Renhong Yan, Pingping Cao, Wenqi Song, Hongwu Qian, Ximing Du, Hudson W Coates, Xin Zhao, Yaning Li, Shuai Gao, Xin Gong, Ximing Liu, Jianhua Sui, Jianlin Lei, Hongyuan Yang, Andrew J Brown, Qiang Zhou, Chuangye Yan, Nieng Yan
The SREBP pathway controls cellular homeostasis of sterols. The key players in this pathway, Scap and Insig-1/2, are membrane-embedded sterol sensors. 25-hydroxycholesterol (25HC)-dependent association of Scap and Insigs acts as the master switch for the SREBP pathway. Here, we present cryo-EM analysis of the human Scap and Insig-2 complex in the presence of 25HC, with the transmembrane (TM) domains determined at an average resolution of 3.7 Å. The sterol sensing domain (SSD) in Scap and all six TMs in Insig-2 were resolved...
January 14, 2021: Science
Kunal Bhutani, Katherine Stansifer, Simina Ticau, Lazar Bojic, Alexandra-Chloé Villani, Joanna Slisz, Claudia M Cremers, Christian Roy, Jerry Donovan, Brian Fiske, Robin C Friedman
Sperm are haploid, but must be functionally equivalent to distribute alleles equally among progeny. Accordingly, gene products are shared through spermatid cytoplasmic bridges which erase phenotypic differences between individual haploid sperm. Here, we show that a large class of mammalian genes are not completely shared across these bridges. We term these genes "genoinformative markers" (GIMs) and show that a subset can act as selfish genetic elements that spread alleles unevenly through murine, bovine, and human populations...
January 14, 2021: Science
Paul-Albert Koenig, Hrishikesh Das, Hejun Liu, Beate M Kümmerer, Florian N Gohr, Lea-Marie Jenster, Lisa D J Schiffelers, Yonas M Tesfamariam, Miki Uchima, Jennifer D Wuerth, Karl Gatterdam, Natalia Ruetalo, Maria H Christensen, Caroline I Fandrey, Sabine Normann, Jan M P Tödtmann, Steffen Pritzl, Leo Hanke, Jannik Boos, Meng Yuan, Xueyong Zhu, Jonathan L Schmid-Burgk, Hiroki Kato, Michael Schindler, Ian A Wilson, Matthias Geyer, Kerstin U Ludwig, B Martin Hällberg, Nicholas C Wu, Florian I Schmidt
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic continues to spread with devastating consequences. For passive immunization efforts, nanobodies have size and cost advantages over conventional antibodies. Here, we generated four neutralizing nanobodies that target the receptor-binding domain of the SARS-CoV-2 spike protein. We defined two distinct binding epitopes using x-ray crystallography and cryo-electron microscopy. Based on the structures, we engineered multivalent nanobodies with more than 100-fold improved neutralizing activity than monovalent nanobodies...
January 12, 2021: Science
Jennie S Lavine, Ottar N Bjornstad, Rustom Antia
We are currently faced with the question of how the CoV-2 severity may change in the years ahead. Our analysis of immunological and epidemiological data on endemic human coronaviruses (HCoVs) shows that infection-blocking immunity wanes rapidly, but disease-reducing immunity is long-lived. Our model, incorporating these components of immunity, recapitulates both the current severity of CoV-2 and the benign nature of HCoVs, suggesting that once the endemic phase is reached and primary exposure is in childhood, CoV-2 may be no more virulent than the common cold...
January 12, 2021: Science
Alexander A Cohen, Priyanthi N P Gnanapragasam, Yu E Lee, Pauline R Hoffman, Susan Ou, Leesa M Kakutani, Jennifer R Keeffe, Hung-Jen Wu, Mark Howarth, Anthony P West, Christopher O Barnes, Michel C Nussenzweig, Pamela J Bjorkman
Protection against SARS-CoV-2 and SARS-related emergent zoonotic coronaviruses is urgently needed. We made homotypic nanoparticles displaying the receptor-binding domain (RBD) of SARS-CoV-2 or co-displaying SARS-CoV-2 RBD along with RBDs from animal betacoronaviruses that represent threats to humans (mosaic nanoparticles; 4-8 distinct RBDs). Mice immunized with RBD-nanoparticles, but not soluble antigen, elicited cross-reactive binding and neutralization responses. Mosaic-RBD-nanoparticles elicited antibodies with superior cross-reactive recognition of heterologous RBDs compared to sera from immunizations with homotypic SARS-CoV-2-RBD-nanoparticles or COVID-19 convalescent human plasmas...
January 12, 2021: Science
Louis du Plessis, John T McCrone, Alexander E Zarebski, Verity Hill, Christopher Ruis, Bernardo Gutierrez, Jayna Raghwani, Jordan Ashworth, Rachel Colquhoun, Thomas R Connor, Nuno R Faria, Ben Jackson, Nicholas J Loman, Áine O'Toole, Samuel M Nicholls, Kris V Parag, Emily Scher, Tetyana I Vasylyeva, Erik M Volz, Alexander Watts, Isaac I Bogoch, Kamran Khan, David M Aanensen, Moritz U G Kraemer, Andrew Rambaut, Oliver G Pybus
The UK's COVID-19 epidemic during early 2020 was one of world's largest and unusually well represented by virus genomic sampling. Here we reveal the fine-scale genetic lineage structure of this epidemic through analysis of 50,887 SARS-CoV-2 genomes, including 26,181 from the UK sampled throughout the country's first wave of infection. Using large-scale phylogenetic analyses, combined with epidemiological and travel data, we quantify the size, spatio-temporal origins and persistence of genetically-distinct UK transmission lineages...
January 8, 2021: Science
Seyed-Fakhreddin Torabi, Anand T Vaidya, Kazimierz T Tycowski, Suzanne J DeGregorio, Jimin Wang, Mei-Di Shu, Thomas A Steitz, Joan A Steitz
Poly(A) tail addition to the 3' end of a wide range of RNAs is a highly conserved modification that plays a central role in cellular RNA function. Elements for nuclear expression (ENEs) are cis-acting RNA elements that stabilize poly(A) tails by sequestering them in RNA triplex structures. A 2.89-Å resolution crystal structure of a double ENE from a rice hAT transposon mRNA complexed with poly(A)28 reveals multiple modes of interaction with poly(A), including major-groove triple helices, extended minor-groove interactions with RNA double helices, a quintuple-base motif that transitions poly(A) from minor-groove associations to major-groove triple helices, and a poly(A) 3'-end binding pocket...
January 7, 2021: Science
Richard C V Tyser, Ximena Ibarra-Soria, Katie McDole, Satish A Jayaram, Jonathan Godwin, Teun A H van den Brand, Antonio M A Miranda, Antonio Scialdone, Philipp J Keller, John C Marioni, Shankar Srinivas
The mammalian heart is derived from multiple cell lineages; however, our understanding of when and how the diverse cardiac cell types arise is limited. We mapped the origin of the embryonic mouse heart at single-cell resolution using a combination of transcriptomic, imaging, and genetic lineage labeling approaches. This provided a transcriptional and anatomic definition of cardiac progenitor types. Furthermore, it revealed a cardiac progenitor pool that is anatomically and transcriptionally distinct from currently known cardiac progenitors...
January 7, 2021: Science
Jennifer M Dan, Jose Mateus, Yu Kato, Kathryn M Hastie, Esther Dawen Yu, Caterina E Faliti, Alba Grifoni, Sydney I Ramirez, Sonya Haupt, April Frazier, Catherine Nakao, Vamseedhar Rayaprolu, Stephen A Rawlings, Bjoern Peters, Florian Krammer, Viviana Simon, Erica Ollmann Saphire, Davey M Smith, Daniela Weiskopf, Alessandro Sette, Shane Crotty
Understanding immune memory to SARS-CoV-2 is critical for improving diagnostics and vaccines, and for assessing the likely future course of the COVID-19 pandemic. We analyzed multiple compartments of circulating immune memory to SARS-CoV-2 in 254 samples from 188 COVID-19 cases, including 43 samples at ≥ 6 months post-infection. IgG to the Spike protein was relatively stable over 6+ months. Spike-specific memory B cells were more abundant at 6 months than at 1 month post symptom onset. SARS-CoV-2-specific CD4+ T cells and CD8+ T cells declined with a half-life of 3-5 months...
January 6, 2021: Science
Andrew C Payne, Zachary D Chiang, Paul L Reginato, Sarah M Mangiameli, Evan M Murray, Chun-Chen Yao, Styliani Markoulaki, Andrew S Earl, Ajay S Labade, Rudolf Jaenisch, George M Church, Edward S Boyden, Jason D Buenrostro, Fei Chen
Understanding genome organization requires integration of DNA sequence and 3D spatial context, however, existing genome-wide methods lack either base-pair sequence resolution or direct spatial localization. Here, we describe in situ genome sequencing (IGS), a method for simultaneously sequencing and imaging genomes within intact biological samples. We applied IGS to human fibroblasts and early mouse embryos, spatially localizing thousands of genomic loci in individual nuclei. Using these data, we characterized parent-specific changes in genome structure across embryonic stages, revealed single-cell chromatin domains in zygotes, and uncovered epigenetic memory of global chromosome positioning within individual embryos...
December 31, 2020: Science
Mads Delbo Larsen, Erik L de Graaf, Myrthe E Sonneveld, H Rosina Plomp, Jan Nouta, Willianne Hoepel, Hung-Jen Chen, Federica Linty, Remco Visser, Maximilian Brinkhaus, Tonći Šuštić, Steven W de Taeye, Arthur E H Bentlage, Suvi Toivonen, Carolien A M Koeleman, Susanna Sainio, Neeltje A Kootstra, Philip J M Brouwer, Chiara Elisabeth Geyer, Ninotska I L Derksen, Gertjan Wolbink, Menno de Winther, Rogier W Sanders, Marit J van Gils, Sanne de Bruin, Alexander P J Vlaar, Theo Rispens, Jeroen den Dunnen, Hans L Zaaijer, Manfred Wuhrer, C Ellen van der Schoot, Gestur Vidarsson
IgG antibodies are crucial for protection against invading pathogens. A highly conserved N-linked glycan within the IgG-Fc tail, essential for IgG function, shows variable composition in humans. Afucosylated IgG variants are already used in anti-cancer therapeutic antibodies for their elevated activity through Fc receptors (FcγRIIIa). Here, we report that afucosylated IgG (~6% of total IgG in humans) are specifically formed against enveloped viruses but generally not against other antigens. This mediates stronger FcγRIIIa responses, but also amplifies brewing cytokine storms and immune-mediated pathologies...
December 23, 2020: Science
Anna Kuchina, Leandra M Brettner, Luana Paleologu, Charles M Roco, Alexander B Rosenberg, Alberto Carignano, Ryan Kibler, Matthew Hirano, R William DePaolo, Georg Seelig
Single-cell RNA-sequencing (scRNA-seq) has become an essential tool for characterizing gene expression in eukaryotes but current methods are incompatible with bacteria. Here, we introduce microSPLiT, a high-throughput scRNA-seq method for gram-negative and gram-positive bacteria that can resolve heterogeneous transcriptional states. We applied microSPLiT to >25,000 Bacillus subtilis cells sampled at different growth stages, creating an atlas of changes in metabolism and lifestyle. We retrieved detailed gene expression profiles associated with known, but rare, states such as competence and prophage induction, and also identified novel and unexpected gene expression states including the heterogeneous activation of a niche metabolic pathway in a subpopulation of cells...
December 17, 2020: Science
B C Kaiser, J C Clemens, S Blouin, P Dufour, R J Hegedus, J S Reding, A Bédard
Tidal disruption and subsequent accretion of planetesimals by white dwarfs can reveal the elemental abundances of rocky bodies in exoplanetary systems. Those abundances provide information on the composition of the nebula from which the systems formed, analogous to how meteorite abundances inform our understanding of the early Solar System. We report the detection of Li, Na, K and Ca in the atmosphere of the white dwarf Gaia DR2 4353607450860305024, which we ascribe to accretion of a planetesimal. Using model atmospheres, we determine abundance ratios of these elements, and with the exception of Li, they are consistent with meteoritic values in the Solar System...
December 17, 2020: Science
M R Raven, R G Keil, S M Webb
Climate change is driving an expansion of marine Oxygen Deficient Zones, which may alter the global cycles of carbon, sulfur, nitrogen, and trace metals. Currently, however, we lack a full mechanistic understanding of how oxygen deficiency affects organic carbon cycling and burial. Here, we show that 'cryptic' microbial sulfate reduction occurs within sinking particles from the Eastern Tropical North Pacific Oxygen Deficient Zone, and that some microbially-produced sulfide reacts rapidly to form organic S that is resistant to acid hydrolysis...
December 17, 2020: Science
Haiyang Yu, Shan Lu, Kelsey Gasior, Digvijay Singh, Sonia Vazquez-Sanchez, Olga Tapia, Divek Toprani, Melinda S Beccari, John R Yates, Sandrine Da Cruz, Jay M Newby, Miguel Lafarga, Amy S Gladfelter, Elizabeth Villa, Don W Cleveland
The RNA-binding protein TDP-43 forms intranuclear or cytoplasmic aggregates in age-related neurodegenerative diseases. Here we found that RNA-binding deficient TDP-43 (produced by neurodegeneration-causing mutations or post-translational acetylation in its RNA recognition motifs) drove TDP-43 de-mixing into intranuclear liquid spherical shells with liquid cores. We named these droplets anisosomes, whose shells exhibited birefringence, evidence of liquid crystal formation. Guided by mathematical modeling, we identified the major components of the liquid core to be HSP70 family chaperones, whose ATP-dependent activity maintained the liquidity of shells and cores...
December 17, 2020: Science
Jan M Brauner, Sören Mindermann, Mrinank Sharma, David Johnston, John Salvatier, Tomáš Gavenčiak, Anna B Stephenson, Gavin Leech, George Altman, Vladimir Mikulik, Alexander John Norman, Joshua Teperowski Monrad, Tamay Besiroglu, Hong Ge, Meghan A Hartwick, Yee Whye Teh, Leonid Chindelevitch, Yarin Gal, Jan Kulveit
Governments are attempting to control the COVID-19 pandemic with nonpharmaceutical interventions (NPIs). However, the effectiveness of different NPIs at reducing transmission is poorly understood. We gathered chronological data on the implementation of NPIs for several European, and other, countries between January and the end of May 2020. We estimate the effectiveness of NPIs, ranging from limiting gathering sizes, business closures, and closure of educational institutions to stay-at-home orders. To do so, we used a Bayesian hierarchical model that links NPI implementation dates to national case and death counts and supported the results with extensive empirical validation...
December 15, 2020: Science
Jacob E Lemieux, Katherine J Siddle, Bennett M Shaw, Christine Loreth, Stephen F Schaffner, Adrianne Gladden-Young, Gordon Adams, Timelia Fink, Christopher H Tomkins-Tinch, Lydia A Krasilnikova, Katherine C DeRuff, Melissa Rudy, Matthew R Bauer, Kim A Lagerborg, Erica Normandin, Sinéad B Chapman, Steven K Reilly, Melis N Anahtar, Aaron E Lin, Amber Carter, Cameron Myhrvold, Molly E Kemball, Sushma Chaluvadi, Caroline Cusick, Katelyn Flowers, Anna Neumann, Felecia Cerrato, Maha Farhat, Damien Slater, Jason B Harris, John A Branda, David Hooper, Jessie M Gaeta, Travis P Baggett, James O'Connell, Andreas Gnirke, Tami D Lieberman, Anthony Philippakis, Meagan Burns, Catherine M Brown, Jeremy Luban, Edward T Ryan, Sarah E Turbett, Regina C LaRocque, William P Hanage, Glen R Gallagher, Lawrence C Madoff, Sandra Smole, Virginia M Pierce, Eric Rosenberg, Pardis C Sabeti, Daniel J Park, Bronwyn L MacInnis
Analysis of 772 complete SARS-CoV-2 genomes from early in the Boston area epidemic revealed numerous introductions of the virus, a small number of which led to most cases. The data revealed two superspreading events. One, in a skilled nursing facility, led to rapid transmission and significant mortality in this vulnerable population but little broader spread, while other introductions into the facility had little effect. The second, at an international business conference, produced sustained community transmission and was exported, resulting in extensive regional, national, and international spread...
December 10, 2020: Science
Erez N Baruch, Ilan Youngster, Guy Ben-Betzalel, Rona Ortenberg, Adi Lahat, Lior Katz, Katerina Adler, Daniela Dick-Necula, Stephen Raskin, Naamah Bloch, Daniil Rotin, Liat Anafi, Camila Avivi, Jenny Melnichenko, Yael Steinberg-Silman, Ronac Mamtani, Hagit Harati, Nethanel Asher, Ronnie Shapira-Frommer, Tal Brosh-Nissimov, Yael Eshet, Shira Ben-Simon, Oren Ziv, Md Abdul Wadud Khan, Moran Amit, Nadim J Ajami, Iris Barshack, Jacob Schachter, Jennifer A Wargo, Omry Koren, Gal Markel, Ben Boursi
The gut microbiome has been shown to influence the response of tumors to anti-PD-1 immunotherapy in pre-clinical mouse models and observational patient cohorts. However, modulation of gut microbiota in cancer patients has not been investigated in clinical trials. Here we performed a phase I clinical trial to assess the safety and feasibility of fecal microbiota transplantation (FMT) and re-induction of anti-PD-1 immunotherapy in ten patients with anti-PD-1-refractory metastatic melanoma. We observed clinical responses in three patients, including two partial responses and one complete response...
December 10, 2020: Science
Christina V Theodoris, Ping Zhou, Lei Liu, Yu Zhang, Tomohiro Nishino, Yu Huang, Aleksandra Kostina, Sanjeev S Ranade, Casey A Gifford, Vladimir Uspenskiy, Anna Malaschicheva, Sheng Ding, Deepak Srivastava
Mapping the gene regulatory networks dysregulated in human disease would allow the design of network-correcting therapies that treat the core disease mechanism. However, small molecules are traditionally screened for their effects on one to several outputs at most, biasing discovery and limiting the likelihood of true disease-modifying drug candidates. Here, we developed a machine learning approach to identify small molecules that broadly correct gene networks dysregulated in a human induced pluripotent stem cell (iPSC) disease model of a common form of heart disease involving the aortic valve...
December 10, 2020: Science
A R Palla, M Ravichandran, Y X Wang, L Alexandrova, A V Yang, P Kraft, C A Holbrook, C M Schürch, A T V Ho, H M Blau
Treatments are lacking for sarcopenia, a debilitating age-related skeletal muscle wasting syndrome. Here we identify elevated 15-PGDH, the Prostaglandin E2 (PGE2)-degrading enzyme, as a hallmark of aged tissues, including skeletal muscle. The resulting reduction in PGE2 signaling is a major contributor to muscle atrophy in aged mice and results from 15-PGDH-expressing myofibers and interstitial cells within muscle. Inhibition of 15-PGDH, by targeted genetic knockdown or a small molecule inhibitor, increases aged muscle mass, strength, and exercise performance...
December 10, 2020: Science
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