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Chang Liu, Wei Shi, Scott T Becker, David G Schatz, Bin Liu, Yang Yang
Coronavirus 3'-5' exoribonuclease (ExoN), residing in the nonstructural protein (nsp) 10-nsp14 complex, boosts replication fidelity by proofreading RNA synthesis and is critical for the virus life cycle. ExoN also recognizes and excises nucleotide analog inhibitors incorporated into the nascent RNA, undermining the effectiveness of nucleotide analog-based antivirals. Here, we present cryo-electron microscopy structures of both wild-type and mutant SARS-CoV-2 nsp10-nsp14 in complex with an RNA substrate bearing a 3'-end mismatch at resolutions ranging from 2...
July 27, 2021: Science
#2
Javier Del Valle, Nicolas M Vargas, Rodolfo Rocco, Pavel Salev, Yoav Kalcheim, Pavel N Lapa, Coline Adda, Min-Han Lee, Paul Y Wang, Lorenzo Fratino, Marcelo J Rozenberg, Ivan K Schuller
Many correlated systems feature an insulator-to-metal transition that can be triggered by an electric field. Although it is known that metallization takes place through filament formation, the details of how this process initiates and evolves remain elusive. We use in-operando optical reflectivity to capture the growth dynamics of the metallic phase with space and time resolution. We demonstrate that filament formation is triggered by nucleation at hotspots, with a subsequent expansion over several decades in time...
July 22, 2021: Science
#3
Ravi V Desai, Xinyue Chen, Benjamin Martin, Sonali Chaturvedi, Dong Woo Hwang, Weihan Li, Chen Yu, Sheng Ding, Matt Thomson, Robert H Singer, Robert A Coleman, Maike M K Hansen, Leor S Weinberger
Stochastic fluctuations in gene expression ('noise') are often considered detrimental, but fluctuations can also be exploited for benefit (e.g., dither). We show here that DNA base-excision repair amplifies transcriptional noise to facilitate cellular reprogramming. Specifically, the DNA-repair protein Apex1, which recognizes both naturally occurring and unnatural base modifications, amplifies expression noise while homeostatically maintaining mean-expression levels. This amplified expression noise originates from shorter duration, higher intensity, transcriptional bursts generated by Apex1-mediated DNA supercoiling...
July 22, 2021: Science
#4
Moritz U G Kraemer, Verity Hill, Christopher Ruis, Simon Dellicour, Sumali Bajaj, John T McCrone, Guy Baele, Kris V Parag, Anya Lindström Battle, Bernardo Gutierrez, Ben Jackson, Rachel Colquhoun, Áine O'Toole, Brennan Klein, Alessandro Vespignani, Erik Volz, Nuno R Faria, David Aanensen, Nicholas J Loman, Louis du Plessis, Simon Cauchemez, Andrew Rambaut, Samuel V Scarpino, Oliver G Pybus
Understanding the causes and consequences of the emergence of SARS-CoV-2 variants of concern is crucial to pandemic control yet difficult to achieve, as they arise in the context of variable human behavior and immunity. We investigate the spatial invasion dynamics of lineage B.1.1.7 by jointly analyzing UK human mobility, virus genomes, and community-based PCR data. We identify a multi-stage spatial invasion process in which early B.1.1.7 growth rates were associated with mobility and asymmetric lineage export from a dominant source location, enhancing the effects of B...
July 22, 2021: Science
#5
Nir Drayman, Jennifer K DeMarco, Krysten A Jones, Saara-Anne Azizi, Heather M Froggatt, Kemin Tan, Natalia Ivanovna Maltseva, Siquan Chen, Vlad Nicolaescu, Steve Dvorkin, Kevin Furlong, Rahul S Kathayat, Mason R Firpo, Vincent Mastrodomenico, Emily A Bruce, Madaline M Schmidt, Robert Jedrzejczak, Miguel Á Muñoz-Alía, Brooke Schuster, Vishnu Nair, Kyu-Yeon Han, Amornrat O'Brien, Anastasia Tomatsidou, Bjoern Meyer, Marco Vignuzzi, Dominique Missiakas, Jason W Botten, Christopher B Brooke, Hyun Lee, Susan C Baker, Bryan C Mounce, Nicholas S Heaton, William E Severson, Kenneth E Palmer, Bryan C Dickinson, Andrzej Joachimiak, Glenn Randall, Savaş Tay
There is an urgent need for antiviral agents that treat SARS-CoV-2 infection. We screened a library of 1,900 clinically safe drugs against OC43, a human beta-coronavirus that causes the common cold and evaluated the top hits against SARS-CoV-2. Twenty drugs significantly inhibited replication of both viruses in vitro. Eight of these drugs inhibited the activity of the SARS-CoV-2 main protease, 3CLpro, with the most potent being masitinib, an orally bioavailable tyrosine kinase inhibitor. X-ray crystallography and biochemistry show that masitinib acts as a competitive inhibitor of 3CLpro...
July 20, 2021: Science
#6
Minkyung Baek, Frank DiMaio, Ivan Anishchenko, Justas Dauparas, Sergey Ovchinnikov, Gyu Rie Lee, Jue Wang, Qian Cong, Lisa N Kinch, R Dustin Schaeffer, Claudia Millán, Hahnbeom Park, Carson Adams, Caleb R Glassman, Andy DeGiovanni, Jose H Pereira, Andria V Rodrigues, Alberdina A van Dijk, Ana C Ebrecht, Diederik J Opperman, Theo Sagmeister, Christoph Buhlheller, Tea Pavkov-Keller, Manoj K Rathinaswamy, Udit Dalwadi, Calvin K Yip, John E Burke, K Christopher Garcia, Nick V Grishin, Paul D Adams, Randy J Read, David Baker
DeepMind presented remarkably accurate predictions at the recent CASP14 protein structure prediction assessment conference. We explored network architectures incorporating related ideas and obtained the best performance with a three-track network in which information at the 1D sequence level, the 2D distance map level, and the 3D coordinate level is successively transformed and integrated. The three-track network produces structure predictions with accuracies approaching those of DeepMind in CASP14, enables the rapid solution of challenging X-ray crystallography and cryo-EM structure modeling problems, and provides insights into the functions of proteins of currently unknown structure...
July 15, 2021: Science
#7
Zhen Cao, F Aharonian, Q An, Axikegu, L X Bai, Y X Bai, Y W Bao, D Bastieri, X J Bi, Y J Bi, H Cai, J T Cai, Zhe Cao, J Chang, J F Chang, B M Chen, E S Chen, J Chen, Liang Chen, Liang Chen, Long Chen, M J Chen, M L Chen, Q H Chen, S H Chen, S Z Chen, T L Chen, X L Chen, Y Chen, N Cheng, Y D Cheng, S W Cui, X H Cui, Y D Cui, B D'Ettorre Piazzoli, B Z Dai, H L Dai, Z G Dai, Danzengluobu, D Della Volpe, X J Dong, K K Duan, J H Fan, Y Z Fan, Z X Fan, J Fang, K Fang, C F Feng, L Feng, S H Feng, Y L Feng, B Gao, C D Gao, L Q Gao, Q Gao, W Gao, M M Ge, L S Geng, G H Gong, Q B Gou, M H Gu, F L Guo, J G Guo, X L Guo, Y Q Guo, Y Y Guo, Y A Han, H H He, H N He, J C He, S L He, X B He, Y He, M Heller, Y K Hor, C Hou, X Hou, H B Hu, S Hu, S C Hu, X J Hu, D H Huang, Q L Huang, W H Huang, X T Huang, X Y Huang, Z C Huang, F Ji, X L Ji, H Y Jia, K Jiang, Z J Jiang, C Jin, T Ke, D Kuleshov, K Levochkin, B B Li, Cheng Li, Cong Li, F Li, H B Li, H C Li, H Y Li, Jian Li, Jie Li, K Li, W L Li, X R Li, Xin Li, Xin Li, Y Li, Y Z Li, Zhe Li, Zhuo Li, E W Liang, Y F Liang, S J Lin, B Liu, C Liu, D Liu, H Liu, H D Liu, J Liu, J L Liu, J S Liu, J Y Liu, M Y Liu, R Y Liu, S M Liu, W Liu, Y Liu, Y N Liu, Z X Liu, W J Long, R Lu, H K Lv, B Q Ma, L L Ma, X H Ma, J R Mao, A Masood, Z Min, W Mitthumsiri, T Montaruli, Y C Nan, B Y Pang, P Pattarakijwanich, Z Y Pei, M Y Qi, Y Q Qi, B Q Qiao, J J Qin, D Ruffolo, V Rulev, A Saiz, L Shao, O Shchegolev, X D Sheng, J Y Shi, H C Song, Yu V Stenkin, V Stepanov, Y Su, Q N Sun, X N Sun, Z B Sun, P H T Tam, Z B Tang, W W Tian, B D Wang, C Wang, H Wang, H G Wang, J C Wang, J S Wang, L P Wang, L Y Wang, R N Wang, Wei Wang, Wei Wang, X G Wang, X J Wang, X Y Wang, Y Wang, Y D Wang, Y J Wang, Y P Wang, Z H Wang, Z X Wang, Zhen Wang, Zheng Wang, D M Wei, J J Wei, Y J Wei, T Wen, C Y Wu, H R Wu, S Wu, W X Wu, X F Wu, S Q Xi, J Xia, J J Xia, G M Xiang, D X Xiao, G Xiao, H B Xiao, G G Xin, Y L Xin, Y Xing, D L Xu, R X Xu, L Xue, D H Yan, J Z Yan, C W Yang, F F Yang, J Y Yang, L L Yang, M J Yang, R Z Yang, S B Yang, Y H Yao, Z G Yao, Y M Ye, L Q Yin, N Yin, X H You, Z Y You, Y H Yu, Q Yuan, H D Zeng, T X Zeng, W Zeng, Z K Zeng, M Zha, X X Zhai, B B Zhang, H M Zhang, H Y Zhang, J L Zhang, J W Zhang, L X Zhang, Li Zhang, Lu Zhang, P F Zhang, P P Zhang, R Zhang, S R Zhang, S S Zhang, X Zhang, X P Zhang, Y F Zhang, Y L Zhang, Yi Zhang, Yong Zhang, B Zhao, J Zhao, L Zhao, L Z Zhao, S P Zhao, F Zheng, Y Zheng, B Zhou, H Zhou, J N Zhou, P Zhou, R Zhou, X X Zhou, C G Zhu, F R Zhu, H Zhu, K J Zhu, X Zuo
The Crab Nebula is a bright source of gamma-rays powered by the Crab Pulsar's rotational energy, through the formation and termination of a relativistic electron-positron wind. We report the detection of γ-rays from this source with energies from 5 × 10-4 to 1.1 petaelectronvolts (PeV), with a spectrum showing gradual steepening over three energy decades. The ultra-high-energy photons imply the presence of a PeV electron accelerator (a pevatron) in the nebula, with an acceleration rate exceeding 15% of the theoretical limit...
July 8, 2021: Science
#8
Matthew McCallum, Jessica Bassi, Anna De Marco, Alex Chen, Alexandra C Walls, Julia Di Iulio, M Alejandra Tortorici, Mary-Jane Navarro, Chiara Silacci-Fregni, Christian Saliba, Kaitlin R Sprouse, Maria Agostini, Dora Pinto, Katja Culap, Siro Bianchi, Stefano Jaconi, Elisabetta Cameroni, John E Bowen, Sasha W Tilles, Matteo Samuele Pizzuto, Sonja Bernasconi Guastalla, Giovanni Bona, Alessandra Franzetti Pellanda, Christian Garzoni, Wesley C Van Voorhis, Laura E Rosen, Gyorgy Snell, Amalio Telenti, Herbert W Virgin, Luca Piccoli, Davide Corti, David Veesler
A novel variant of concern (VOC) named CAL.20C (B.1.427/B.1.429), originally detected in California, carries spike glycoprotein mutations S13I in the signal peptide, W152C in the N-terminal domain (NTD), and L452R in the receptor-binding domain (RBD). Plasma from individuals vaccinated with a Wuhan-1 isolate-based mRNA vaccine or convalescent individuals exhibited neutralizing titers, which were reduced 2-3.5 fold against the B.1.427/B.1.429 variant relative to wildtype pseudoviruses. The L452R mutation reduced neutralizing activity of 14 out of 34 RBD-specific monoclonal antibodies (mAbs)...
July 1, 2021: Science
#9
Lingshu Wang, Tongqing Zhou, Yi Zhang, Eun Sung Yang, Chaim A Schramm, Wei Shi, Amarendra Pegu, Olamide K Oloniniyi, Amy R Henry, Samuel Darko, Sandeep R Narpala, Christian Hatcher, David R Martinez, Yaroslav Tsybovsky, Emily Phung, Olubukola M Abiona, Avan Antia, Evan M Cale, Lauren A Chang, Misook Choe, Kizzmekia S Corbett, Rachel L Davis, Anthony T DiPiazza, Ingelise J Gordon, Sabrina Helmold Hait, Tandile Hermanus, Prudence Kgagudi, Farida Laboune, Kwanyee Leung, Tracy Liu, Rosemarie D Mason, Alexandra F Nazzari, Laura Novik, Sarah O'Connell, Sijy O'Dell, Adam S Olia, Stephen D Schmidt, Tyler Stephens, Christopher D Stringham, Chloe Adrienna Talana, I-Ting Teng, Danielle A Wagner, Alicia T Widge, Baoshan Zhang, Mario Roederer, Julie E Ledgerwood, Tracy J Ruckwardt, Martin R Gaudinski, Penny L Moore, Nicole A Doria-Rose, Ralph S Baric, Barney S Graham, Adrian B McDermott, Daniel C Douek, Peter D Kwong, John R Mascola, Nancy J Sullivan, John Misasi
The emergence of highly transmissible SARS-CoV-2 variants of concern (VOC) that are resistant to therapeutic antibodies highlights the need for continuing discovery of broadly reactive antibodies. We identify four receptor-binding domain targeting antibodies from three early-outbreak convalescent donors with potent neutralizing activity against 23 variants including the B.1.1.7, B.1.351, P.1, B.1.429, B.1.526 and B.1.617 VOCs. Two antibodies are ultrapotent, with sub-nanomolar neutralization titers (IC50 0...
July 1, 2021: Science
#10
Sofia M Landi, Pooja Viswanathan, Stephen Serene, Winrich A Freiwald
The question of how the brain recognizes the faces of familiar individuals has been important throughout the history of neuroscience. Cells linking visual processing to person memory have been proposed, but not found. Here we report the discovery of such cells through recordings from an fMRI-identified area in the macaque temporal pole. These cells responded to faces when they were personally familiar. They responded non-linearly to step-wise changes in face visibility and detail, and holistically to face parts, reflecting key signatures of familiar face recognition...
July 1, 2021: Science
#11
Sophie M-C Gobeil, Katarzyna Janowska, Shana McDowell, Katayoun Mansouri, Robert Parks, Victoria Stalls, Megan F Kopp, Kartik Manne, Dapeng Li, Kevin Wiehe, Kevin O Saunders, Robert J Edwards, Bette Korber, Barton F Haynes, Rory Henderson, Priyamvada Acharya
SARS-CoV-2 variants with multiple spike mutations enable increased transmission and antibody resistance. Here, we combine cryo-EM, binding and computational analyses to study variant spikes, including one that was involved in transmission between minks and humans, and others that originated and spread in human populations. All variants showed increased ACE2 receptor binding and increased propensity for RBD up states. While adaptation to mink resulted in spike destabilization, the B.1.1.7 (UK) spike balanced stabilizing and destabilizing mutations...
June 24, 2021: Science
#12
Yongfei Cai, Jun Zhang, Tianshu Xiao, Christy L Lavine, Shaun Rawson, Hanqin Peng, Haisun Zhu, Krishna Anand, Pei Tong, Avneesh Gautam, Shen Lu, Sarah M Sterling, Richard M Walsh, Sophia Rits-Volloch, Jianming Lu, Duane R Wesemann, Wei Yang, Michael S Seaman, Bing Chen
Several fast-spreading variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have become the dominant circulating strains in the COVID-19 pandemic. We report here cryo-EM structures of the full-length spike (S) trimers of the B.1.1.7 and B.1.351 variants, as well as their biochemical and antigenic properties. Amino acid substitutions in the B.1.1.7 protein increase the accessibility of its receptor binding domain and also the binding affinity for receptor angiotensin-converting enzyme 2 (ACE2)...
June 24, 2021: Science
#13
David R Martinez, Alexandra Schäfer, Sarah R Leist, Gabriela De la Cruz, Ande West, Elena N Atochina-Vasserman, Lisa C Lindesmith, Norbert Pardi, Robert Parks, Maggie Barr, Dapeng Li, Boyd Yount, Kevin O Saunders, Drew Weissman, Barton F Haynes, Stephanie A Montgomery, Ralph S Baric
The emergence of SARS-CoV in 2003 and SARS-CoV-2 in 2019 highlights the need to develop universal vaccination strategies against the broader Sarbecovirus subgenus. Using chimeric spike designs, we demonstrate protection against challenge from SARS-CoV, SARS-CoV-2, SARS-CoV-2 B.1.351, bat CoV (Bt-CoV) RsSHC014, and a heterologous Bt-CoV WIV-1 in vulnerable aged mice. Chimeric spike mRNAs induced high levels of broadly protective neutralizing antibodies against high-risk Sarbecoviruses. In contrast, SARS-CoV-2 mRNA vaccination not only showed a marked reduction in neutralizing titers against heterologous Sarbecoviruses, but SARS-CoV and WIV-1 challenge in mice resulted in breakthrough infections...
June 22, 2021: Science
#14
Pierre Jacob, Nak Hyun Kim, Feihua Wu, Farid El-Kasmi, Yuan Chi, William G Walton, Oliver J Furzer, Adam D Lietzan, Sruthi Sunil, Korina Kempthorn, Matthew R Redinbo, Zhen-Ming Pei, Li Wan, Jeffery L Dangl
Plant nucleotide-binding leucine-rich repeat receptors (NLRs) regulate immunity and cell death. In Arabidopsis , a subfamily of "helper" NLRs are required by many "sensor" NLRs. Active NRG1.1 oligomerized, was enriched in plasma membrane puncta and conferred cytoplasmic Ca2+ influx in plant and human cells. NRG1.1-dependent Ca2+ influx and cell death were sensitive to Ca2+ channel blockers and were suppressed by mutations impacting oligomerization or plasma membrane enrichment. Ca2+ influx and cell death mediated by NRG1...
June 17, 2021: Science
#15
M Vizner Stern, Y Waschitz, W Cao, I Nevo, K Watanabe, T Taniguchi, E Sela, M Urbakh, O Hod, M Ben Shalom
Despite their partial ionic nature, many layered diatomic crystals avoid internal electric polarization by forming a centrosymmetric lattice at their optimal van-der-Waals stacking. Here, we report a stable ferroelectric order emerging at the interface between two naturally-grown flakes of hexagonal-boron-nitride, which are stacked together in a metastable non-centrosymmetric parallel orientation. We observe alternating domains of inverted normal polarization, caused by a lateral shift of one lattice site between the domains...
June 10, 2021: Science
#16
REVIEW
Mohd Farooq Azam, Jeffrey S Kargel, Joseph M Shea, Santosh Nepal, Umesh K Haritashya, Smriti Srivastava, Fabien Maussion, Nuzhat Qazi, Pierre Chevallier, A P Dimri, Anil V Kulkarni, J Graham Cogley, Isa M Bahuguna
Understanding the response of Himalayan-Karakoram (HK) rivers to climate change is crucial for ~1 billion people who partly depend on these water resources. Policymakers tasked with the sustainable water resources management for agriculture, hydropower, drinking, sanitation, and hazards require an assessment of rivers' current status and potential future changes. This review demonstrates that glacier and snow melt are important components of HK rivers, with greater hydrological importance for the Indus than Ganges and Brahmaputra basins...
June 10, 2021: Science
#17
D H Shugar, M Jacquemart, D Shean, S Bhushan, K Upadhyay, A Sattar, W Schwanghart, S McBride, M Van Wyk de Vries, M Mergili, A Emmer, C Deschamps-Berger, M McDonnell, R Bhambri, S Allen, E Berthier, J L Carrivick, J J Clague, M Dokukin, S A Dunning, H Frey, S Gascoin, U K Haritashya, C Huggel, A Kääb, J S Kargel, J L Kavanaugh, P Lacroix, D Petley, S Rupper, M F Azam, S J Cook, A P Dimri, M Eriksson, D Farinotti, J Fiddes, K R Gnyawali, S Harrison, M Jha, M Koppes, A Kumar, S Leinss, U Majeed, S Mal, A Muhuri, J Noetzli, F Paul, I Rashid, K Sain, J Steiner, F Ugalde, C S Watson, M J Westoby
On 7 Feb 2021, a catastrophic mass flow descended the Ronti Gad, Rishiganga, and Dhauliganga valleys in Chamoli, Uttarakhand, India, causing widespread devastation and severely damaging two hydropower projects. Over 200 people were killed or are missing. Our analysis of satellite imagery, seismic records, numerical model results, and eyewitness videos reveals that ~27x106 m3 of rock and glacier ice collapsed from the steep north face of Ronti Peak. The rock and ice avalanche rapidly transformed into an extraordinarily large and mobile debris flow that transported boulders >20 m in diameter, and scoured the valley walls up to 220 m above the valley floor...
June 10, 2021: Science
#18
Christina D Camell, Matthew J Yousefzadeh, Yi Zhu, Larissa G P Langhi Prata, Matthew A Huggins, Mark Pierson, Lei Zhang, Ryan D O'Kelly, Tamar Pirtskhalava, Pengcheng Xun, Keisuke Ejima, Ailing Xue, Utkarsh Tripathi, Jair Machado Espindola-Netto, Nino Giorgadze, Elizabeth J Atkinson, Christina L Inman, Kurt O Johnson, Stephanie H Cholensky, Timothy W Carlson, Nathan K LeBrasseur, Sundeep Khosla, M Gerard O'Sullivan, David B Allison, Stephen C Jameson, Alexander Meves, Ming Li, Y S Prakash, Sergio E Chiarella, Sara E Hamilton, Tamara Tchkonia, Laura J Niedernhofer, James L Kirkland, Paul D Robbins
The COVID-19 pandemic has revealed the pronounced vulnerability of the elderly and chronically-ill to SARS-CoV-2-induced morbidity and mortality. Cellular senescence contributes to inflammation, multiple chronic diseases, and age-related dysfunction, but effects on responses to viral infection are unclear. Here, we demonstrate that senescent cells (SnC) become hyper-inflammatory in response to pathogen-associated molecular patterns (PAMPs), including SARS-CoV-2 Spike protein-1, increasing expression of viral entry proteins and reducing anti-viral gene expression in non-SnCs through a paracrine mechanism...
June 8, 2021: Science
#19
James A Hay, Lee Kennedy-Shaffer, Sanjat Kanjilal, Niall J Lennon, Stacey B Gabriel, Marc Lipsitch, Michael J Mina
Estimating an epidemic's trajectory is crucial for developing public health responses to infectious diseases, but case data used for such estimation are confounded by variable testing practices. We show that the population distribution of viral loads observed under random or symptom-based surveillance, in the form of cycle threshold (Ct) values obtained from reverse-transcription quantitative polymerase chain reaction testing, changes during an epidemic. Thus, Ct values from even limited numbers of random samples can provide improved estimates of an epidemic's trajectory...
June 3, 2021: Science
#20
Simone Brioschi, Wei-Le Wang, Vincent Peng, Meng Wang, Irina Shchukina, Zev J Greenberg, Jennifer K Bando, Natalia Jaeger, Rafael S Czepielewski, Amanda Swain, Denis A Mogilenko, Wandy L Beatty, Peter Bayguinov, James A J Fitzpatrick, Laura G Schuettpelz, Catrina C Fronick, Igor Smirnov, Jonathan Kipnis, Virginia S Shapiro, Gregory F Wu, Susan Gilfillan, Marina Cella, Maxim N Artyomov, Steven H Kleinstein, Marco Colonna
The meninges contain adaptive immune cells that provide immunosurveillance of the CNS. These cells are thought to derive from the systemic circulation. Through single-cell analyses, confocal imaging, bone marrow chimeras, and parabiosis experiments, we show that meningeal B cells derive locally from the calvaria, which harbors a bone marrow niche for hematopoiesis. B cells reach the meninges from the calvaria through specialized vascular connections. This calvarial-meningeal path of B cell development may provide the CNS with a constant supply of B cells educated by CNS antigens...
June 3, 2021: Science
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