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Max E Wilkinson, Sebastian M Fica, Wojciech P Galej, Christine M Norman, Andrew J Newman, Kiyoshi Nagai
Introns are removed from eukaryotic mRNA precursors by the spliceosome in two transesterification reactions-branching and exon ligation. The mechanism of 3'-splice site recognition during exon ligation has remained unclear. Here we present the 3.7Å cryo-EM structure of the yeast P complex spliceosome immediately after exon ligation. The 3'-splice site AG dinucleotide is recognized through non-Watson-Crick pairing with the 5'-splice site and the branch point adenosine. After the branching reaction protein factors work together to remodel the spliceosome and stabilize a conformation competent for 3'-splice site docking, thereby promoting exon ligation...
November 16, 2017: Science
Shiheng Liu, Xueni Li, Lingdi Zhang, Jiansen Jiang, Ryan C Hill, Yanxiang Cui, Kirk C Hansen, Z Hong Zhou, Rui Zhao
The spliceosome undergoes dramatic changes in a splicing cycle. Structures of B, B(act), C, C*, and ILS complexes revealed mechanisms of 5' splice site (ss) recognition, branching, and intron release, but lacked information on 3' ss recognition, exon ligation and release. Here, we report a cryoEM structure of the postcatalytic P complex at 3.3Å resolution, revealing that 3' ss is mainly recognized through non-Watson-Crick basepairing with the 5' ss and branch point. Furthermore, an unidentified protein becomes stably associated with the P complex, securing the 3' exon and potentially regulating Prp22 activity...
November 16, 2017: Science
Joppe Nieuwenhuis, Athanassios Adamopoulos, Onno B Bleijerveld, Abdelghani Mazouzi, Elmer Stickel, Patrick Celie, Maarten Altelaar, Puck Knipscheer, Anastassis Perrakis, Vincent A Blomen, Thijn R Brummelkamp
Tubulin is subjected to a number of posttranslational modifications to generate heterogeneous microtubules. The modifications include removal and ligation of the carboxy-terminal tyrosine of ⍺-tubulin. Whereas enzymes for most modifications have been assigned, the enzymes responsible for detyrosination, an activity observed forty years ago, have remained elusive. We applied a haploid genetic screen to find regulators of tubulin detyrosination. We identified SVBP, a peptide that regulates the abundance of Vasohibins (VASH1 and VASH2)...
November 16, 2017: Science
Chrystelle Aillaud, Christophe Bosc, Leticia Peris, Anouk Bosson, Pierre Heemeryck, Juliette Van Dijk, Julien Le Friec, Benoit Boulan, Frédérique Vossier, Laura E Sanman, Salahuddin Syed, Neri Amara, Yohann Couté, Laurence Lafanechère, Eric Denarier, Christian Delphin, Laurent Pelletier, Sandrine Humbert, Matthew Bogyo, Annie Andrieux, Krzysztof Rogowski, Marie-Jo Moutin
Reversible detyrosination of α-tubulin is crucial to microtubule dynamics and functions and defects have been implicated in cancer, brain disorganization, and cardiomyopathies. The identity of the tubulin tyrosine carboxypeptidase (TCP) responsible for detyrosination has remained unclear. We used chemical proteomics with a potent unique irreversible inhibitor to show that the major brain TCP is a complex of vasohibin-1 (VASH1) with the Small Vasohibin Binding Protein (SVBP). VASH1 and its homolog VASH2, when complexed with SVBP, exhibited robust and specific Tyr/Phe carboxypeptidase activity on microtubules...
November 16, 2017: Science
Yi Hou, Xiaoyan Du, Simon Scheiner, David P McMeekin, Zhiping Wang, Ning Li, Manuela S Killian, Haiwei Chen, Moses Richter, Ievgen Levchuk, Nadine Schrenker, Erdmann Spiecker, Tobias Stubhan, Norman A Luechinger, Andreas Hirsch, Patrik Schmuki, Hans-Peter Steinrück, Rainer H Fink, Marcus Halik, Henry J Snaith, Christoph J Brabec
A major bottleneck delaying the further commercialization of thin-film solar cells based on hybrid organohalide lead perovskites is the interface losses in state-of-the-art devices. We present a generic interface architecture that combines solution-processed, reliable, and cost-efficient hole-transporting materials, without compromising efficiency, stability or scalability of perovskite solar cells. Tantalum doped tungsten oxide (Ta-WO x )/conjugated polymer multilayers offer a surprisingly small interface barrier and form quasi-ohmic contacts universally with various scalable conjugated polymers...
November 9, 2017: Science
Feng Rao, Keyuan Ding, Yuxing Zhou, Yonghui Zheng, Mengjiao Xia, Shilong Lv, Zhitang Song, Songlin Feng, Ider Ronneberger, Riccardo Mazzarello, Wei Zhang, Evan Ma
Operation speed is a key challenge in phase-change random-access memory (PCRAM) technology, especially for achieving subnanosecond high-speed cache-memory. Commercialized PCRAM products are limited by the tens of nanoseconds writing speed, originating from the stochastic crystal nucleation during the crystallization of amorphous Ge2Sb2Te5 Here, we demonstrate an alloying strategy to speed up the crystallization kinetics. The Sc0.2Sb2Te3 compound we designed allows a writing speed of only 700 picoseconds without preprogramming in a large conventional PCRAM device...
November 9, 2017: Science
Yong Yao Loh, Kazunori Nagao, Andrew J Hoover, David Hesk, Nelo R Rivera, Steven L Colletti, Ian W Davies, David W C MacMillan
Deuterium- and tritium-labeled pharmaceutical compounds are pivotal diagnostic tools in pharmaceutical drug discovery research, providing vital information about the biological fate of drugs and drug metabolites. Herein, we demonstrate that a photoredox-mediated hydrogen atom transfer (HAT) protocol can efficiently and selectively install deuterium and tritium at α-amino sp(3) C-H bonds in a single step, using isotopically labeled water (D2O or T2O) as the source of hydrogen isotope. In this context, we also report a convenient synthesis of T2O from T2, providing access to high specific activity T2O...
November 9, 2017: Science
Bertrand Routy, Emmanuelle Le Chatelier, Lisa Derosa, Connie P M Duong, Maryam Tidjani Alou, Romain Daillère, Aurélie Fluckiger, Meriem Messaoudene, Conrad Rauber, Maria P Roberti, Marine Fidelle, Caroline Flament, Vichnou Poirier-Colame, Paule Opolon, Christophe Klein, Kristina Iribarren, Laura Mondragón, Nicolas Jacquelot, Bo Qu, Gladys Ferrere, Céline Clémenson, Laura Mezquita, Jordi Remon Masip, Charles Naltet, Solenn Brosseau, Coureche Kaderbhai, Corentin Richard, Hira Rizvi, Florence Levenez, Nathalie Galleron, Benoit Quinquis, Nicolas Pons, Bernhard Ryffel, Véronique Minard-Colin, Patrick Gonin, Jean-Charles Soria, Eric Deutsch, Yohann Loriot, François Ghiringhelli, Gérard Zalcman, François Goldwasser, Bernard Escudier, Matthew D Hellmann, Alexander Eggermont, Didier Raoult, Laurence Albiges, Guido Kroemer, Laurence Zitvogel
Immune checkpoint inhibitors (ICI) targeting the PD-1/PD-L1 axis induce sustained clinical responses in a sizeable minority of cancer patients. Here, we show that primary resistance to ICI can be due to abnormal gut microbiome composition. Antibiotics (ATB) inhibited the clinical benefit of ICI in patients with advanced cancer. Fecal microbiota transplantation (FMT) from cancer patients who responded to ICI (but not from non-responding patients) into germ-free or ATB-treated mice ameliorated the antitumor effects of PD-1 blockade...
November 2, 2017: Science
V Gopalakrishnan, C N Spencer, L Nezi, A Reuben, M C Andrews, T V Karpinets, P A Prieto, D Vicente, K Hoffman, S C Wei, A P Cogdill, L Zhao, C W Hudgens, D S Hutchinson, T Manzo, M Petaccia de Macedo, T Cotechini, T Kumar, W S Chen, S M Reddy, R Szczepaniak Sloane, J Galloway-Pena, H Jiang, P L Chen, E J Shpall, K Rezvani, A M Alousi, R F Chemaly, S Shelburne, L M Vence, P C Okhuysen, V B Jensen, A G Swennes, F McAllister, E Marcelo Riquelme Sanchez, Y Zhang, E Le Chatelier, L Zitvogel, N Pons, J L Austin-Breneman, L E Haydu, E M Burton, J M Gardner, E Sirmans, J Hu, A J Lazar, T Tsujikawa, A Diab, H Tawbi, I C Glitza, W J Hwu, S P Patel, S E Woodman, R N Amaria, M A Davies, J E Gershenwald, P Hwu, J E Lee, J Zhang, L M Coussens, Z A Cooper, P A Futreal, C R Daniel, N J Ajami, J F Petrosino, M T Tetzlaff, P Sharma, J P Allison, R R Jenq, J A Wargo
Pre-clinical mouse models suggest that the gut microbiome modulates tumor response to checkpoint blockade immunotherapy; however, this has not been well-characterized in human cancer patients. Here we examined the oral and gut microbiome of melanoma patients undergoing anti-PD-1 immunotherapy (n=112). Significant differences were observed in the diversity and composition of the patient gut microbiome of responders (R) versus non-responders (NR). Analysis of patient fecal microbiome samples (n=43, 30R, 13NR) showed significantly higher alpha diversity (p<0...
November 2, 2017: Science
Ana Casañal, Ananthanarayanan Kumar, Chris H Hill, Ashley D Easter, Paul Emsley, Gianluca Degliesposti, Yuliya Gordiyenko, Balaji Santhanam, Jana Wolf, Katrin Wiederhold, Gillian L Dornan, Mark Skehel, Carol V Robinson, Lori A Passmore
Newly transcribed eukaryotic pre-mRNAs are processed at their 3'-ends by the ~1 MDa multiprotein cleavage and polyadenylation factor (CPF). CPF cleaves pre-mRNAs, adds a poly(A) tail and triggers transcription termination but it is unclear how its different enzymes are coordinated and assembled. Here, we show that the nuclease, polymerase and phosphatase activities of yeast CPF are organized into three modules. Using cryo-EM, we determine a 3.5 Å resolution structure of the ~200 kDa polymerase module. This reveals four beta propellers in an assembly strikingly similar to other protein complexes that bind nucleic acid...
October 26, 2017: Science
D George, W Lehrach, K Kansky, M Lázaro-Gredilla, C Laan, B Marthi, X Lou, Z Meng, Y Liu, H Wang, A Lavin, D S Phoenix
Learning from few examples and generalizing to dramatically different situations are capabilities of human visual intelligence that are yet to be matched by leading machine learning models. By drawing inspiration from systems neuroscience, we introduce a probabilistic generative model for vision in which message-passing based inference handles recognition, segmentation and reasoning in a unified way. The model demonstrates excellent generalization and occlusion-reasoning capabilities, and outperforms deep neural networks on a challenging scene text recognition benchmark while being 300-fold more data efficient...
October 26, 2017: Science
Pin Wang, Junfang Xu, Yujia Wang, Xuetao Cao
Viruses regulate host metabolic networks to improve their survival. Hardly known are molecules responsive to viral infection that regulate such metabolic changes, which is essential for understanding viral infection. Here we identify a lncRNA induced by multiple viruses, but not by type I interferon (IFN-I), that facilitates viral replication in mouse and human cells. In vivo deficiency of lncRNA-ACOD1 significantly attenuates viral infection through IFN-I/IRF3-independent pathways. Cytoplasmic lncRNA-ACOD1 directly binds the metabolic enzyme glutamic-oxaloacetic transaminase (GOT2) near the substrate niche, enhancing its catalytic activity...
October 26, 2017: Science
David B T Cox, Jonathan S Gootenberg, Omar O Abudayyeh, Brian Franklin, Max J Kellner, Julia Joung, Feng Zhang
Nucleic acid editing holds promise for treating genetic disease, particularly at the RNA level, where disease-relevant sequences can be rescued to yield functional protein products. Type VI CRISPR-Cas systems contain the programmable single-effector RNA-guided RNases Cas13. Here, we profile Type VI systems to engineer a Cas13 ortholog capable of robust knockdown and demonstrate RNA editing by using catalytically-inactive Cas13 (dCas13) to direct adenosine to inosine deaminase activity by ADAR2 to transcripts in mammalian cells...
October 25, 2017: Science
M R Drout, A L Piro, B J Shappee, C D Kilpatrick, J D Simon, C Contreras, D A Coulter, R J Foley, M R Siebert, N Morrell, K Boutsia, F Di Mille, T W-S Holoien, D Kasen, J A Kollmeier, B F Madore, A J Monson, A Murguia-Berthier, Y-C Pan, J X Prochaska, E Ramirez-Ruiz, A Rest, C Adams, K Alatalo, E Bañados, J Baughman, T C Beers, R A Bernstein, T Bitsakis, A Campillay, T T Hansen, C R Higgs, A P Ji, G Maravelias, J L Marshall, C Moni Bidin, J L Prieto, K C Rasmussen, C Rojas-Bravo, A L Strom, N Ulloa, J Vargas-González, Z Wan, D D Whitten
On 17 August 2017, gravitational waves were detected from a binary neutron star merger, GW170817, along with a coincident short gamma-ray burst, GRB170817A. An optical transient source, Swope Supernova Survey 17a (SSS17a), was subsequently identified as the counterpart of this event. We present ultraviolet, optical, and infrared light curves of SSS17a extending from 10.9 hours to 18 days post-merger. We constrain the radioactively powered transient resulting from the ejection of neutron-rich material. The fast rise of the light curves, subsequent decay, and rapid color evolution are consistent with multiple ejecta components of differing lanthanide abundance...
October 16, 2017: Science
B J Shappee, J D Simon, M R Drout, A L Piro, N Morrell, J L Prieto, D Kasen, T W-S Holoien, J A Kollmeier, D D Kelson, D A Coulter, R J Foley, C D Kilpatrick, M R Siebert, B F Madore, A Murguia-Berthier, Y-C Pan, J X Prochaska, E Ramirez-Ruiz, A Rest, C Adams, K Alatalo, E Bañados, J Baughman, R A Bernstein, T Bitsakis, K Boutsia, J R Bravo, F Di Mille, C R Higgs, A P Ji, G Maravelias, J L Marshall, V M Placco, G Prieto, Z Wan
On 17 August 2017, Swope Supernova Survey 2017a (SSS17a) was discovered as the optical counterpart of the binary neutron star gravitational wave event GW170817. We report time-series spectroscopy of SSS17a from 11.75 hours until 8.5 days after merger. Over the first hour of observations the ejecta rapidly expanded and cooled. Applying blackbody fits to the spectra, we measure the photosphere cooling from [Formula: see text] K to [Formula: see text] K, and determine a photospheric velocity of roughly 30% of the speed of light...
October 16, 2017: Science
M M Kasliwal, E Nakar, L P Singer, D L Kaplan, D O Cook, A Van Sistine, R M Lau, C Fremling, O Gottlieb, J E Jencson, S M Adams, U Feindt, K Hotokezaka, S Ghosh, D A Perley, P-C Yu, T Piran, J R Allison, G C Anupama, A Balasubramanian, K W Bannister, J Bally, J Barnes, S Barway, E Bellm, V Bhalerao, D Bhattacharya, N Blagorodnova, J S Bloom, P R Brady, C Cannella, D Chatterjee, S B Cenko, B E Cobb, C Copperwheat, A Corsi, K De, D Dobie, S W K Emery, P A Evans, O D Fox, D A Frail, C Frohmaier, A Goobar, G Hallinan, F Harrison, G Helou, T Hinderer, A Y Q Ho, A Horesh, W-H Ip, R Itoh, D Kasen, H Kim, N P M Kuin, T Kupfer, C Lynch, K Madsen, P A Mazzali, A A Miller, K Mooley, T Murphy, C-C Ngeow, D Nichols, S Nissanke, P Nugent, E O Ofek, H Qi, R M Quimby, S Rosswog, F Rusu, E M Sadler, P Schmidt, J Sollerman, I Steele, A R Williamson, Y Xu, L Yan, Y Yatsu, C Zhang, W Zhao
Merging neutron stars offer an exquisite laboratory for simultaneously studying strong-field gravity and matter in extreme environments. We establish the physical association of an electromagnetic counterpart (EM170817) to gravitational waves (GW170817) detected from merging neutron stars. By synthesizing a panchromatic dataset, we demonstrate that merging neutron stars are a long-sought production site forging heavy elements by r-process nucleosynthesis. The weak gamma-rays seen in EM170817 are dissimilar to classical short gamma-ray bursts with ultra-relativistic jets...
October 16, 2017: Science
G Hallinan, A Corsi, K P Mooley, K Hotokezaka, E Nakar, M M Kasliwal, D L Kaplan, D A Frail, S T Myers, T Murphy, K De, D Dobie, J R Allison, K W Bannister, V Bhalerao, P Chandra, T E Clarke, S Giacintucci, A Y Q Ho, A Horesh, N E Kassim, S R Kulkarni, E Lenc, F J Lockman, C Lynch, D Nichols, S Nissanke, N Palliyaguru, W M Peters, T Piran, J Rana, E M Sadler, L P Singer
Gravitational waves have been detected from a binary neutron star merger event, GW170817. The detection of electromagnetic radiation from the same source has shown that the merger occurred in the outskirts of the galaxy NGC 4993, at a distance of 40 megaparsecs from Earth. We report the detection of a counterpart radio source that appears 16 days after the event, allowing us to diagnose the energetics and environment of the merger. The observed radio emission can be explained by either a collimated ultra-relativistic jet viewed off-axis, or a cocoon of mildly relativistic ejecta...
October 16, 2017: Science
P A Evans, S B Cenko, J A Kennea, S W K Emery, N P M Kuin, O Korobkin, R T Wollaeger, C L Fryer, K K Madsen, F A Harrison, Y Xu, E Nakar, K Hotokezaka, A Lien, S Campana, S R Oates, E Troja, A A Breeveld, F E Marshall, S D Barthelmy, A P Beardmore, D N Burrows, G Cusumano, A D'Aì, P D'Avanzo, V D'Elia, M de Pasquale, W P Even, C J Fontes, K Forster, J Garcia, P Giommi, B Grefenstette, C Gronwall, D H Hartmann, M Heida, A L Hungerford, M M Kasliwal, H A Krimm, A J Levan, D Malesani, A Melandri, H Miyasaka, J A Nousek, P T O'Brien, J P Osborne, C Pagani, K L Page, D M Palmer, M Perri, S Pike, J L Racusin, S Rosswog, M H Siegel, T Sakamoto, B Sbarufatti, G Tagliaferri, N R Tanvir, A Tohuvavohu
With the first direct detection of merging black holes in 2015, the era of gravitational wave (GW) astrophysics began. A complete picture of compact object mergers, however, requires the detection of an electromagnetic (EM) counterpart. We report ultraviolet (UV) and x-ray observations by Swift and the Nuclear Spectroscopic Telescope ARray (NuSTAR) of the EM counterpart of the binary neutron star merger GW 170817. The bright, rapidly fading ultraviolet emission indicates a high mass (≈ 0.03 solar masses) wind-driven outflow with moderate electron fraction (Ye ≈ 0...
October 16, 2017: Science
C D Kilpatrick, R J Foley, D Kasen, A Murguia-Berthier, E Ramirez-Ruiz, D A Coulter, M R Drout, A L Piro, B J Shappee, K Boutsia, C Contreras, F Di Mille, B F Madore, N Morrell, Y-C Pan, J X Prochaska, A Rest, C Rojas-Bravo, M R Siebert, J D Simon, N Ulloa
11 hours after the detection of gravitational wave source GW170817 by the Laser Interferometer Gravitational-Wave Observatory and Virgo Interferometers, an associated optical transient, SSS17a, was identified in the galaxy NGC 4993. While the gravitational wave data indicate GW170817 is consistent with the merger of two compact objects, the electromagnetic observations provide independent constraints of the nature of that system. We synthesize the optical to near-infrared photometry and spectroscopy of SSS17a collected by the One-Meter Two-Hemisphere collaboration, finding that SSS17a is unlike other known transients...
October 16, 2017: Science
D A Coulter, R J Foley, C D Kilpatrick, M R Drout, A L Piro, B J Shappee, M R Siebert, J D Simon, N Ulloa, D Kasen, B F Madore, A Murguia-Berthier, Y-C Pan, J X Prochaska, E Ramirez-Ruiz, A Rest, C Rojas-Bravo
On 2017 August 17, the Laser Interferometer Gravitational-Wave Observatory (LIGO) and the Virgo interferometer detected gravitational waves emanating from a binary neutron star merger, GW170817. Nearly simultaneously, the Fermi and INTEGRAL telescopes detected a gamma-ray transient, GRB 170817A. 10.9 hours after the gravitational wave trigger, we discovered a transient and fading optical source, Swope Supernova Survey 2017a (SSS17a), coincident with GW170817. SSS17a is located in NGC 4993, an S0 galaxy at a distance of 40 megaparsecs...
October 16, 2017: Science
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