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Rui Zhou, Guanghui Yang, Xuefei Guo, Qiang Zhou, Jianlin Lei, Yigong Shi
Cleavage of amyloid precursor protein (APP) by the intramembrane protease γ-secretase is linked to Alzheimer's disease. We report an atomic structure of human γ-secretase in complex with a transmembrane APP fragment at 2.6-Å resolution. The transmembrane helix (TM) of APP closely interacts with five surrounding TMs of PS1 (the catalytic subunit of γ-secretase). A hybrid β-sheet, which is formed by a β-strand from APP and two β-strands from PS1, guides γ-secretase to the scissile peptide bond of APP between its TM and β-strand...
January 10, 2019: Science
Dheeraj R Pasham, Ronald A Remillard, P Chris Fragile, Alessia Franchini, Nicholas C Stone, Giuseppe Lodato, Jeroen Homan, Deepto Chakrabarty, Frederick K Baganoff, James F Steiner, Eric R Coughlin, Nishanth R Pasham
The tidal forces close to massive black holes can rip apart stars that come too close to them. As the resulting stellar debris spirals toward the black hole, it heats up and emits x-rays. We report observations of a stable 131-s x-ray quasi-periodic oscillation from the tidal disruption event ASASSN-14li. Assuming the black hole mass indicated by host galaxy scaling relations, this implies that (i) the periodicity originates from close to the event horizon, and (ii) the black hole is rapidly spinning. Our findings demonstrate that tidal disruption events can generate quasi-periodic oscillations which encode information about the physical properties of their black holes...
January 9, 2019: Science
Dario Nicetto, Greg Donahue, Tanya Jain, Tao Peng, Simone Sidoli, Lihong Sheng, Thomas Montavon, Justin S Becker, Jessica M Grindheim, Kimberly Blahnik, Benjamin A Garcia, Kai Tan, Roberto Bonasio, Thomas Jenuwein, Kenneth S Zaret
Gene silencing by chromatin compaction is integral to establishing and maintaining cell fates. H3K9me3-marked heterochromatin is reduced in embryonic stem cells compared to differentiated cells. However, the establishment and dynamics of closed regions of chromatin at protein coding genes, in embryologic development, remain elusive. We developed an antibody-independent method to isolate and map compacted heterochromatin from low cell number samples. We discovered high levels of compacted heterochromatin, H3K9me3-decorated, at protein coding genes in early, uncommitted cells at the germ layer stage, undergoing profound rearrangements and reduction upon differentiation, concomitant with cell type-specific gene expression...
January 3, 2019: Science
Talar Tokatlian, Benjamin J Read, Christopher A Jones, Daniel W Kulp, Sergey Menis, Jason Y H Chang, Jon M Steichen, Sudha Kumari, Joel D Allen, Eric L Dane, Alessia Liguori, Maya Sangesland, Daniel Lingwood, Max Crispin, William R Schief, Darrell J Irvine
In vaccine design, arraying antigens in a multivalent nanoparticle form is often employed, but in vivo mechanisms underlying the enhanced immunity elicited by such vaccines remain poorly understood. Here we compared the fate of two different heavily glycosylated HIV antigens, a gp120-derived mini-protein and a large, stabilized envelope trimer, in protein nanoparticle or "free" forms following primary immunization. Unlike monomeric antigens, nanoparticles were rapidly shuttled to the follicular dendritic cell (FDC) network and then concentrated in germinal centers in a complement-, mannose-binding lectin (MBL)-, and immunogen glycan-dependent manner...
December 20, 2018: Science
Jan M Schuller, James A Birrell, Hideaki Tanaka, Tsuyoshi Konuma, Hannes Wulfhorst, Nicholas Cox, Sandra K Schuller, Jacqueline Thiemann, Wolfgang Lubitz, Pierre Sétif, Takahisa Ikegami, Benjamin D Engel, Genji Kurisu, Marc M Nowaczyk
Photosynthetic complex I enables cyclic electron flow around photosystem I, a regulatory mechanism for photosynthetic energy conversion. We report a 3.3-Å resolution cryo-EM structure of photosynthetic complex I from the cyanobacterium Thermosynechococcus elongatus. The model reveals structural adaptations that facilitate binding and electron transfer from the photosynthetic electron carrier ferredoxin. By mimicking cyclic electron flow with isolated components in vitro, we demonstrate that ferredoxin directly mediates electron transfer between photosystem I and complex I, instead of using intermediates such as NADPH...
December 20, 2018: Science
Eric R Welin, Aurapat Ngamnithiporn, Max Klatte, Guillaume Lapointe, Gerit M Pototschnig, Martina S J McDermott, Dylan Conklin, Christopher D Gilmore, Pamela M Tadross, Christopher K Haley, Kenji Negoro, Emil Glibstrup, Christian U Grünanger, Kevin M Allan, Scott C Virgil, Dennis J Slamon, Brian M Stoltz
The bis-tetrahydroisoquinoline (bis-THIQ) natural products have been studied intensively over the past four decades for their exceptionally potent anticancer activity, in addition to strong gram-positive and -negative antibiotic character. Synthetic strategies toward these complex polycyclic compounds have relied heavily on electrophilic aromatic chemistry, such as the Pictet-Spengler reaction, that mimics their biosynthetic pathways. Herein we report an approach to two bis-THIQ natural products, jorunnamycin A and jorumycin, that instead harnesses the power of modern transition-metal catalysis for the three major bond-forming events and proceeds with high efficiency (15 and 16 steps, respectively)...
December 20, 2018: Science
Navneet Matharu, Sawitree Rattanasopha, Serena Tamura, Lenka Maliskova, Yi Wang, Adelaide Bernard, Aaron Hardin, Walter L Eckalbar, Christian Vaisse, Nadav Ahituv
A wide-range of human diseases result from haploinsufficiency, where the function of one of the two gene copies is lost. Here, we targeted the remaining functional copy of a haploinsufficient gene using CRISPR-mediated activation (CRISPRa) in Sim1 and Mc4r heterozygous mouse models to rescue their obesity phenotype. Transgenic-based CRISPRa targeting of the Sim1 promoter or its distant hypothalamic enhancer upregulated its expression from the endogenous functional allele in a tissue-specific manner, rescuing the obesity phenotype in Sim1 heterozygous mice...
December 13, 2018: Science
Li Chen, Jascha A Lau, Dirk Schwarzer, Jörg Meyer, Varun B Verma, Alec M Wodtke
Using a mid-infrared emission spectrometer based on a superconducting nanowire single-photon detector (SNSPD), we observe the dynamics of vibrational energy pooling of CO adsorbed at the surface of a NaCl crystal. After exciting a majority of the CO molecules to their first vibrationally excited state (v = 1), we observe infrared emission from states up to v = 27. Kinetic Monte Carlo simulations show that vibrational energy collects in a few CO molecules at the expense of those up to eight lattice sites away by selective excitation of NaCl's transverse phonons...
December 13, 2018: Science
Samuel Itskanov, Eunyong Park
The Sec61 protein-conducting channel mediates transport of many proteins, such as secretory proteins, across the endoplasmic reticulum (ER) membrane during or after translation. Posttranslational transport is enabled by two additional membrane proteins associated with the channel, Sec63 and Sec62, but its mechanism is poorly understood. We determined a structure of the Sec complex (Sec61-Sec63-Sec71-Sec72) from Saccharomyces cerevisiae by cryo-electron microscopy (cryo-EM). The structure shows that Sec63 tightly associates with Sec61 though interactions in cytosolic, transmembrane, and ER-luminal domains, prying open Sec61's lateral gate and translocation pore and thus activating the channel for substrate engagement...
December 13, 2018: Science
Ankit Awasthi, Binu Ramachandran, Saheeb Ahmed, Eva Benito, Yo Shinoda, Noam Nitzan, Alina Heukamp, Sabine Rannio, Henrik Martens, Jonas Barth, Katja Burk, Yu Tian Wang, Andre Fischer, Camin Dean
Forgetting is important. Without it, the relative importance of acquired memories in a changing environment is lost. We discovered that Synaptotagmin-3 (Syt3) localizes to post-synaptic endocytic zones and removes AMPA receptors from synaptic plasma membranes in response to stimulation. AMPA receptor internalization, long-term-depression (LTD), and decay of long-term-potentiation (LTP) of synaptic strength required calcium-sensing by Syt3, and were abolished by Syt3 knockout. In spatial memory tasks Syt3 knockout mice learned normally, but exhibited a lack of forgetting...
December 13, 2018: Science
Philip B Duffy, Christopher B Field, Noah S Diffenbaugh, Scott C Doney, Zoe Dutton, Sherri Goodman, Lisa Heinzerling, Solomon Hsiang, David B Lobell, Loretta J Mickley, Samuel Myers, Susan M Natali, Camille Parmesan, Susan Tierney, A Park Williams
We assess scientific evidence that has emerged since the U.S. Environmental Protection Agency's 2009 Endangerment Finding for six well-mixed greenhouse gases, and find that this new evidence lends increased support to the conclusion that these gases pose a danger to public health and welfare. Newly available evidence about a wide range of observed and projected impacts strengthens the association between risk of some of these impacts and anthropogenic climate change; indicates that some impacts or combinations of impacts have the potential to be more severe than previously understood; and identifies substantial risk of additional impacts through processes and pathways not considered in the endangerment finding...
December 13, 2018: Science
C A Neal, S R Brantley, L Antolik, J Babb, M Burgess, K Calles, M Cappos, J C Chang, S Conway, L Desmither, P Dotray, T Elias, P Fukunaga, S Fuke, I A Johanson, K Kamibayashi, J Kauahikaua, R L Lee, S Pekalib, A Miklius, W Million, C J Moniz, P A Nadeau, P Okubo, C Parcheta, M P Patrick, B Shiro, D A Swanson, W Tollett, F Trusdell, E F Younger, M H Zoeller, E K Montgomery-Brown, K R Anderson, M P Poland, J Ball, J Bard, M Coombs, H R Dietterich, C Kern, W A Thelen, P F Cervelli, T Orr, B F Houghton, C Gansecki, R Hazlett, P Lundgren, A K Diefenbach, A H Lerner, G Waite, P Kelly, L Clor, C Werner, K Mulliken, G Fisher
In 2018, Kīlauea Volcano experienced its largest lower East Rift Zone (LERZ) eruption and caldera collapse in at least 200 years. After collapse of the Pu'u 'Ō'ō vent on 30 April, magma propagated downrift. Eruptive fissures opened in the LERZ on 3 May, eventually extending ~6.8 km. A 4 May earthquake (M6.9) produced ~5 m of fault slip. Lava erupted at rates exceeding 100 m3 /s, eventually covering 35.5 km2 The summit magma system partially drained, producing minor explosions and near-daily collapses releasing energy equivalent to M4...
December 11, 2018: Science
Lisa Nortmann, Enric Pallé, Michael Salz, Jorge Sanz-Forcada, Evangelos Nagel, F Javier Alonso-Floriano, Stefan Czesla, Fei Yan, Guo Chen, Ignas A G Snellen, Mathias Zechmeister, Jürgen H M M Schmitt, Manuel López-Puertas, Núria Casasayas-Barris, Florian F Bauer, Pedro J Amado, José A Caballero, Stefan Dreizler, Thomas Henning, Manuel Lampón, David Montes, Karan Molaverdikhani, Andreas Quirrenbach, Ansgar Reiners, Ignasi Ribas, Alejandro Sánchez-López, P Christian Schneider, María R Zapatero Osorio
Hot gas giant exoplanets can lose part of their atmosphere due to strong stellar irradiation, affecting their physical and chemical evolution. Studies of atmospheric escape from exoplanets have mostly relied on space-based observations of the hydrogen Lyman-α line in the far ultraviolet which is strongly affected by interstellar absorption. Using ground-based high-resolution spectroscopy we detect excess absorption in the helium triplet at 1083 nm during the transit of the Saturn-mass exoplanet WASP-69b, at a signal-to-noise ratio of 18...
December 6, 2018: Science
Matthew A Nichols, Lawrence W Cheuk, Melih Okan, Thomas R Hartke, Enrique Mendez, T Senthil, Ehsan Khatami, Hao Zhang, Martin W Zwierlein
Strongly correlated materials are expected to feature unconventional transport properties, where charge, spin, and heat conduction are potentially independent probes of the dynamics. In contrast to charge transport, the measurement of spin transport in such materials is highly challenging. Here we observe spin conduction and diffusion in a system of ultracold fermionic atoms that realizes the half-filled Fermi-Hubbard model. For strong interactions, spin diffusion is driven by super-exchange and doublon-hole-assisted tunneling, and strongly violates the quantum limit of charge diffusion...
December 6, 2018: Science
Peter T Brown, Debayan Mitra, Elmer Guardado-Sanchez, Reza Nourafkan, Alexis Reymbaut, Charles-David Hébert, Simon Bergeron, A-M S Tremblay, Jure Kokalj, David A Huse, Peter Schauß, Waseem S Bakr
Strong interactions in many-body quantum systems complicate the interpretation of charge transport in such materials. To shed light on this problem, we study transport in a clean quantum system: ultracold 6 Li in a two-dimensional (2D) optical lattice, a testing ground for strong interaction physics in the Fermi-Hubbard model. We determine the diffusion constant by measuring the relaxation of an imposed density modulation and modeling its decay hydrodynamically. The diffusion constant is converted to a resistivity using the Nernst-Einstein relation...
December 6, 2018: Science
Winston X Yan, Pratyusha Hunnewell, Lauren E Alfonse, Jason M Carte, Elise Keston-Smith, Shanmugapriya Sothiselvam, Anthony J Garrity, Shaorong Chong, Kira S Makarova, Eugene V Koonin, David R Cheng, David A Scott
Type V CRISPR-Cas systems are distinguished by a single RNA-guided RuvC domain-containing effector, Cas12. Although effectors of subtypes V-A (Cas12a) and V-B (Cas12b) have been studied in detail, the distinct domain architectures and diverged RuvC sequences of uncharacterized Cas12 proteins suggest unexplored functional diversity. Here, we identify and characterize Cas12c, g, h, and i. Cas12c, h, and i demonstrate RNA-guided double-stranded (ds) DNA interference activity. Cas12i exhibits markedly different efficiencies of crRNA spacer complementary and non-complementary strand cleavage resulting in predominant dsDNA nicking...
December 6, 2018: Science
Oliver J Harrison, Jonathan L Linehan, Han-Yu Shih, Nicolas Bouladoux, Seong-Ji Han, Margery Smelkinson, Shurjo K Sen, Allyson L Byrd, Michel Enamorado, Chen Yao, Samira Tamoutounour, Francois Van Laethem, Charlotte Hurabielle, Nicholas Collins, Andrea Paun, Rosalba Salcedo, John J O'Shea, Yasmine Belkaid
Barrier tissues are primary targets of environmental stressors and home to the largest number of antigen-experienced lymphocytes in the body, including commensal-specific T cells. Here, we show that skin-resident commensal-specific T cells harbor a paradoxical program characterized by a type-17 program associated with a poised type-2 state. Thus, in the context of injury and exposure to inflammatory mediators such as IL-18, these cells rapidly release type-2 cytokines, thereby acquiring contextual functions...
December 6, 2018: Science
Kasper Skov Kjær, Nidhi Kaul, Om Prakash, Pavel Chábera, Nils W Rosemann, Alireza Honarfar, Olga Gordivska, Lisa A Fredin, Karl-Erik Bergquist, Lennart Häggström, Tore Ericsson, Linnea Lindh, Arkady Yartsev, Stenbjörn Styring, Ping Huang, Jens Uhlig, Jesper Bendix, Daniel Strand, Villy Sundström, Petter Persson, Reiner Lomoth, Kenneth Wärnmark
Iron's abundance and rich coordination chemistry are potentially appealing features for photochemical applications. However, the photoexcitable charge-transfer (CT) states of most Fe complexes are limited by picosecond or sub-picosecond deactivation through low-lying metal centered (MC) states, resulting in inefficient electron transfer reactivity and complete lack of photoluminescence. Here we show that octahedral coordination of Fe(III) by two mono-anionic facial tris -carbene ligands can suppress such deactivation dramatically...
November 29, 2018: Science
Sebastian Steiner, Jakob Wolf, Stefan Glatzel, Anna Andreou, Jarosław M Granda, Graham Keenan, Trevor Hinkley, Gerardo Aragon-Camarasa, Philip J Kitson, Davide Angelone, Leroy Cronin
The synthesis of complex organic compounds is largely a manual process that is often incompletely documented. To address these shortcomings, we developed an abstraction that maps commonly reported methodological instructions into discrete steps amenable to automation. These unit operations were implemented in a modular robotic platform using a chemical programming language which formalizes and controls the assembly of the molecules. We validated the concept by directing the automated system to synthesize three pharmaceutical compounds, Nytol, rufinamide, and sildenafil, without any human intervention...
November 29, 2018: Science
Longfei Wang, Tian-Min Fu, Yiming Zhou, Shiyu Xia, Anna Greka, Hao Wu
Transient receptor potential (TRP) melastatin 2 (TRPM2) is a cation channel associated with numerous diseases. It has a C-terminal NUDT9 homology (NUDT9H) domain responsible for binding ADP-ribose (ADPR), and both ADPR and Ca2+ are required for TRPM2 activation. Here we report cryo-EM structures of human TRPM2, alone, with ADPR, and with ADPR and Ca2+ NUDT9H forms both intra- and inter-subunit interactions with the N-terminal TRPM homology region (MHR1/2/3) in the apo state, but undergoes conformational changes upon ADPR binding, resulting in rotation of MHR1/2 and disruption of the inter-subunit interaction...
November 22, 2018: Science
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