Qihui Zhu, Bernardo Rodriguez-Martin, David Porubsky, Marc Jan Bonder, Arvis Sulovari, Jana Ebler, Weichen Zhou, Rebecca Serra Mari, Feyza Yilmaz, Xuefang Zhao, PingHsun Hsieh, Joyce Lee, Sushant Kumar, Jiadong Lin, Tobias Rausch, Yu Chen, Jingwen Ren, Martin Santamarina, Wolfram Höps, Hufsah Ashraf, Nelson T Chuang, Xiaofei Yang, Katherine M Munson, Alexandra P Lewis, Susan Fairley, Luke J Tallon, Wayne E Clarke, Anna O Basile, Marta Byrska-Bishop, André Corvelo, Uday S Evani, Tsung-Yu Lu, Mark J P Chaisson, Junjie Chen, Chong Li, Harrison Brand, Aaron M Wenger, Maryam Ghareghani, William T Harvey, Benjamin Raeder, Patrick Hasenfeld, Allison A Regier, Haley J Abel, Ira M Hall, Paul Flicek, Oliver Stegle, Mark B Gerstein, Jose M C Tubio, Zepeng Mu, Yang I Li, Xinghua Shi, Alex R Hastie, Kai Ye, Zechen Chong, Ashley D Sanders, Michael C Zody, Michael E Talkowski, Ryan E Mills, Scott E Devine, Charles Lee, Jan O Korbel, Tobias Marschall, Evan E Eichler
Long-read and strand-specific sequencing technologies together facilitate the de novo assembly of high-quality haplotype-resolved human genomes without parent-child trio data. We present 64 assembled haplotypes from 32 diverse human genomes. These highly contiguous haplotype assemblies (average contig N50: 26 Mbp) integrate all forms of genetic variation even across complex loci. We identify 107,590 structural variants (SVs), of which 68% are not discovered by short-read sequencing, and 278 SV hotspots (spanning megabases of gene-rich sequence)...
February 25, 2021: Science
D Bluvstein, A Omran, H Levine, A Keesling, G Semeghini, S Ebadi, T T Wang, A A Michailidis, N Maskara, W W Ho, S Choi, M Serbyn, M Greiner, V Vuletić, M D Lukin
The control of non-equilibrium quantum dynamics in many-body systems is challenging as interactions typically lead to thermalization and a chaotic spreading throughout Hilbert space. We investigate non-equilibrium dynamics following rapid quenches in a many-body system composed of 3 to 200 strongly interacting qubits in one and two spatial dimensions. Using a programmable quantum simulator based on Rydberg atom arrays, we show that coherent revivals associated with so-called quantum many-body scars can be stabilized by periodic driving, which generates a robust subharmonic response akin to discrete time-crystalline order...
February 25, 2021: Science
Rogelio A Hernandez-Lopez, Wei Yu, Katelyn A Cabral, Olivia A Creasey, Maria Del Pilar Lopez Pazmino, Yurie Tonai, Arsenia De Guzman, Anna Mäkelä, Kalle Saksela, Zev J Gartner, Wendell A Lim
Overexpressed tumor associated antigens (e.g., HER2 and epidermal growth factor receptor) are attractive targets for therapeutic T cells, but toxic "off-tumor" cross-reaction with normal tissues expressing low levels of target antigen can occur with Chimeric Antigen Receptor (CAR) T cells. Inspired by natural ultrasensitive response circuits, we engineered a two-step positive feedback circuit that allows T cells to discriminate targets based on a sigmoidal antigen density threshold. In this circuit, a low affinity synthetic Notch receptor for HER2 controls the expression of a high affinity CAR for HER2...
February 25, 2021: Science
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