Eric J Topol
COVID-19 has a spectrum of potential heart manifestations with diverse mechanisms.
September 23, 2020: Science
Matthew D Snape, Russell M Viner
Children have a low risk of COVID-19 and are disproportionately harmed by precautions.
September 21, 2020: Science
Chadi M Saad-Roy, Caroline E Wagner, Rachel E Baker, Sinead E Morris, Jeremy Farrar, Andrea L Graham, Simon A Levin, Michael J Mina, C Jessica E Metcalf, Bryan T Grenfell
The future trajectory of the Covid-19 pandemic hinges on the dynamics of adaptive immunity against SARS-CoV2; however, salient features of the immune response elicited by natural infection or vaccination are still uncertain. We use simple epidemiological models to explore estimates for the magnitude and timing of future Covid-19 cases given different protective efficacy and duration of the adaptive immune response to SARS-CoV-2, as well as its interaction with vaccines and nonpharmaceutical interventions. We find that variations in the immune response to primary SARS-CoV-2 infections and a potential vaccine can lead to dramatically different immune landscapes and burdens of critically severe cases, ranging from sustained epidemics to near elimination...
September 21, 2020: Science
Christine Toelzer, Kapil Gupta, Sathish K N Yadav, Ufuk Borucu, Andrew D Davidson, Maia Kavanagh Williamson, Deborah K Shoemark, Frederic Garzoni, Oskar Staufer, Rachel Milligan, Julien Capin, Adrian J Mulholland, Joachim Spatz, Daniel Fitzgerald, Imre Berger, Christiane Schaffitzel
COVID-19, caused by severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2), represents a global crisis. Key to SARS-CoV-2 therapeutic development is unraveling the mechanisms driving high infectivity, broad tissue tropism and severe pathology. Our 2.85 Å cryo-EM structure of SARS-CoV-2 spike (S) glycoprotein reveals that the receptor binding domains (RBDs) tightly bind the essential free fatty acid (FFA) linoleic acid (LA) in three composite binding pockets. The pocket also appears to be present in the highly pathogenic coronaviruses SARS-CoV and MERS-CoV...
September 21, 2020: Science
Christi J Guerrini, Jacob S Sherkow, Michelle N Meyer, Patricia J Zettler
DIY COVID-19 vaccines raise legal and ethical questions.
September 17, 2020: Science
Jos R Wendrich, BaoJun Yang, Niels Vandamme, Kevin Verstaen, Wouter Smet, Celien Van de Velde, Max Minne, Brecht Wybouw, Eliana Mor, Helena E Arents, Jonah Nolf, Julie Van Duyse, Gert Van Isterdael, Steven Maere, Yvan Saeys, Bert De Rybel
Optimal plant growth is hampered by deficiency of the essential macronutrient phosphate in most soils. Plant roots can, however, increase their root hair density to efficiently forage the soil for this immobile nutrient. By generating and exploiting a high-resolution single-cell gene expression atlas of Arabidopsis roots, we show an enrichment of TARGET OF MONOPTEROS 5 / LONESOME HIGHWAY (TMO5/LHW) target gene responses in root hair cells. The TMO5/LHW heterodimer triggers biosynthesis of mobile cytokinin in vascular cells and increases root hair density during low phosphate conditions by modifying both the length and cell fate of epidermal cells...
September 17, 2020: Science
H Holden Thorp
No abstract text is available yet for this article.
September 11, 2020: Science
Trevor Bedford, Alexander L Greninger, Pavitra Roychoudhury, Lea M Starita, Michael Famulare, Meei-Li Huang, Arun Nalla, Gregory Pepper, Adam Reinhardt, Hong Xie, Lasata Shrestha, Truong N Nguyen, Amanda Adler, Elisabeth Brandstetter, Shari Cho, Danielle Giroux, Peter D Han, Kairsten Fay, Chris D Frazar, Misja Ilcisin, Kirsten Lacombe, Jover Lee, Anahita Kiavand, Matthew Richardson, Thomas R Sibley, Melissa Truong, Caitlin R Wolf, Deborah A Nickerson, Mark J Rieder, Janet A Englund, James Hadfield, Emma B Hodcroft, John Huddleston, Louise H Moncla, Nicola F Müller, Richard A Neher, Xianding Deng, Wei Gu, Scot Federman, Charles Chiu, Jeff S Duchin, Romesh Gautom, Geoff Melly, Brian Hiatt, Philip Dykema, Scott Lindquist, Krista Queen, Ying Tao, Anna Uehara, Suxiang Tong, Duncan MacCannell, Gregory L Armstrong, Geoffrey S Baird, Helen Y Chu, Jay Shendure, Keith R Jerome
Following its emergence in Wuhan, China, in late November or early December 2019, the SARS-CoV-2 virus has rapidly spread globally. Genome sequencing of SARS-CoV-2 allows reconstruction of its transmission history, although this is contingent on sampling. We have analyzed 453 SARS-CoV-2 genomes collected between 20 February and 15 March 2020 from infected patients in Washington State, USA. We find that most SARS-CoV-2 infections sampled during this time derive from a single introduction in late January or early February 2020 which subsequently spread locally before active community surveillance was implemented...
September 10, 2020: Science
Boyang Yu, Jiangjiang Duan, Hengjiang Cong, Wenke Xie, Rong Liu, Xinyan Zhuang, Hui Wang, Bei Qi, Ming Xu, Zhong Lin Wang, Jun Zhou
Low-grade heat (below 373 K) is abundant and ubiquitous, but mostly wasted due to the lack of cost-effective recovery technologies. The liquid-state thermocell (LTC), an inexpensive and scalable thermoelectric device, may be commercially viable for harvesting low-grade heat energy if its Carnot-relative efficiency (ηr ) reaches ~5%, which is a challenging metric to achieve experimentally. We used a thermosensitive crystallization and dissolution process to induce persistent concentration gradient of redox ions, a highly enhanced Seebeck coefficient (~3...
September 10, 2020: Science
Joshua A Boyer, Cathy J Spangler, Joshua D Strauss, Andrew P Cesmat, Pengda Liu, Robert K McGinty, Qi Zhang
Cyclic GMP-AMP synthase (cGAS) recognizes cytosolic foreign or damaged DNA to activate the innate immune response to infection, inflammatory diseases, and cancer. In contrast, cGAS reactivity against self-DNA in the nucleus is suppressed by chromatin tethering. We report a 3.3-angstrom-resolution cryo-electron microscopy structure of cGAS in complex with the nucleosome core particle. The structure reveals that cGAS employs two conserved arginines to anchor to the nucleosome acidic patch. The nucleosome binding interface exclusively occupies the strong dsDNA binding surface on cGAS and sterically prevents cGAS from oligomerizing into the functionally active 2:2 cGAS-dsDNA state...
September 10, 2020: Science
Tomoya Kujirai, Christian Zierhut, Yoshimasa Takizawa, Ryan Kim, Lumi Negishi, Nobuki Uruma, Seiya Hirai, Hironori Funabiki, Hitoshi Kurumizaka
The cyclic GMP-AMP synthase (cGAS) senses invasion of pathogenic DNA and stimulates inflammatory signaling, autophagy and apoptosis. Organization of host DNA into nucleosomes was proposed to limit cGAS autoinduction, but the underlying mechanism was unknown. Here, we report the structural basis for this inhibition. In the cryo-EM structure of the human cGAS-nucleosome core particle (NCP) complex, two cGAS monomers bridge two NCPs by binding the acidic patch of H2A-H2B and nucleosomal DNA. In this configuration, all three known cGAS DNA-binding sites, required for cGAS activation, are repurposed or become inaccessible, and cGAS dimerization, another prerequisite for activation, is inhibited...
September 10, 2020: Science
Michael Worobey, Jonathan Pekar, Brendan B Larsen, Martha I Nelson, Verity Hill, Jeffrey B Joy, Andrew Rambaut, Marc A Suchard, Joel O Wertheim, Philippe Lemey
Accurate understanding of the global spread of emerging viruses is critically important for public health responses and for anticipating and preventing future outbreaks. Here, we elucidate when, where and how the earliest sustained SARS-CoV-2 transmission networks became established in Europe and North America. Our results suggest that rapid early interventions successfully prevented early introductions of the virus into Germany and the US from taking hold. Other, later introductions of the virus from China to both Italy and to Washington State founded the earliest sustained European and North America transmission networks...
September 10, 2020: Science
Longxing Cao, Inna Goreshnik, Brian Coventry, James Brett Case, Lauren Miller, Lisa Kozodoy, Rita E Chen, Lauren Carter, Alexandra C Walls, Young-Jun Park, Eva-Maria Strauch, Lance Stewart, Michael S Diamond, David Veesler, David Baker
Targeting the interaction between the SARS-CoV-2 Spike protein and the human ACE2 receptor is a promising therapeutic strategy. We designed inhibitors using two de novo design approaches. Computer generated scaffolds were either built around an ACE2 helix that interacts with the Spike receptor binding domain (RBD), or docked against the RBD to identify new binding modes, and their amino acid sequences designed to optimize target binding, folding and stability. Ten designs bound the RBD with affinities ranging from 100pM to 10nM, and blocked ARS-CoV-2 infection of Vero E6 cells with IC 50 values between 24 pM and 35 nM; The most potent, with new binding modes, are 56 and 64 residue proteins (IC 50 ~ 0...
September 9, 2020: Science
Ezekiel J Emanuel, Govind Persad, Adam Kern, Allen Buchanan, Cécile Fabre, Daniel Halliday, Joseph Heath, Lisa Herzog, R J Leland, Ephrem T Lemango, Florencia Luna, Matthew S McCoy, Ole F Norheim, Trygve Ottersen, G Owen Schaefer, Kok-Chor Tan, Christopher Heath Wellman, Jonathan Wolff, Henry S Richardson
The Fair Priority Model offers a practical way to fulfill pledges to distribute vaccine fairly and equitably.
September 3, 2020: Science
Paul A Muller, Fanny Matheis, Marc Schneeberger, Zachary Kerner, Veronica Jové, Daniel Mucida
The gut microbiota affects tissue physiology, metabolism, and function of both the immune and nervous systems. We found that intrinsic enteric-associated neurons (iEAN) in mice are functionally adapted to the intestinal segment they occupy; ileal and colonic neurons are more responsive to microbial colonization than duodenal neurons. Specifically, a microbially-responsive subset of viscerofugal CART+ neurons, enriched in the ileum and colon, modulated feeding and glucose metabolism. These CART+ neurons send axons to the prevertebral ganglia and are poly-synaptically connected to the liver and pancreas...
August 27, 2020: Science
Anna Bruchez, Ky Sha, Joshua Johnson, Li Chen, Caroline Stefani, Hannah McConnell, Lea Gaucherand, Rachel Prins, Kenneth A Matreyek, Adam J Hume, Elke Mühlberger, Emmett V Schmidt, Gene G Olinger, Lynda M Stuart, Adam Lacy-Hulbert
Recent outbreaks of Ebola virus (EBOV) and SARS-CoV-2 have exposed our limited therapeutic options and poor understanding of cellular mechanisms that block viral infections. Using a transposon-mediated gene-activation screen in human cells, we identify that the MHC class II transactivator (CIITA) has antiviral activity against EBOV. CIITA induces resistance by activating expression of the p41 isoform of invariant chain CD74, which inhibits viral entry by blocking cathepsin-mediated processing of the Ebola glycoprotein (EboGP)...
August 27, 2020: Science
Fiachra Humphries, Liraz Shmuel-Galia, Natalia Ketelut-Carneiro, Sheng Li, Bingwei Wang, Venkatesh V Nemmara, Ruth Wilson, Zhaozhao Jiang, Farnaz Khalighinejad, Khaja Muneeruddin, Scott A Shaffer, Ranjan Dutta, Carolina Ionete, Scott Pesiridis, Shuo Yang, Paul R Thompson, Katherine A Fitzgerald
Activated macrophages undergo a metabolic switch to aerobic glycolysis accumulating Krebs cycle intermediates that alter transcription of immune response genes. Here we extend these observations by defining fumarate as an inhibitor of pyroptotic cell death. We found that dimethyl fumarate (DMF) delivered to cells or endogenous fumarate reacts with gasdermin D (GSDMD) at critical cysteine residues to form S-(2-succinyl)-cysteine. GSDMD succination prevents its interaction with caspases, limiting its processing, oligomerization, and capacity to induce cell death...
August 20, 2020: Science
Michael William Webster, Maria Takacs, Chengjin Zhu, Vita Vidmar, Ayesha Eduljee, Mo'men Abdelkareem, Albert Weixlbaumer
Prokaryotic messenger RNAs (mRNAs) are translated as they are transcribed. The pioneering ribosome potentially contacts RNA polymerase (RNAP), forming a supramolecular complex known as the expressome. The basis of expressome assembly and its consequences for transcription and translation are poorly understood. Here we present a series of structures representing uncoupled, coupled and collided expressome states determined by electron cryomicroscopy. A bridge between the ribosome and RNAP can be formed by the transcription factor NusG, stabilizing an otherwise variable interaction interface...
August 20, 2020: Science
Chengyuan Wang, Vadim Molodtsov, Emre Firlar, Jason T Kaelber, Gregor Blaha, Min Su, Richard H Ebright
In bacteria, transcription and translation are coupled processes, in which movement of RNA polymerase (RNAP) synthesizing mRNA is coordinated with movement of the first ribosome translating mRNA. Coupling is modulated by the transcription factors NusG-which is thought to bridge RNAP and ribosome-and NusA. Here, we report cryo-EM structures of Escherichia coli transcription-translation complexes (TTCs) containing different-length mRNA spacers between RNAP and the ribosome active-center P-site. Structures of TTCs containing short spacers show a state incompatible with NusG bridging and NusA binding (TTC-A; previously termed "expressome")...
August 20, 2020: Science
Marc J Lajoie, Scott E Boyken, Alexander I Salter, Jilliane Bruffey, Anusha Rajan, Robert A Langan, Audrey Olshefsky, Vishaka Muhunthan, Matthew J Bick, Mesfin Gewe, Alfredo Quijano-Rubio, JayLee Johnson, Garreck Lenz, Alisha Nguyen, Suzie Pun, Colin E Correnti, Stanley R Riddell, David Baker
Precise cell targeting is challenging because most mammalian cell types lack a single surface marker that distinguishes them from other cells. A solution would be to target cells based on specific combinations of proteins present on their surfaces. We design colocalization-dependent protein switches (Co-LOCKR) that perform AND, OR, and NOT Boolean logic operations. These switches activate through a conformational change only when all conditions are met, generating rapid, transcription-independent responses at single-cell resolution within complex cell populations...
August 20, 2020: Science
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