Tunable quantum criticality and super-ballistic transport in a “charge” Kondo circuit Science (IF 37.205) Pub Date : 2018-06-22 Z. Iftikhar, A. Anthore, A. K. Mitchell, F. D. Parmentier, U. Gennser, A. Ouerghi, A. Cavanna, C. Mora, P. Simon, F. Pierre
Quantum phase transitions (QPTs) are ubiquitous in strongly correlated materials. However, the microscopic complexity of these systems impedes the quantitative understanding of QPTs. We observed and thoroughly analyzed the rich strongly correlated physics in two profoundly dissimilar regimes of quantum criticality. With a circuit implementing a quantum simulator for the three-channel Kondo model, we reveal the universal scalings toward different low-temperature fixed points and along the multiple crossovers from quantum criticality. An unanticipated violation of the maximum conductance for ballistic free electrons is uncovered. The present charge pseudospin implementation of a Kondo impurity opens access to a broad variety of strongly correlated phenomena.
A molecular mechanism for choosing alcohol over an alternative reward Science (IF 37.205) Pub Date : 2018-06-22 Eric Augier, Estelle Barbier, Russell S. Dulman, Valentina Licheri, Gaëlle Augier, Esi Domi, Riccardo Barchiesi, Sean Farris, Daniel Nätt, R. Dayne Mayfield, Louise Adermark, Markus Heilig
Alcohol addiction leads to increased choice of alcohol over healthy rewards. We established an exclusive choice procedure in which ~15% of outbred rats chose alcohol over a high-value reward. These animals displayed addiction-like traits, including high motivation to obtain alcohol and pursuit of this drug despite adverse consequences. Expression of the γ-aminobutyric acid (GABA) transporter GAT-3 was selectively decreased within the amygdala of alcohol-choosing rats, whereas a knockdown of this transcript reversed choice preference of rats that originally chose a sweet solution over alcohol. GAT-3 expression was selectively decreased in the central amygdala of alcohol-dependent people compared to those who died of unrelated causes. Impaired GABA clearance within the amygdala contributes to alcohol addiction, appears to translate between species, and may offer targets for new pharmacotherapies for treating this disorder.
Orientation-dependent stereo Wigner time delay and electron localization in a small molecule Science (IF 37.205) Pub Date : 2018-06-22 J. Vos, L. Cattaneo, S. Patchkovskii, T. Zimmermann, C. Cirelli, M. Lucchini, A. Kheifets, A. S. Landsman, U. Keller
Attosecond metrology of atoms has accessed the time scale of the most fundamental processes in quantum mechanics. Transferring the time-resolved photoelectric effect from atoms to molecules considerably increases experimental and theoretical challenges. Here we show that orientation- and energy-resolved measurements characterize the molecular stereo Wigner time delay. This observable provides direct information on the localization of the excited electron wave packet within the molecular potential. Furthermore, we demonstrate that photoelectrons resulting from the dissociative ionization process of the CO molecule are preferentially emitted from the carbon end for dissociative 2Σ states and from the center and oxygen end for the 2Π states of the molecular ion. Supported by comprehensive theoretical calculations, this work constitutes a complete spatially and temporally resolved reconstruction of the molecular photoelectric effect.
Separation of enantiomers by their enantiospecific interaction with achiral magnetic substrates Science (IF 37.205) Pub Date : 2018-06-22 Koyel Banerjee-Ghosh, Oren Ben Dor, Francesco Tassinari, Eyal Capua, Shira Yochelis, Amir Capua, See-Hun Yang, Stuart S. P. Parkin, Soumyajit Sarkar, Leeor Kronik, Lech Tomasz Baczewski, Ron Naaman, Yossi Paltiel
It is commonly assumed that recognition and discrimination of chirality, both in nature and in artificial systems, depend solely on spatial effects. However, recent studies have suggested that charge redistribution in chiral molecules manifests an enantiospecific preference in electron spin orientation. We therefore reasoned that the induced spin polarization may affect enantiorecognition through exchange interactions. Here we show experimentally that the interaction of chiral molecules with a perpendicularly magnetized substrate is enantiospecific. Thus, one enantiomer adsorbs preferentially when the magnetic dipole is pointing up, whereas the other adsorbs faster for the opposite alignment of the magnetization. The interaction is not controlled by the magnetic field per se, but rather by the electron spin orientations, and opens prospects for a distinct approach to enantiomeric separations.
Observed rapid bedrock uplift in Amundsen Sea Embayment promotes ice-sheet stability Science (IF 37.205) Pub Date : 2018-06-22 Valentina R. Barletta, Michael Bevis, Benjamin E. Smith, Terry Wilson, Abel Brown, Andrea Bordoni, Michael Willis, Shfaqat Abbas Khan, Marc Rovira-Navarro, Ian Dalziel, Robert Smalley, Eric Kendrick, Stephanie Konfal, Dana J. Caccamise, Richard C. Aster, Andy Nyblade, Douglas A. Wiens
The marine portion of the West Antarctic Ice Sheet (WAIS) in the Amundsen Sea Embayment (ASE) accounts for one-fourth of the cryospheric contribution to global sea-level rise and is vulnerable to catastrophic collapse. The bedrock response to ice mass loss, glacial isostatic adjustment (GIA), was thought to occur on a time scale of 10,000 years. We used new GPS measurements, which show a rapid (41 millimeters per year) uplift of the ASE, to estimate the viscosity of the mantle underneath. We found a much lower viscosity (4 × 1018 pascal-second) than global average, and this shortens the GIA response time scale from tens to hundreds of years. Our finding requires an upward revision of ice mass loss from gravity data of 10% and increases the potential stability of the WAIS against catastrophic collapse.
Anomalously low dielectric constant of confined water Science (IF 37.205) Pub Date : 2018-06-22 L. Fumagalli, A. Esfandiar, R. Fabregas, S. Hu, P. Ares, A. Janardanan, Q. Yang, B. Radha, T. Taniguchi, K. Watanabe, G. Gomila, K. S. Novoselov, A. K. Geim
The dielectric constant ε of interfacial water has been predicted to be smaller than that of bulk water (ε ≈ 80) because the rotational freedom of water dipoles is expected to decrease near surfaces, yet experimental evidence is lacking. We report local capacitance measurements for water confined between two atomically flat walls separated by various distances down to 1 nanometer. Our experiments reveal the presence of an interfacial layer with vanishingly small polarization such that its out-of-plane ε is only ~2. The electrically dead layer is found to be two to three molecules thick. These results provide much-needed feedback for theories describing water-mediated surface interactions and the behavior of interfacial water, and show a way to investigate the dielectric properties of other fluids and solids under extreme confinement.
A precise extragalactic test of General Relativity Science (IF 37.205) Pub Date : 2018-06-22 Thomas E. Collett, Lindsay J. Oldham, Russell J. Smith, Matthew W. Auger, Kyle B. Westfall, David Bacon, Robert C. Nichol, Karen L. Masters, Kazuya Koyama, Remco van den Bosch
Einstein’s theory of gravity, General Relativity, has been precisely tested on Solar System scales, but the long-range nature of gravity is still poorly constrained. The nearby strong gravitational lens ESO 325-G004 provides a laboratory to probe the weak-field regime of gravity and measure the spatial curvature generated per unit mass, γ. By reconstructing the observed light profile of the lensed arcs and the observed spatially resolved stellar kinematics with a single self-consistent model, we conclude that γ = 0.97 ± 0.09 at 68% confidence. Our result is consistent with the prediction of 1 from General Relativity and provides a strong extragalactic constraint on the weak-field metric of gravity.
New genus of extinct Holocene gibbon associated with humans in Imperial China Science (IF 37.205) Pub Date : 2018-06-22 Samuel T. Turvey, Kristoffer Bruun, Alejandra Ortiz, James Hansford, Songmei Hu, Yan Ding, Tianen Zhang, Helen J. Chatterjee
Although all extant apes are threatened with extinction, there is no evidence for human-caused extinctions of apes or other primates in postglacial continental ecosystems, despite intensive anthropogenic pressures associated with biodiversity loss for millennia in many regions. Here, we report a new, globally extinct genus and species of gibbon, Junzi imperialis, described from a partial cranium and mandible from a ~2200- to 2300-year-old tomb from Shaanxi, China. Junzi can be differentiated from extant hylobatid genera and the extinct Quaternary gibbon Bunopithecus by using univariate and multivariate analyses of craniodental morphometric data. Primates are poorly represented in the Chinese Quaternary fossil record, but historical accounts suggest that China may have contained an endemic ape radiation that has only recently disappeared.
Locally coordinated synaptic plasticity of visual cortex neurons in vivo Science (IF 37.205) Pub Date : 2018-06-22 Sami El-Boustani, Jacque P. K. Ip, Vincent Breton-Provencher, Graham W. Knott, Hiroyuki Okuno, Haruhiko Bito, Mriganka Sur
Plasticity of cortical responses in vivo involves activity-dependent changes at synapses, but the manner in which different forms of synaptic plasticity act together to create functional changes in neurons remains unknown. We found that spike timing–induced receptive field plasticity of visual cortex neurons in mice is anchored by increases in the synaptic strength of identified spines. This is accompanied by a decrease in the strength of adjacent spines on a slower time scale. The locally coordinated potentiation and depression of spines involves prominent AMPA receptor redistribution via targeted expression of the immediate early gene product Arc. Hebbian strengthening of activated synapses and heterosynaptic weakening of adjacent synapses thus cooperatively orchestrate cell-wide plasticity of functional neuronal responses.
Adaptive introgression underlies polymorphic seasonal camouflage in snowshoe hares Science (IF 37.205) Pub Date : 2018-06-22 Matthew R. Jones, L. Scott Mills, Paulo Célio Alves, Colin M. Callahan, Joel M. Alves, Diana J. R. Lafferty, Francis M. Jiggins, Jeffrey D. Jensen, José Melo-Ferreira, Jeffrey M. Good
Snowshoe hares (Lepus americanus) maintain seasonal camouflage by molting to a white winter coat, but some hares remain brown during the winter in regions with low snow cover. We show that cis-regulatory variation controlling seasonal expression of the Agouti gene underlies this adaptive winter camouflage polymorphism. Genetic variation at Agouti clustered by winter coat color across multiple hare and jackrabbit species, revealing a history of recurrent interspecific gene flow. Brown winter coats in snowshoe hares likely originated from an introgressed black-tailed jackrabbit allele that has swept to high frequency in mild winter environments. These discoveries show that introgression of genetic variants that underlie key ecological traits can seed past and ongoing adaptation to rapidly changing environments.
Antihomotypic affinity maturation improves human B cell responses against a repetitive epitope Science (IF 37.205) Pub Date : 2018-06-22 Katharina Imkeller, Stephen W. Scally, Alexandre Bosch, Gemma Pidelaserra Martí, Giulia Costa, Gianna Triller, Rajagopal Murugan, Valerio Renna, Hassan Jumaa, Peter G. Kremsner, B. Kim Lee Sim, Stephen L. Hoffman, Benjamin Mordmüller, Elena A. Levashina, Jean-Philippe Julien, Hedda Wardemann
Affinity maturation selects B cells expressing somatically mutated antibody variants with improved antigen-binding properties to protect from invading pathogens. We determined the molecular mechanism underlying the clonal selection and affinity maturation of human B cells expressing protective antibodies against the circumsporozoite protein of the malaria parasite Plasmodium falciparum (PfCSP). We show in molecular detail that the repetitive nature of PfCSP facilitates direct homotypic interactions between two PfCSP repeat-bound monoclonal antibodies, thereby improving antigen affinity and B cell activation. These data provide a mechanistic explanation for the strong selection of somatic mutations that mediate homotypic antibody interactions after repeated parasite exposure in humans. Our findings demonstrate a different mode of antigen-mediated affinity maturation to improve antibody responses to PfCSP and presumably other repetitive antigens.
In vivo brain GPCR signaling elucidated by phosphoproteomics Science (IF 37.205) Pub Date : 2018-06-22 Jeffrey J. Liu, Kirti Sharma, Luca Zangrandi, Chongguang Chen, Sean J. Humphrey, Yi-Ting Chiu, Mariana Spetea, Lee-Yuan Liu-Chen, Christoph Schwarzer, Matthias Mann
A systems view of G protein–coupled receptor (GPCR) signaling in its native environment is central to the development of GPCR therapeutics with fewer side effects. Using the kappa opioid receptor (KOR) as a model, we employed high-throughput phosphoproteomics to investigate signaling induced by structurally diverse agonists in five mouse brain regions. Quantification of 50,000 different phosphosites provided a systems view of KOR in vivo signaling, revealing novel mechanisms of drug action. Thus, we discovered enrichment of the mechanistic target of rapamycin (mTOR) pathway by U-50,488H, an agonist causing aversion, which is a typical KOR-mediated side effect. Consequently, mTOR inhibition during KOR activation abolished aversion while preserving beneficial antinociceptive and anticonvulsant effects. Our results establish high-throughput phosphoproteomics as a general strategy to investigate GPCR in vivo signaling, enabling prediction and modulation of behavioral outcomes.
Analysis of shared heritability in common disorders of the brain Science (IF 37.205) Pub Date : 2018-06-22 The Brainstorm Consortium, Verneri Anttila, Brendan Bulik-Sullivan, Hilary K. Finucane, Raymond K. Walters, Jose Bras, Laramie Duncan, Valentina Escott-Price, Guido J. Falcone, Padhraig Gormley, Rainer Malik, Nikolaos A. Patsopoulos, Stephan Ripke, Zhi Wei, Dongmei Yu, Phil H. Lee, Patrick Turley, Benjamin Grenier-Boley, Vincent Chouraki, Yoichiro Kamatani, Claudine Berr, Luc Letenneur, Didier Hannequin, Philippe Amouyel, Anne Boland, Jean-François Deleuze, Emmanuelle Duron, Badri N. Vardarajan, Christiane Reitz, Alison M. Goate, Matthew J. Huentelman, M. Ilyas Kamboh, Eric B. Larson, Ekaterina Rogaeva, Peter St George-Hyslop, Hakon Hakonarson, Walter A. Kukull, Lindsay A. Farrer, Lisa L. Barnes, Thomas G. Beach, F. Yesim Demirci, Elizabeth Head, Christine M. Hulette, Gregory A. Jicha, John S.K. Kauwe, Jeffrey A. Kaye, James B. Leverenz, Allan I. Levey, Andrew P. Lieberman, Vernon S. Pankratz, Wayne W. Poon, Joseph F. Quinn, Andrew J. Saykin, Lon S. Schneider, Amanda G. Smith, Joshua A. Sonnen, Robert A. Stern, Vivianna M. Van Deerlin, Linda J. Van Eldik, Denise Harold, Giancarlo Russo, David C. Rubinsztein, Anthony Bayer, Magda Tsolaki, Petra Proitsi, Nick C. Fox, Harald Hampel, Michael J. Owen, Simon Mead, Peter Passmore, Kevin Morgan, Markus M. Nöthen, Martin Rossor, Michelle K. Lupton, Per Hoffmann, Johannes Kornhuber, Brian Lawlor, Andrew McQuillin, Ammar Al-Chalabi, Joshua C Bis, Agustin Ruiz, Mercè Boada, Sudha Seshadri, Alexa Beiser, Kenneth Rice, Sven J. van der Lee, Philip L. De Jager, Daniel H. Geschwind, Matthias Riemenschneider, Steffi Riedel-Heller, Jerome I Rotter, Gerhard Ransmayr, Bradley T. Hyman, Carlos Cruchaga, Montserrat Alegret, Bendik Winsvold, Priit Palta, Kai-How Farh, Ester Cuenca-Leon, Nicholas Furlotte, Tobias Kurth, Lannie Ligthart, Gisela M. Terwindt, Tobias Freilinger, Caroline Ran, Scott D. Gordon, Guntram Borck, Hieab H.H. Adams, Terho Lehtimäki, Juho Wedenoja, Julie E. Buring, Markus Schürks, Maria Hrafnsdottir, Jouke-Jan Hottenga, Brenda Penninx, Ville Artto, Mari Kaunisto, Salli Vepsäläinen, Nicholas G. Martin, Grant W. Montgomery, Mitja I. Kurki, Eija Hämäläinen, Hailiang Huang, Jie Huang, Cynthia Sandor, Caleb Webber, Bertram Muller-Myhsok, Stefan Schreiber, Veikko Salomaa, Elizabeth Loehrer, Hartmut Göbel, Alfons Macaya, Patricia Pozo-Rosich, Thomas Hansen, Thomas Werge, Jaakko Kaprio, Andres Metspalu, Christian Kubisch, Michel D. Ferrari, Andrea C. Belin, Arn M.J.M. van den Maagdenberg, John-Anker Zwart, Dorret Boomsma, Nicholas Eriksson, Jes Olesen, Daniel I. Chasman, Dale R. Nyholt, Andreja Avbersek, Larry Baum, Samuel Berkovic, Jonathan Bradfield, Russell Buono, Claudia B. Catarino, Patrick Cossette, Peter De Jonghe, Chantal Depondt, Dennis Dlugos, Thomas N. Ferraro, Jacqueline French, Helle Hjalgrim, Jennifer Jamnadas-Khoda, Reetta Kälviäinen, Wolfram S. Kunz, Holger Lerche, Costin Leu, Dick Lindhout, Warren Lo, Daniel Lowenstein, Mark McCormack, Rikke S. Møller, Anne Molloy, Ping-Wing Ng, Karen Oliver, Michael Privitera, Rodney Radtke, Ann-Kathrin Ruppert, Thomas Sander, Steven Schachter, Christoph Schankin, Ingrid Scheffer, Susanne Schoch, Sanjay M. Sisodiya, Philip Smith, Michael Sperling, Pasquale Striano, Rainer Surges, G. Neil Thomas, Frank Visscher, Christopher D. Whelan, Federico Zara, Erin L. Heinzen, Anthony Marson, Felicitas Becker, Hans Stroink, Fritz Zimprich, Thomas Gasser, Raphael Gibbs, Peter Heutink, Maria Martinez, Huw R. Morris, Manu Sharma, Mina Ryten, Kin Y. Mok, Sara Pulit, Steve Bevan, Elizabeth Holliday, John Attia, Thomas Battey, Giorgio Boncoraglio, Vincent Thijs, Wei-Min Chen, Braxton Mitchell, Peter Rothwell, Pankaj Sharma, Cathie Sudlow, Astrid Vicente, Hugh Markus, Christina Kourkoulis, Joana Pera, Miriam Raffeld, Scott Silliman, Vesna Boraska Perica, Laura M. Thornton, Laura M. Huckins, N. William Rayner, Cathryn M. Lewis, Monica Gratacos, Filip Rybakowski, Anna Keski-Rahkonen, Anu Raevuori, James I. Hudson, Ted Reichborn-Kjennerud, Palmiero Monteleone, Andreas Karwautz, Katrin Mannik, Jessica H. Baker, Julie K. O’Toole, Sara E. Trace, Oliver S. P. Davis, Sietske G. Helder, Stefan Ehrlich, Beate Herpertz-Dahlmann, Unna N. Danner, Annemarie A. van Elburg, Maurizio Clementi, Monica Forzan, Elisa Docampo, Jolanta Lissowska, Joanna Hauser, Alfonso Tortorella, Mario Maj, Fragiskos Gonidakis, Konstantinos Tziouvas, Hana Papezova, Zeynep Yilmaz, Gudrun Wagner, Sarah Cohen-Woods, Stefan Herms, Antonio Julià, Raquel Rabionet, Danielle M. Dick, Samuli Ripatti, Ole A. Andreassen, Thomas Espeseth, Astri J. Lundervold, Vidar M. Steen, Dalila Pinto, Stephen W. Scherer, Harald Aschauer, Alexandra Schosser, Lars Alfredsson, Leonid Padyukov, Katherine A. Halmi, James Mitchell, Michael Strober, Andrew W. Bergen, Walter Kaye, Jin Peng Szatkiewicz, Bru Cormand, Josep Antoni Ramos-Quiroga, Cristina Sánchez-Mora, Marta Ribasés, Miguel Casas, Amaia Hervas, Maria Jesús Arranz, Jan Haavik, Tetyana Zayats, Stefan Johansson, Nigel Williams, Astrid Dempfle, Aribert Rothenberger, Jonna Kuntsi, Robert D. Oades, Tobias Banaschewski, Barbara Franke, Jan K. Buitelaar, Alejandro Arias Vasquez, Alysa E. Doyle, Andreas Reif, Klaus-Peter Lesch, Christine Freitag, Olga Rivero, Haukur Palmason, Marcel Romanos, Kate Langley, Marcella Rietschel, Stephanie H. Witt, Soeren Dalsgaard, Anders D. Børglum, Irwin Waldman, Beth Wilmot, Nikolas Molly, Claiton H.D. Bau, Jennifer Crosbie, Russell Schachar, Sandra K. Loo, James J. McGough, Eugenio H. Grevet, Sarah E. Medland, Elise Robinson, Lauren A. Weiss, Elena Bacchelli, Anthony Bailey, Vanessa Bal, Agatino Battaglia, Catalina Betancur, Patrick Bolton, Rita Cantor, Patrícia Celestino-Soper, Geraldine Dawson, Silvia De Rubeis, Frederico Duque, Andrew Green, Sabine M. Klauck, Marion Leboyer, Pat Levitt, Elena Maestrini, Shrikant Mane, Daniel Moreno- De-Luca, Jeremy Parr, Regina Regan, Abraham Reichenberg, Sven Sandin, Jacob Vorstman, Thomas Wassink, Ellen Wijsman, Edwin Cook, Susan Santangelo, Richard Delorme, Bernadette Rogé, Tiago Magalhaes, Dan Arking, Thomas G. Schulze, Robert C. Thompson, Jana Strohmaier, Keith Matthews, Ingrid Melle, Derek Morris, Douglas Blackwood, Andrew McIntosh, Sarah E Bergen, Martin Schalling, Stéphane Jamain, Anna Maaser, Sascha B. Fischer, Céline S. Reinbold, Janice M. Fullerton, José Guzman-Parra, Fermin Mayoral, Peter R. Schofield, Sven Cichon, Thomas W. Mühleisen, Franziska Degenhardt, Johannes Schumacher, Michael Bauer, Philip B. Mitchell, Elliot S. Gershon, John Rice, James B. Potash, Peter P. Zandi, Nick Craddock, I. Nicol Ferrier, Martin Alda, Guy A. Rouleau, Gustavo Turecki, Roel Ophoff, Carlos Pato, Adebayo Anjorin, Eli Stahl, Markus Leber, Piotr M. Czerski, Cristiana Cruceanu, Ian R. Jones, Danielle Posthuma, Till F.M. Andlauer, Andreas J. Forstner, Fabian Streit, Bernhard T. Baune, Tracy Air, Grant Sinnamon, Naomi R. Wray, Donald J. MacIntyre, David Porteous, Georg Homuth, Margarita Rivera, Jakob Grove, Christel M. Middeldorp, Ian Hickie, Michele Pergadia, Divya Mehta, Johannes H. Smit, Rick Jansen, Eco de Geus, Erin Dunn, Qingqin S. Li, Matthias Nauck, Robert A. Schoevers, Aartjan TF Beekman, James A. Knowles, Alexander Viktorin, Paul Arnold, Cathy L. Barr, Gabriel Bedoya-Berrio, O. Joseph Bienvenu, Helena Brentani, Christie Burton, Beatriz Camarena, Carolina Cappi, Danielle Cath, Maria Cavallini, Daniele Cusi, Sabrina Darrow, Damiaan Denys, Eske M. Derks, Andrea Dietrich, Thomas Fernandez, Martijn Figee, Nelson Freimer, Gloria Gerber, Marco Grados, Erica Greenberg, Gregory L. Hanna, Andreas Hartmann, Matthew E. Hirschtritt, Pieter J. Hoekstra, Alden Huang, Chaim Huyser, Cornelia Illmann, Michael Jenike, Samuel Kuperman, Bennett Leventhal, Christine Lochner, Gholson J. Lyon, Fabio Macciardi, Marcos Madruga-Garrido, Irene A. Malaty, Athanasios Maras, Lauren McGrath, Eurípedes C. Miguel, Pablo Mir, Gerald Nestadt, Humberto Nicolini, Michael S. Okun, Andrew Pakstis, Peristera Paschou, John Piacentini, Christopher Pittenger, Kerstin Plessen, Vasily Ramensky, Eliana M. Ramos, Victor Reus, Margaret A. Richter, Mark A. Riddle, Mary M. Robertson, Veit Roessner, Maria Rosário, Jack F. Samuels, Paul Sandor, Dan J. Stein, Fotis Tsetsos, Filip Van Nieuwerburgh, Sarah Weatherall, Jens R. Wendland, Tomasz Wolanczyk, Yulia Worbe, Gwyneth Zai, Fernando S. Goes, Nicole McLaughlin, Paul S. Nestadt, Hans-Jorgen Grabe, Christel Depienne, Anuar Konkashbaev, Nuria Lanzagorta, Ana Valencia-Duarte, Elvira Bramon, Nancy Buccola, Wiepke Cahn, Murray Cairns, Siow A. Chong, David Cohen, Benedicto Crespo-Facorro, James Crowley, Michael Davidson, Lynn DeLisi, Timothy Dinan, Gary Donohoe, Elodie Drapeau, Jubao Duan, Lieuwe Haan, David Hougaard, Sena Karachanak-Yankova, Andrey Khrunin, Janis Klovins, Vaidutis Kučinskas, Jimmy Lee Chee Keong, Svetlana Limborska, Carmel Loughland, Jouko Lönnqvist, Brion Maher, Manuel Mattheisen, Colm McDonald, Kieran C. Murphy, Igor Nenadic, Jim van Os, Christos Pantelis, Michele Pato, Tracey Petryshen, Digby Quested, Panos Roussos, Alan R. Sanders, Ulrich Schall, Sibylle G. Schwab, Kang Sim, Hon-Cheong So, Elisabeth Stögmann, Mythily Subramaniam, Draga Toncheva, John Waddington, James Walters, Mark Weiser, Wei Cheng, Robert Cloninger, David Curtis, Pablo V. Gejman, Frans Henskens, Morten Mattingsdal, Sang-Yun Oh, Rodney Scott, Bradley Webb, Gerome Breen, Claire Churchhouse, Cynthia M. Bulik, Mark Daly, Martin Dichgans, Stephen V. Faraone, Rita Guerreiro, Peter Holmans, Kenneth S. Kendler, Bobby Koeleman, Carol A. Mathews, Alkes Price, Jeremiah Scharf, Pamela Sklar, Julie Williams, Nicholas W. Wood, Chris Cotsapas, Aarno Palotie, Jordan W. Smoller, Patrick Sullivan, Jonathan Rosand, Aiden Corvin, Benjamin M. Neale
Disorders of the brain can exhibit considerable epidemiological comorbidity and often share symptoms, provoking debate about their etiologic overlap. We quantified the genetic sharing of 25 brain disorders from genome-wide association studies of 265,218 patients and 784,643 control participants and assessed their relationship to 17 phenotypes from 1,191,588 individuals. Psychiatric disorders share common variant risk, whereas neurological disorders appear more distinct from one another and from the psychiatric disorders. We also identified significant sharing between disorders and a number of brain phenotypes, including cognitive measures. Further, we conducted simulations to explore how statistical power, diagnostic misclassification, and phenotypic heterogeneity affect genetic correlations. These results highlight the importance of common genetic variation as a risk factor for brain disorders and the value of heritability-based methods in understanding their etiology.
Three-dimensional intact-tissue sequencing of single-cell transcriptional states Science (IF 37.205) Pub Date : 2018-06-21 Xiao Wang, William E. Allen, Matthew A. Wright, Emily L. Sylwestrak, Nikolay Samusik, Sam Vesuna, Kathryn Evans, Cindy Liu, Charu Ramakrishnan, Jia Liu, Garry P. Nolan, Felice-Alessio Bava, Karl Deisseroth
Retrieving high-content gene-expression information while retaining 3D positional anatomy at cellular resolution has been difficult, limiting integrative understanding of structure and function in complex biological tissues. Here we develop and apply a technology for 3D intact-tissue RNA sequencing, termed STARmap (Spatially-resolved Transcript Amplicon Readout Mapping), which integrates hydrogel-tissue chemistry, targeted signal amplification, and in situ sequencing. The capabilities of STARmap were tested by mapping 160 to 1,020 genes simultaneously in sections of mouse brain at single-cell resolution with high efficiency, accuracy and reproducibility. Moving to thick tissue blocks, we observed a molecularly-defined gradient distribution of excitatory-neuron subtypes across cubic millimeter-scale volumes (>30,000 cells), and discovered a short-range 3D self-clustering in many inhibitory-neuron subtypes that could be identified and described with 3D STARmap.
Atmospheric blocking as a traffic jam in the jet stream Science (IF 37.205) Pub Date : 2018-06-21 Noboru Nakamura, Clare S. Y. Huang
Atmospheric blocking due to anomalous, persistent meandering of the jet stream often causes weather extremes in the midlatitudes. Despite its ubiquity, the onset mechanism of blocking is not well understood. Here we demonstrate with meteorological data that there exists a close analogy between blocking and traffic congestion on a highway, and that they can be described by a common mathematical theory. The theory predicts that the jet stream has a capacity for the flux of wave activity (a measure of meandering), just as the highway has traffic capacity, and when it is exceeded, blocking manifests as congestion. Stationary waves modulate the jet stream’s capacity for transient waves and localize block formation. Climate change likely affects blocking frequency by modifying the jet stream’s proximity to capacity.
Seeded growth of single-crystal two-dimensional covalent organic frameworks Science (IF 37.205) Pub Date : 2018-06-21 Austin M. Evans, Lucas R. Parent, Nathan C. Flanders, Ryan P. Bisbey, Edon Vitaku, Matthew S. Kirschner, Richard D. Schaller, Lin X. Chen, Nathan C. Gianneschi, William R. Dichtel
Polymerizing monomers into periodic two-dimensional (2D) networks provides structurally precise, layered macromolecular sheets that exhibit desirable mechanical, optoelectrotronic, and molecular transport properties. 2D covalent organic frameworks (COFs) offer broad monomer scope but are generally isolated as powders comprised of aggregated nanometer-scale crystallites. Here we control 2D COF formation using a two-step procedure, in which monomers are added slowly to preformed nanoparticle seeds. The resulting 2D COFs are isolated as single-crystalline, micron-sized particles. Transient absorption spectroscopy of the dispersed COF nanoparticles provides two to three orders of magnitude improvement in signal quality relative to polycrystalline powder samples and suggests exciton diffusion over longer length scales than those obtained through previous approaches. These findings will enable a broad exploration of synthetic 2D polymer structures and properties.
Assessment of methane emissions from the U.S. oil and gas supply chain Science (IF 37.205) Pub Date : 2018-06-21 Ramón A. Alvarez, Daniel Zavala-Araiza, David R. Lyon, David T. Allen, Zachary R. Barkley, Adam R. Brandt, Kenneth J. Davis, Scott C. Herndon, Daniel J. Jacob, Anna Karion, Eric A. Kort, Brian K. Lamb, Thomas Lauvaux, Joannes D. Maasakkers, Anthony J. Marchese, Mark Omara, Stephen W. Pacala, Jeff Peischl, Allen L. Robinson, Paul B. Shepson, Colm Sweeney, Amy Townsend-Small, Steven C. Wofsy, Steven P. Hamburg
Methane emissions from the U.S. oil and natural gas supply chain were estimated using ground-based, facility-scale measurements and validated with aircraft observations in areas accounting for ~30% of U.S. gas production. When scaled up nationally, our facility-based estimate of 2015 supply chain emissions is 13 ± 2 Tg/y, equivalent to 2.3% of gross U.S. gas production. This value is ~60% higher than the U.S. EPA inventory estimate, likely because existing inventory methods miss emissions released during abnormal operating conditions. Methane emissions of this magnitude, per unit of natural gas consumed, produce radiative forcing over a 20-year time horizon comparable to the CO2 from natural gas combustion. Significant emission reductions are feasible through rapid detection of the root causes of high emissions and deployment of less failure-prone systems.
Mediator and RNA polymerase II clusters associate in transcription-dependent condensates Science (IF 37.205) Pub Date : 2018-06-21 Won-Ki Cho, Jan-Hendrik Spille, Micca Hecht, Choongman Lee, Charles Li, Valentin Grube, Ibrahim I. Cisse
Models of gene control have emerged from genetic and biochemical studies, with limited consideration of the spatial organization and dynamics of key components in living cells. Here we used live cell super-resolution and light sheet imaging to study the organization and dynamics of the Mediator coactivator and RNA polymerase II (Pol II) directly. Mediator and Pol II each form small transient and large stable clusters in living embryonic stem cells. Mediator and Pol II are colocalized in the stable clusters, which associate with chromatin, have properties of phase-separated condensates, and are sensitive to transcriptional inhibitors. We suggest that large clusters of Mediator, recruited by transcription factors at large or clustered enhancer elements, interact with large Pol II clusters in transcriptional condensates in vivo.
Coactivator condensation at super-enhancers links phase separation and gene control Science (IF 37.205) Pub Date : 2018-06-21 Benjamin R. Sabari, Alessandra Dall'Agnese, Ann Boija, Isaac A. Klein, Eliot L. Coffey, Krishna Shrinivas, Brian J. Abraham, Nancy M. Hannett, Alicia V. Zamudio, John C. Manteiga, Charles H. Li, Yang E. Guo, Daniel S. Day, Jurian Schuijers, Eliza Vasile, Sohail Malik, Denes Hnisz, Tong Ihn Lee, Ibrahim I. Cisse, Robert G. Roeder, Phillip A. Sharp, Arup K. Chakraborty, Richard A. Young
Super-enhancers (SEs) are clusters of enhancers that cooperatively assemble a high density of transcriptional apparatus to drive robust expression of genes with prominent roles in cell identity. Here, we demonstrate that the SE-enriched transcriptional coactivators BRD4 and MED1 form nuclear puncta at SEs that exhibit properties of liquid-like condensates and are disrupted by chemicals that perturb condensates. The intrinsically disordered regions (IDRs) of BRD4 and MED1 can form phase-separated droplets and MED1-IDR droplets can compartmentalize and concentrate transcription apparatus from nuclear extracts. These results support the idea that coactivators form phase-separated condensates at SEs that compartmentalize and concentrate the transcription apparatus, suggest a role for coactivator IDRs in this process, and offer insights into mechanisms involved in control of key cell identity genes.
Imaging dynamic and selective low-complexity domain interactions that control gene transcription Science (IF 37.205) Pub Date : 2018-06-21 Shasha Chong, Claire Dugast-Darzacq, Zhe Liu, Peng Dong, Gina M. Dailey, Claudia Cattoglio, Alec Heckert, Sambashiva Banala, Luke Lavis, Xavier Darzacq, Robert Tjian
Many eukaryotic transcription factors (TFs) contain intrinsically disordered low-complexity domains (LCDs), but how they drive transactivation remains unclear. Here, live-cell single-molecule imaging reveals that TF-LCDs form local high-concentration interaction hubs at synthetic and endogenous genomic loci. TF-LCD hubs stabilize DNA binding, recruit RNA polymerase II (Pol II), and activate transcription. LCD-LCD interactions within hubs are highly dynamic, display selectivity with binding partners, and are differentially sensitive to disruption by hexanediols. Under physiological conditions, rapid and reversible LCD-LCD interactions occur between TFs and the Pol II machinery without detectable phase separation. Our findings reveal fundamental mechanisms underpinning transcriptional control and suggest a framework for developing single-molecule imaging screens for novel drugs targeting gene regulatory interactions implicated in disease.
Neural scene representation and rendering Science (IF 37.205) Pub Date : 2018-06-15 S. M. Ali Eslami, Danilo Jimenez Rezende, Frederic Besse, Fabio Viola, Ari S. Morcos, Marta Garnelo, Avraham Ruderman, Andrei A. Rusu, Ivo Danihelka, Karol Gregor, David P. Reichert, Lars Buesing, Theophane Weber, Oriol Vinyals, Dan Rosenbaum, Neil Rabinowitz, Helen King, Chloe Hillier, Matt Botvinick, Daan Wierstra, Koray Kavukcuoglu, Demis Hassabis
Scene representation—the process of converting visual sensory data into concise descriptions—is a requirement for intelligent behavior. Recent work has shown that neural networks excel at this task when provided with large, labeled datasets. However, removing the reliance on human labeling remains an important open problem. To this end, we introduce the Generative Query Network (GQN), a framework within which machines learn to represent scenes using only their own sensors. The GQN takes as input images of a scene taken from different viewpoints, constructs an internal representation, and uses this representation to predict the appearance of that scene from previously unobserved viewpoints. The GQN demonstrates representation learning without human labels or domain knowledge, paving the way toward machines that autonomously learn to understand the world around them.
Photochemistry beyond the red limit in chlorophyll f–containing photosystems Science (IF 37.205) Pub Date : 2018-06-15 Dennis J. Nürnberg, Jennifer Morton, Stefano Santabarbara, Alison Telfer, Pierre Joliot, Laura A. Antonaru, Alexander V. Ruban, Tanai Cardona, Elmars Krausz, Alain Boussac, Andrea Fantuzzi, A. William Rutherford
Photosystems I and II convert solar energy into the chemical energy that powers life. Chlorophyll a photochemistry, using red light (680 to 700 nm), is near universal and is considered to define the energy “red limit” of oxygenic photosynthesis. We present biophysical studies on the photosystems from a cyanobacterium grown in far-red light (750 nm). The few long-wavelength chlorophylls present are well resolved from each other and from the majority pigment, chlorophyll a. Charge separation in photosystem I and II uses chlorophyll f at 745 nm and chlorophyll f (or d) at 727 nm, respectively. Each photosystem has a few even longer-wavelength chlorophylls f that collect light and pass excitation energy uphill to the photochemically active pigments. These photosystems function beyond the red limit using far-red pigments in only a few key positions.
Giant tunneling magnetoresistance in spin-filter van der Waals heterostructures Science (IF 37.205) Pub Date : 2018-06-15 Tiancheng Song, Xinghan Cai, Matisse Wei-Yuan Tu, Xiaoou Zhang, Bevin Huang, Nathan P. Wilson, Kyle L. Seyler, Lin Zhu, Takashi Taniguchi, Kenji Watanabe, Michael A. McGuire, David H. Cobden, Di Xiao, Wang Yao, Xiaodong Xu
Magnetic multilayer devices that exploit magnetoresistance are the backbone of magnetic sensing and data storage technologies. Here, we report multiple-spin-filter magnetic tunnel junctions (sf-MTJs) based on van der Waals (vdW) heterostructures in which atomically thin chromium triiodide (CrI3) acts as a spin-filter tunnel barrier sandwiched between graphene contacts. We demonstrate tunneling magnetoresistance that is drastically enhanced with increasing CrI3 layer thickness, reaching a record 19,000% for magnetic multilayer structures using four-layer sf-MTJs at low temperatures. Using magnetic circular dichroism measurements, we attribute these effects to the intrinsic layer-by-layer antiferromagnetic ordering of the atomically thin CrI3. Our work reveals the possibility to push magnetic information storage to the atomically thin limit and highlights CrI3 as a superlative magnetic tunnel barrier for vdW heterostructure spintronic devices.
Probing magnetism in 2D van der Waals crystalline insulators via electron tunneling Science (IF 37.205) Pub Date : 2018-06-15 D. R. Klein, D. MacNeill, J. L. Lado, D. Soriano, E. Navarro-Moratalla, K. Watanabe, T. Taniguchi, S. Manni, P. Canfield, J. Fernández-Rossier, P. Jarillo-Herrero
Magnetic insulators are a key resource for next-generation spintronic and topological devices. The family of layered metal halides promises varied magnetic states, including ultrathin insulating multiferroics, spin liquids, and ferromagnets, but device-oriented characterization methods are needed to unlock their potential. Here, we report tunneling through the layered magnetic insulator CrI3 as a function of temperature and applied magnetic field. We electrically detect the magnetic ground state and interlayer coupling and observe a field-induced metamagnetic transition. The metamagnetic transition results in magnetoresistances of 95, 300, and 550% for bilayer, trilayer, and tetralayer CrI3 barriers, respectively. We further measure inelastic tunneling spectra for our junctions, unveiling a rich spectrum consistent with collective magnetic excitations (magnons) in CrI3.
Normative brain size variation and brain shape diversity in humans Science (IF 37.205) Pub Date : 2018-06-15 P. K. Reardon, Jakob Seidlitz, Simon Vandekar, Siyuan Liu, Raihaan Patel, Min Tae M. Park, Aaron Alexander-Bloch, Liv S. Clasen, Jonathan D. Blumenthal, Francois M. Lalonde, Jay N. Giedd, Ruben C. Gur, Raquel E. Gur, Jason P. Lerch, M. Mallar Chakravarty, Theodore D. Satterthwaite, Russell T. Shinohara, Armin Raznahan
Brain size variation over primate evolution and human development is associated with shifts in the proportions of different brain regions. Individual brain size can vary almost twofold among typically developing humans, but the consequences of this for brain organization remain poorly understood. Using in vivo neuroimaging data from more than 3000 individuals, we find that larger human brains show greater areal expansion in distributed frontoparietal cortical networks and related subcortical regions than in limbic, sensory, and motor systems. This areal redistribution recapitulates cortical remodeling across evolution, manifests by early childhood in humans, and is linked to multiple markers of heightened metabolic cost and neuronal connectivity. Thus, human brain shape is systematically coupled to naturally occurring variations in brain size through a scaling map that integrates spatiotemporally diverse aspects of neurobiology.
Synapse-specific representation of the identity of overlapping memory engrams Science (IF 37.205) Pub Date : 2018-06-15 Kareem Abdou, Mohammad Shehata, Kiriko Choko, Hirofumi Nishizono, Mina Matsuo, Shin-ichi Muramatsu, Kaoru Inokuchi
Memories are integrated into interconnected networks; nevertheless, each memory has its own identity. How the brain defines specific memory identity out of intermingled memories stored in a shared cell ensemble has remained elusive. We found that after complete retrograde amnesia of auditory fear conditioning in mice, optogenetic stimulation of the auditory inputs to the lateral amygdala failed to induce memory recall, implying that the memory engram no longer existed in that circuit. Complete amnesia of a given fear memory did not affect another linked fear memory encoded in the shared ensemble. Optogenetic potentiation or depotentiation of the plasticity at synapses specific to one memory affected the recall of only that memory. Thus, the sharing of engram cells underlies the linkage between memories, whereas synapse-specific plasticity guarantees the identity and storage of individual memories.
The influence of human disturbance on wildlife nocturnality Science (IF 37.205) Pub Date : 2018-06-15 Kaitlyn M. Gaynor, Cheryl E. Hojnowski, Neil H. Carter, Justin S. Brashares
Rapid expansion of human activity has driven well-documented shifts in the spatial distribution of wildlife, but the cumulative effect of human disturbance on the temporal dynamics of animals has not been quantified. We examined anthropogenic effects on mammal diel activity patterns, conducting a meta-analysis of 76 studies of 62 species from six continents. Our global study revealed a strong effect of humans on daily patterns of wildlife activity. Animals increased their nocturnality by an average factor of 1.36 in response to human disturbance. This finding was consistent across continents, habitats, taxa, and human activities. As the global human footprint expands, temporal avoidance of humans may facilitate human-wildlife coexistence. However, such responses can result in marked shifts away from natural patterns of activity, with consequences for fitness, population persistence, community interactions, and evolution.
Missing enzymes in the biosynthesis of the anticancer drug vinblastine in Madagascar periwinkle Science (IF 37.205) Pub Date : 2018-06-15 Lorenzo Caputi, Jakob Franke, Scott C. Farrow, Khoa Chung, Richard M. E. Payne, Trinh-Don Nguyen, Thu-Thuy T. Dang, Inês Soares Teto Carqueijeiro, Konstantinos Koudounas, Thomas Dugé de Bernonville, Belinda Ameyaw, D. Marc Jones, Ivo Jose Curcino Vieira, Vincent Courdavault, Sarah E. O’Connor
Vinblastine, a potent anticancer drug, is produced by Catharanthus roseus (Madagascar periwinkle) in small quantities, and heterologous reconstitution of vinblastine biosynthesis could provide an additional source of this drug. However, the chemistry underlying vinblastine synthesis makes identification of the biosynthetic genes challenging. Here we identify the two missing enzymes necessary for vinblastine biosynthesis in this plant: an oxidase and a reductase that isomerize stemmadenine acetate into dihydroprecondylocarpine acetate, which is then deacetoxylated and cyclized to either catharanthine or tabersonine via two hydrolases characterized herein. The pathways show how plants create chemical diversity and also enable development of heterologous platforms for generation of stemmadenine-derived bioactive compounds.
Reactivation of recall-induced neurons contributes to remote fear memory attenuation Science (IF 37.205) Pub Date : 2018-06-15 Ossama Khalaf, Siegfried Resch, Lucie Dixsaut, Victoire Gorden, Liliane Glauser, Johannes Gräff
Whether fear attenuation is mediated by inhibition of the original memory trace of fear with a new memory trace of safety or by updating of the original fear trace toward safety has been a long-standing question in neuroscience and psychology alike. In particular, which of the two scenarios underlies the attenuation of remote (month-old) fear memories is completely unknown, despite the impetus to better understand this process against the backdrop of enduring traumata. We found—chemogenetically and in an engram-specific manner—that effective remote fear attenuation is accompanied by the reactivation of memory recall–induced neurons in the dentate gyrus and that the continued activity of these neurons is critical for fear reduction. This suggests that the original memory trace of fear actively contributes to remote fear attenuation.
Near-atomic model of microtubule-tau interactions Science (IF 37.205) Pub Date : 2018-06-15 Elizabeth H. Kellogg, Nisreen M. A. Hejab, Simon Poepsel, Kenneth H. Downing, Frank DiMaio, Eva Nogales
Tau is a developmentally regulated axonal protein that stabilizes and bundles microtubules (MTs). Its hyperphosphorylation is thought to cause detachment from MTs and subsequent aggregation into fibrils implicated in Alzheimer’s disease. It is unclear which tau residues are crucial for tau-MT interactions, where tau binds on MTs, and how it stabilizes them. We used cryo–electron microscopy to visualize different tau constructs on MTs and computational approaches to generate atomic models of tau-tubulin interactions. The conserved tubulin-binding repeats within tau adopt similar extended structures along the crest of the protofilament, stabilizing the interface between tubulin dimers. Our structures explain the effect of phosphorylation on MT affinity and lead to a model of tau repeats binding in tandem along protofilaments, tethering together tubulin dimers and stabilizing polymerization interfaces.
Ghost cytometry Science (IF 37.205) Pub Date : 2018-06-15 Sadao Ota, Ryoichi Horisaki, Yoko Kawamura, Masashi Ugawa, Issei Sato, Kazuki Hashimoto, Ryosuke Kamesawa, Kotaro Setoyama, Satoko Yamaguchi, Katsuhito Fujiu, Kayo Waki, Hiroyuki Noji
Ghost imaging is a technique used to produce an object’s image without using a spatially resolving detector. Here we develop a technique we term “ghost cytometry,” an image-free ultrafast fluorescence “imaging” cytometry based on a single-pixel detector. Spatial information obtained from the motion of cells relative to a static randomly patterned optical structure is compressively converted into signals that arrive sequentially at a single-pixel detector. Combinatorial use of the temporal waveform with the intensity distribution of the random pattern allows us to computationally reconstruct cell morphology. More importantly, we show that applying machine-learning methods directly on the compressed waveforms without image reconstruction enables efficient image-free morphology-based cytometry. Despite a compact and inexpensive instrumentation, image-free ghost cytometry achieves accurate and high-throughput cell classification and selective sorting on the basis of cell morphology without a specific biomarker, both of which have been challenging to accomplish using conventional flow cytometers.
Technology Feature | Translating big data: The proteomics challenge Science (IF 37.205) Pub Date : 2018-06-15 Mike May
Getting the most out of protein-related information depends on teamwork among scientists around the world, and that involves sharing large datasets. Simply passing big data back and forth is not a problem, however—the main obstacle is sharing that data in a way that other scientists can use it. Building software that can interpret information from different experiments and equipment remains complicated; likewise, exploring and analyzing large datasets from proteomics experiments even from one lab requires software that is most often developed in-house. Read the Feature (Full-Text HTML)Read the Feature (PDF)Read New Products (PDF)
Induction of CD4 T cell memory by local cellular collectivity Science (IF 37.205) Pub Date : 2018-06-15 Michal Polonsky, Jacob Rimer, Amos Kern-Perets, Irina Zaretsky, Stav Miller, Chamutal Bornstein, Eyal David, Naama Meira Kopelman, Gil Stelzer, Ziv Porat, Benjamin Chain, Nir Friedman
Cell differentiation is directed by signals driving progenitors into specialized cell types. This process can involve collective decision-making, when differentiating cells determine their lineage choice by interacting with each other. We used live-cell imaging in microwell arrays to study collective processes affecting differentiation of naïve CD4+ T cells into memory precursors. We found that differentiation of precursor memory T cells sharply increases above a threshold number of locally interacting cells. These homotypic interactions involve the cytokines interleukin-2 (IL-2) and IL-6, which affect memory differentiation orthogonal to their effect on proliferation and survival. Mathematical modeling suggests that the differentiation rate is continuously modulated by the instantaneous number of locally interacting cells. This cellular collectivity can prioritize allocation of immune memory to stronger responses.
Unresolved endoplasmic reticulum stress engenders immune-resistant, latent pancreatic cancer metastases Science (IF 37.205) Pub Date : 2018-06-15 Arnaud Pommier, Naishitha Anaparthy, Nicoletta Memos, Z. Larkin Kelley, Alizée Gouronnec, Ran Yan, Cédric Auffray, Jean Albrengues, Mikala Egeblad, Christine A. Iacobuzio-Donahue, Scott K. Lyons, Douglas T. Fearon
The majority of patients with pancreatic ductal adenocarcinoma (PDA) develop metastatic disease after resection of their primary tumor. We found that livers from patients and mice with PDA harbor single disseminated cancer cells (DCCs) lacking expression of cytokeratin 19 (CK19) and major histocompatibility complex class I (MHCI). We created a mouse model to determine how these DCCs develop. Intraportal injection of immunogenic PDA cells into preimmunized mice seeded livers only with single, nonreplicating DCCs that were CK19– and MHCI–. The DCCs exhibited an endoplasmic reticulum (ER) stress response but paradoxically lacked both inositol-requiring enzyme 1α activation and expression of the spliced form of transcription factor XBP1 (XBP1s). Inducible expression of XBP1s in DCCs, in combination with T cell depletion, stimulated the outgrowth of macrometastatic lesions that expressed CK19 and MHCI. Thus, unresolved ER stress enables DCCs to escape immunity and establish latent metastases.
Improving mechanical sensor performance through larger damping Science (IF 37.205) Pub Date : 2018-06-15 Swapan K. Roy, Vincent T. K. Sauer, Jocelyn N. Westwood-Bachman, Anandram Venkatasubramanian, Wayne K. Hiebert
Mechanical resonances are used in a wide variety of devices, from smartphone accelerometers to computer clocks and from wireless filters to atomic force microscopes. Frequency stability, a critical performance metric, is generally assumed to be tantamount to resonance quality factor (the inverse of the linewidth and of the damping). We show that the frequency stability of resonant nanomechanical sensors can be improved by lowering the quality factor. At high bandwidths, quality-factor reduction is completely mitigated by increases in signal-to-noise ratio. At low bandwidths, notably, increased damping leads to better stability and sensor resolution, with improvement proportional to damping. We confirm the findings by demonstrating temperature resolution of 60 microkelvin at 300-hertz bandwidth. These results open the door to high-performance ultrasensitive resonators in gaseous or liquid environments, single-cell nanocalorimetry, nanoscale gas chromatography, atmospheric-pressure nanoscale mass spectrometry, and new approaches in crystal oscillator stability.
Ultrastable laser interferometry for earthquake detection with terrestrial and submarine cables Science (IF 37.205) Pub Date : 2018-06-14 Giuseppe Marra, Cecilia Clivati, Richard Luckett, Anna Tampellini, Jochen Kronjäger, Louise Wright, Alberto Mura, Filippo Levi, Stephen Robinson, André Xuereb, Brian Baptie, Davide Calonico
Detecting ocean-floor seismic activity is crucial for our understanding of the interior structure and dynamic behavior of the Earth. However, 70% of the planet’s surface is covered by water and seismometers coverage is limited to a handful of permanent ocean bottom stations. We show that existing telecommunication optical fiber cables can detect seismic events when combined with state-of-the-art frequency metrology techniques by using the fiber itself as the sensing element. We detected earthquakes over terrestrial and submarine links with length ranging from 75 to 535 km and a geographical distance from the earthquake's epicenter ranging from 25 to 18,500 km. Implementing a global seismic network for real-time detection of underwater earthquakes requires applying the proposed technique to the existing extensive submarine optical fiber network.
Retinal isomerization in bacteriorhodopsin captured by a femtosecond x-ray laser Science (IF 37.205) Pub Date : 2018-06-14 Przemyslaw Nogly, Tobias Weinert, Daniel James, Sergio Carbajo, Dmitry Ozerov, Antonia Furrer, Dardan Gashi, Veniamin Borin, Petr Skopintsev, Kathrin Jaeger, Karol Nass, Petra Båth, Robert Bosman, Jason Koglin, Matthew Seaberg, Thomas Lane, Demet Kekilli, Steffen Brünle, Tomoyuki Tanaka, Wenting Wu, Christopher Milne, Thomas White, Anton Barty, Uwe Weierstall, Valerie Panneels, Eriko Nango, So Iwata, Mark Hunter, Igor Schapiro, Gebhard Schertler, Richard Neutze, Jörg Standfuss
Ultrafast isomerization of retinal is the primary step in photoresponsive biological functions including vision in humans and ion-transport across bacterial membranes. We studied the sub-picosecond structural dynamics of retinal isomerization in the light-driven proton pump bacteriorhodopsin using an x-ray laser. A series of structural snapshots with near-atomic spatial and temporal resolution in the femtosecond regime show how the excited all-trans retinal samples conformational states within the protein binding pocket prior to passing through a twisted geometry and emerging in the 13-cis conformation. Our findings suggest ultrafast collective motions of aspartic acid residues and functional water molecules in the proximity of the retinal Schiff base as a key ingredient for this stereo-selective and efficient photochemical reaction.
Sex reversal following deletion of a single distal enhancer of Sox9 Science (IF 37.205) Pub Date : 2018-06-14 Nitzan Gonen, Chris R. Futtner, Sophie Wood, S. Alexandra Garcia-Moreno, Isabella M. Salamone, Shiela C. Samson, Ryohei Sekido, Francis Poulat, Danielle M. Maatouk, Robin Lovell-Badge
Cell fate decisions require appropriate regulation of key genes. Sox9, a direct target of SRY, is pivotal in mammalian sex determination. In vivo high-throughput chromatin accessibility techniques, transgenic assays, and genome editing revealed several novel gonadal regulatory elements in the 2-megabase gene desert upstream of Sox9. Although others are redundant, Enh13, a 557–base pair element located 565 kilobases 5′, is essential to initiate mouse testis development; its deletion giving XY females with Sox9 transcript levels equivalent to XX gonads. Our data are consistent with the time-sensitive activity of SRY and indicate a strict order of enhancer usage. Enh13 is conserved and embedded within a 32.5-kilobase region whose deletion in patients is associated with XY sex reversal, suggesting it is also critical in humans.
The South Asian monsoon—Pollution pump and purifier Science (IF 37.205) Pub Date : 2018-06-14 J. Lelieveld, E. Bourtsoukidis, C. Brühl, H. Fischer, H. Fuchs, H. Harder, A. Hofzumahaus, F. Holland, D. Marno, M. Neumaier, A. Pozzer, H. Schlager, J. Williams, A. Zahn, H. Ziereis
Air pollution is growing fastest in monsoon-impacted South Asia. During the dry, winter monsoon the fumes disperse toward the Indian Ocean, creating a vast pollution haze, but their fate during the wet, summer monsoon has been unclear. We performed atmospheric chemistry measurements by aircraft in the “Oxidation Mechanism Observations” campaign, sampling the summer monsoon outflow in the upper troposphere between the Mediterranean and the Indian Ocean. The measurements, supported by model calculations, show that the monsoon sustains a remarkably efficient cleansing mechanism in which contaminants are rapidly oxidized and deposited to Earth’s surface. However, some pollutants are lofted above the monsoon clouds, and chemically processed in a reactive reservoir before being redistributed globally, including to the stratosphere.
Dirac-source field-effect transistors as energy-efficient, high-performance electronic switches Science (IF 37.205) Pub Date : 2018-06-14 Chenguang Qiu, Fei Liu, Lin Xu, Bing Deng, Mengmeng Xiao, Jia Si, Li Lin, Zhiyong Zhang, Jian Wang, Hong Guo, Hailin Peng, Lian-Mao Peng
An efficient way to reduce the power is to lower the supply voltage VDD, but this voltage is restricted by the 60 millivolts per decade thermionic limit of subthreshold swing (SS) in field-effect transistors (FETs). We show that a graphene Dirac source (DS) with a much narrower electron density distribution around the Fermi level than that of conventional FETs can lower SS. A DS-FET with a carbon nanotube channel provided an average SS of 40 millivolt per decade over four decades of current at room temperature and high device current I60 of up to 40 microampere per micrometer at 60 millivolts per decade. When compared with state-of-the-art Si 14-nanometer node FETs, a similar Ion is realized but at much lower supply voltage of 0.5 versus 0.7 volts for Si, and a much steeper SS below 35 millivolts per decade in the off-state.
A dust-enshrouded tidal disruption event with a resolved radio jet in a galaxy merger Science (IF 37.205) Pub Date : 2018-06-14 S. Mattila, M. Pérez-Torres, A. Efstathiou, P. Mimica, M. Fraser, E. Kankare, A. Alberdi, M. Á. Aloy, T. Heikkilä, P. G. Jonker, P. Lundqvist, I. Martí-Vidal, W. P. S. Meikle, C. Romero-Cañizales, S. J. Smartt, S. Tsygankov, E. Varenius, A. Alonso-Herrero, M. Bondi, C. Fransson, R. Herrero-Illana, T. Kangas, R. Kotak, N. Ramírez-Olivencia, P. Väisänen, R. J. Beswick, D. L. Clements, R. Greimel, J. Harmanen, J. Kotilainen, K. Nandra, T. Reynolds, S. Ryder, N. A. Walton, K. Wiik, G. Östlin
Tidal disruption events (TDEs) are transient flares produced when a star is ripped apart by the gravitational field of a supermassive black hole (SMBH). We have observed a transient source in the western nucleus of the merging galaxy pair Arp 299 that radiated >1.5 × 1052 erg in the infrared and radio but was not luminous at optical or x-ray wavelengths. We interpret this as a TDE with much of its emission reradiated at infrared wavelengths by dust. Efficient reprocessing by dense gas and dust may explain the difference between theoretical predictions and observed luminosities of TDEs. The radio observations resolve an expanding and decelerating jet, probing the jet formation and evolution around a SMBH.
A LIMA1 variant promotes low plasma LDL cholesterol and decreases intestinal cholesterol absorption Science (IF 37.205) Pub Date : 2018-06-08 Ying-Yu Zhang, Zhen-Yan Fu, Jian Wei, Wei Qi, Gulinaer Baituola, Jie Luo, Ya-Jie Meng, Shu-Yuan Guo, Huiyong Yin, Shi-You Jiang, Yun-Feng Li, Hong-Hua Miao, Yong Liu, Yan Wang, Bo-Liang Li, Yi-Tong Ma, Bao-Liang Song
A high concentration of low-density lipoprotein cholesterol (LDL-C) is a major risk factor for cardiovascular disease. Although LDL-C levels vary among humans and are heritable, the genetic factors affecting LDL-C are not fully characterized. We identified a rare frameshift variant in the LIMA1 (also known as EPLIN or SREBP3) gene from a Chinese family of Kazakh ethnicity with inherited low LDL-C and reduced cholesterol absorption. In a mouse model, LIMA1 was mainly expressed in the small intestine and localized on the brush border membrane. LIMA1 bridged NPC1L1, an essential protein for cholesterol absorption, to a transportation complex containing myosin Vb and facilitated cholesterol uptake. Similar to the human phenotype, Lima1-deficient mice displayed reduced cholesterol absorption and were resistant to diet-induced hypercholesterolemia. Through our study of both mice and humans, we identify LIMA1 as a key protein regulating intestinal cholesterol absorption.
Background levels of methane in Mars’ atmosphere show strong seasonal variations Science (IF 37.205) Pub Date : 2018-06-08 Christopher R. Webster, Paul R. Mahaffy, Sushil K. Atreya, John E. Moores, Gregory J. Flesch, Charles Malespin, Christopher P. McKay, German Martinez, Christina L. Smith, Javier Martin-Torres, Javier Gomez-Elvira, Maria-Paz Zorzano, Michael H. Wong, Melissa G. Trainer, Andrew Steele, Doug Archer, Brad Sutter, Patrice J. Coll, Caroline Freissinet, Pierre-Yves Meslin, Raina V. Gough, Christopher H. House, Alexander Pavlov, Jennifer L. Eigenbrode, Daniel P. Glavin, John C. Pearson, Didier Keymeulen, Lance E. Christensen, Susanne P. Schwenzer, Rafael Navarro-Gonzalez, Jorge Pla-García, Scot C. R. Rafkin, Álvaro Vicente-Retortillo, Henrik Kahanpää, Daniel Viudez-Moreiras, Michael D. Smith, Ari-Matti Harri, Maria Genzer, Donald M. Hassler, Mark Lemmon, Joy Crisp, Stanley P. Sander, Richard W. Zurek, Ashwin R. Vasavada
Variable levels of methane in the martian atmosphere have eluded explanation partly because the measurements are not repeatable in time or location. We report in situ measurements at Gale crater made over a 5-year period by the Tunable Laser Spectrometer on the Curiosity rover. The background levels of methane have a mean value 0.41 ± 0.16 parts per billion by volume (ppbv) (95% confidence interval) and exhibit a strong, repeatable seasonal variation (0.24 to 0.65 ppbv). This variation is greater than that predicted from either ultraviolet degradation of impact-delivered organics on the surface or from the annual surface pressure cycle. The large seasonal variation in the background and occurrences of higher temporary spikes (~7 ppbv) are consistent with small localized sources of methane released from martian surface or subsurface reservoirs.
Organic matter preserved in 3-billion-year-old mudstones at Gale crater, Mars Science (IF 37.205) Pub Date : 2018-06-08 Jennifer L. Eigenbrode, Roger E. Summons, Andrew Steele, Caroline Freissinet, Maëva Millan, Rafael Navarro-González, Brad Sutter, Amy C. McAdam, Heather B. Franz, Daniel P. Glavin, Paul D. Archer, Paul R. Mahaffy, Pamela G. Conrad, Joel A. Hurowitz, John P. Grotzinger, Sanjeev Gupta, Doug W. Ming, Dawn Y. Sumner, Cyril Szopa, Charles Malespin, Arnaud Buch, Patrice Coll
Establishing the presence and state of organic matter, including its possible biosignatures, in martian materials has been an elusive quest, despite limited reports of the existence of organic matter on Mars. We report the in situ detection of organic matter preserved in lacustrine mudstones at the base of the ~3.5-billion-year-old Murray formation at Pahrump Hills, Gale crater, by the Sample Analysis at Mars instrument suite onboard the Curiosity rover. Diverse pyrolysis products, including thiophenic, aromatic, and aliphatic compounds released at high temperatures (500° to 820°C), were directly detected by evolved gas analysis. Thiophenes were also observed by gas chromatography–mass spectrometry. Their presence suggests that sulfurization aided organic matter preservation. At least 50 nanomoles of organic carbon persists, probably as macromolecules containing 5% carbon as organic sulfur molecules.
Evidence for a quantum dipole liquid state in an organic quasi–two-dimensional material Science (IF 37.205) Pub Date : 2018-06-08 Nora Hassan, Streit Cunningham, Martin Mourigal, Elena I. Zhilyaeva, Svetlana A. Torunova, Rimma N. Lyubovskaya, John A. Schlueter, Natalia Drichko
Mott insulators are commonly pictured with electrons localized on lattice sites, with their low-energy degrees of freedom involving spins only. Here, we observe emergent charge degrees of freedom in a molecule-based Mott insulator κ-(BEDT-TTF)2Hg(SCN)2Br, resulting in a quantum dipole liquid state. Electrons localized on molecular dimer lattice sites form electric dipoles that do not order at low temperatures and fluctuate with frequency detected experimentally in our Raman spectroscopy experiments. The heat capacity and Raman scattering response are consistent with a scenario in which the composite spin and electric dipole degrees of freedom remain fluctuating down to the lowest measured temperatures.
Imaging-based molecular barcoding with pixelated dielectric metasurfaces Science (IF 37.205) Pub Date : 2018-06-08 Andreas Tittl, Aleksandrs Leitis, Mingkai Liu, Filiz Yesilkoy, Duk-Yong Choi, Dragomir N. Neshev, Yuri S. Kivshar, Hatice Altug
Metasurfaces provide opportunities for wavefront control, flat optics, and subwavelength light focusing. We developed an imaging-based nanophotonic method for detecting mid-infrared molecular fingerprints and implemented it for the chemical identification and compositional analysis of surface-bound analytes. Our technique features a two-dimensional pixelated dielectric metasurface with a range of ultrasharp resonances, each tuned to a discrete frequency; this enables molecular absorption signatures to be read out at multiple spectral points, and the resulting information is then translated into a barcode-like spatial absorption map for imaging. The signatures of biological, polymer, and pesticide molecules can be detected with high sensitivity, covering applications such as biosensing and environmental monitoring. Our chemically specific technique can resolve absorption fingerprints without the need for spectrometry, frequency scanning, or moving mechanical parts, thereby paving the way toward sensitive and versatile miniaturized mid-infrared spectroscopy devices.
Structure of the maize photosystem I supercomplex with light-harvesting complexes I and II Science (IF 37.205) Pub Date : 2018-06-08 Xiaowei Pan, Jun Ma, Xiaodong Su, Peng Cao, Wenrui Chang, Zhenfeng Liu, Xinzheng Zhang, Mei Li
Plants regulate photosynthetic light harvesting to maintain balanced energy flux into photosystems I and II (PSI and PSII). Under light conditions favoring PSII excitation, the PSII antenna, light-harvesting complex II (LHCII), is phosphorylated and forms a supercomplex with PSI core and the PSI antenna, light-harvesting complex I (LHCI). Both LHCI and LHCII then transfer excitation energy to the PSI core. We report the structure of maize PSI-LHCI-LHCII solved by cryo–electron microscopy, revealing the recognition site between LHCII and PSI. The PSI subunits PsaN and PsaO are observed at the PSI-LHCI interface and the PSI-LHCII interface, respectively. Each subunit relays excitation to PSI core through a pair of chlorophyll molecules, thus revealing previously unseen paths for energy transfer between the antennas and the PSI core.
A silicon Brillouin laser Science (IF 37.205) Pub Date : 2018-06-08 Nils T. Otterstrom, Ryan O. Behunin, Eric A. Kittlaus, Zheng Wang, Peter T. Rakich
Brillouin laser oscillators offer powerful and flexible dynamics as the basis for mode-locked lasers, microwave oscillators, and optical gyroscopes in a variety of optical systems. However, Brillouin interactions are markedly weak in conventional silicon photonic waveguides, stifling progress toward silicon-based Brillouin lasers. The recent advent of hybrid photonic-phononic waveguides has revealed Brillouin interactions to be one of the strongest and most tailorable nonlinearities in silicon. In this study, we have harnessed these engineered nonlinearities to demonstrate Brillouin lasing in silicon. Moreover, we show that this silicon-based Brillouin laser enters a regime of dynamics in which optical self-oscillation produces phonon linewidth narrowing. Our results provide a platform to develop a range of applications for monolithic integration within silicon photonic circuits.
Experimental evidence for tipping points in social convention Science (IF 37.205) Pub Date : 2018-06-08 Damon Centola, Joshua Becker, Devon Brackbill, Andrea Baronchelli
Theoretical models of critical mass have shown how minority groups can initiate social change dynamics in the emergence of new social conventions. Here, we study an artificial system of social conventions in which human subjects interact to establish a new coordination equilibrium. The findings provide direct empirical demonstration of the existence of a tipping point in the dynamics of changing social conventions. When minority groups reached the critical mass—that is, the critical group size for initiating social change—they were consistently able to overturn the established behavior. The size of the required critical mass is expected to vary based on theoretically identifiable features of a social setting. Our results show that the theoretically predicted dynamics of critical mass do in fact emerge as expected within an empirical system of social coordination.
A tetrapod fauna from within the Devonian Antarctic Circle Science (IF 37.205) Pub Date : 2018-06-08 Robert Gess, Per Erik Ahlberg
Until now, all known fossils of tetrapods (limbed vertebrates with digits) and near-tetrapods (such as Elpistostege, Tiktaalik, and Panderichthys) from the Devonian period have come from localities in tropical to subtropical paleolatitudes. Most are from Laurussia, a continent incorporating Europe, Greenland, and North America, with only one body fossil and one footprint locality from Australia representing the southern supercontinent Gondwana. Here we describe two previously unknown tetrapods from the Late Devonian (late Famennian) Gondwana locality of Waterloo Farm in South Africa, then located within the Antarctic Circle, which demonstrate that Devonian tetrapods were not restricted to warm environments and suggest that they may have been global in distribution.
Numerical ordering of zero in honey bees Science (IF 37.205) Pub Date : 2018-06-08 Scarlett R. Howard, Aurore Avarguès-Weber, Jair E. Garcia, Andrew D. Greentree, Adrian G. Dyer
Some vertebrates demonstrate complex numerosity concepts—including addition, sequential ordering of numbers, or even the concept of zero—but whether an insect can develop an understanding for such concepts remains unknown. We trained individual honey bees to the numerical concepts of “greater than” or “less than” using stimuli containing one to six elemental features. Bees could subsequently extrapolate the concept of less than to order zero numerosity at the lower end of the numerical continuum. Bees demonstrated an understanding that parallels animals such as the African grey parrot, nonhuman primates, and even preschool children.
Plants send small RNAs in extracellular vesicles to fungal pathogen to silence virulence genes Science (IF 37.205) Pub Date : 2018-06-08 Qiang Cai, Lulu Qiao, Ming Wang, Baoye He, Feng-Mao Lin, Jared Palmquist, Sienna-Da Huang, Hailing Jin
Some pathogens and pests deliver small RNAs (sRNAs) into host cells to suppress host immunity. Conversely, hosts also transfer sRNAs into pathogens and pests to inhibit their virulence. Although sRNA trafficking has been observed in a wide variety of interactions, how sRNAs are transferred, especially from hosts to pathogens and pests, is still unknown. Here, we show that host Arabidopsis cells secrete exosome-like extracellular vesicles to deliver sRNAs into fungal pathogen Botrytis cinerea. These sRNA-containing vesicles accumulate at the infection sites and are taken up by the fungal cells. Transferred host sRNAs induce silencing of fungal genes critical for pathogenicity. Thus, Arabidopsis has adapted exosome-mediated cross-kingdom RNA interference as part of its immune responses during the evolutionary arms race with the pathogen.
A selfish genetic element confers non-Mendelian inheritance in rice Science (IF 37.205) Pub Date : 2018-06-08 Xiaowen Yu, Zhigang Zhao, Xiaoming Zheng, Jiawu Zhou, Weiyi Kong, Peiran Wang, Wenting Bai, Hai Zheng, Huan Zhang, Jing Li, Jiafan Liu, Qiming Wang, Long Zhang, Kai Liu, Yang Yu, Xiuping Guo, Jiulin Wang, Qibing Lin, Fuqing Wu, Yulong Ren, Shanshan Zhu, Xin Zhang, Zhijun Cheng, Cailin Lei, Shijia Liu, Xi Liu, Yunlu Tian, Ling Jiang, Song Ge, Chuanyin Wu, Dayun Tao, Haiyang Wang, Jianmin Wan
Selfish genetic elements are pervasive in eukaryote genomes, but their role remains controversial. We show that qHMS7, a major quantitative genetic locus for hybrid male sterility between wild rice (Oryza meridionalis) and Asian cultivated rice (O. sativa), contains two tightly linked genes [Open Reading Frame 2 (ORF2) and ORF3]. ORF2 encodes a toxic genetic element that aborts pollen in a sporophytic manner, whereas ORF3 encodes an antidote that protects pollen in a gametophytic manner. Pollens lacking ORF3 are selectively eliminated, leading to segregation distortion in the progeny. Analysis of the genetic sequence suggests that ORF3 arose first, followed by gradual functionalization of ORF2. Furthermore, this toxin-antidote system may have promoted the differentiation and/or maintained the genome stability of wild and cultivated rice.
Noninvasive blood tests for fetal development predict gestational age and preterm delivery Science (IF 37.205) Pub Date : 2018-06-08 Thuy T. M. Ngo, Mira N. Moufarrej, Marie-Louise H. Rasmussen, Joan Camunas-Soler, Wenying Pan, Jennifer Okamoto, Norma F. Neff, Keli Liu, Ronald J. Wong, Katheryne Downes, Robert Tibshirani, Gary M. Shaw, Line Skotte, David K. Stevenson, Joseph R. Biggio, Michal A. Elovitz, Mads Melbye, Stephen R. Quake
Noninvasive blood tests that provide information about fetal development and gestational age could potentially improve prenatal care. Ultrasound, the current gold standard, is not always affordable in low-resource settings and does not predict spontaneous preterm birth, a leading cause of infant death. In a pilot study of 31 healthy pregnant women, we found that measurement of nine cell-free RNA (cfRNA) transcripts in maternal blood predicted gestational age with comparable accuracy to ultrasound but at substantially lower cost. In a related study of 38 women (23 full-term and 15 preterm deliveries), all at elevated risk of delivering preterm, we identified seven cfRNA transcripts that accurately classified women who delivered preterm up to 2 months in advance of labor. These tests hold promise for prenatal care in both the developed and developing worlds, although they require validation in larger, blinded clinical trials.
High-resolution comparative analysis of great ape genomes Science (IF 37.205) Pub Date : 2018-06-08 Zev N. Kronenberg, Ian T. Fiddes, David Gordon, Shwetha Murali, Stuart Cantsilieris, Olivia S. Meyerson, Jason G. Underwood, Bradley J. Nelson, Mark J. P. Chaisson, Max L. Dougherty, Katherine M. Munson, Alex R. Hastie, Mark Diekhans, Fereydoun Hormozdiari, Nicola Lorusso, Kendra Hoekzema, Ruolan Qiu, Karen Clark, Archana Raja, AnneMarie E. Welch, Melanie Sorensen, Carl Baker, Robert S. Fulton, Joel Armstrong, Tina A. Graves-Lindsay, Ahmet M. Denli, Emma R. Hoppe, PingHsun Hsieh, Christopher M. Hill, Andy Wing Chun Pang, Joyce Lee, Ernest T. Lam, Susan K. Dutcher, Fred H. Gage, Wesley C. Warren, Jay Shendure, David Haussler, Valerie A. Schneider, Han Cao, Mario Ventura, Richard K. Wilson, Benedict Paten, Alex Pollen, Evan E. Eichler
Genetic studies of human evolution require high-quality contiguous ape genome assemblies that are not guided by the human reference. We coupled long-read sequence assembly and full-length complementary DNA sequencing with a multiplatform scaffolding approach to produce ab initio chimpanzee and orangutan genome assemblies. By comparing these with two long-read de novo human genome assemblies and a gorilla genome assembly, we characterized lineage-specific and shared great ape genetic variation ranging from single– to mega–base pair–sized variants. We identified ~17,000 fixed human-specific structural variants identifying genic and putative regulatory changes that have emerged in humans since divergence from nonhuman apes. Interestingly, these variants are enriched near genes that are down-regulated in human compared to chimpanzee cerebral organoids, particularly in cells analogous to radial glial neural progenitors.
Pulmonary neuroendocrine cells amplify allergic asthma responses Science (IF 37.205) Pub Date : 2018-06-08 Pengfei Sui, Darin L. Wiesner, Jinhao Xu, Yan Zhang, Jinwoo Lee, Steven Van Dyken, Amber Lashua, Chuyue Yu, Bruce S. Klein, Richard M. Locksley, Gail Deutsch, Xin Sun
Pulmonary neuroendocrine cells (PNECs) are rare airway epithelial cells whose function is poorly understood. Here we show that Ascl1-mutant mice that have no PNECs exhibit severely blunted mucosal type 2 response in models of allergic asthma. PNECs reside in close proximity to group 2 innate lymphoid cells (ILC2s) near airway branch points. PNECs act through calcitonin gene-related peptide (CGRP) to stimulate ILC2s and elicit downstream immune responses. In addition, PNECs act through the neurotransmitter γ-aminobutyric acid (GABA) to induce goblet cell hyperplasia. The instillation of a mixture of CGRP and GABA in Ascl1-mutant airways restores both immune and goblet cell responses. In accordance, lungs from human asthmatics show increased PNECs. These findings demonstrate that the PNEC-ILC2 neuroimmunological modules function at airway branch points to amplify allergic asthma responses.
Friction at the bed does not control fast glacier flow Science (IF 37.205) Pub Date : 2018-06-07 L. A. Stearns, C. J. van der Veen
The largest uncertainty in ice sheet models used to predict future sea-level rise originates from our limited understanding of processes at the ice-bed interface. Near glacier termini, where basal sliding controls ice flow, most predictive ice sheet models use a parameterization of sliding that has been theoretically derived for glacier flow over a hard bed. We find that this sliding relation does not apply to the 140 Greenland glaciers that we analyzed. There is no relationship between basal sliding and frictional stress at the glacier bed, contrary to theoretical predictions. There is a strong relationship between sliding speed and net pressure at the glacier bed. This latter finding is in agreement with earlier observations on mountain glaciers that have been largely overlooked by the glaciological community.
Structure basis for RNA-guided DNA degradation by Cascade and Cas3 Science (IF 37.205) Pub Date : 2018-06-07 Yibei Xiao, Min Luo, Adam E. Dolan, Maofu Liao, Ailong Ke
Type I CRISPR-Cas system features a sequential target-searching and degradation process on double-stranded DNA, by the RNA-guided Cascade complex and the nuclease-helicase fusion enzyme Cas3, respectively. Here we present a 3.7 Å resolution cryo-EM structure of the Type I-E Cascade/R-loop/Cas3 complex, poised to initiate DNA degradation. Cas3 distinguishes Cascade conformations and only captures the R-loop forming Cascade, to avoid cleaving partially complementary targets. Its nuclease domain recruits the non-target strand (NTS) DNA at a bulged region for the nicking of single-stranded DNA. An additional 4.7 Å resolution cryo-EM structure captures the post-nicking state, in which the severed NTS retracts to the helicase entrance, to be threaded for ATP-dependent processive degradation. These snapshots form the basis for understanding RNA-guided DNA degradation in Type I-E CRISPR-Cas systems.
Single-proton spin detection by diamond magnetometry Science (IF 37.205) Pub Date : 2014-10-16 M. Loretz, T. Rosskopf, J. M. Boss, S. Pezzagna, J. Meijer, C. L. Degen
Extending magnetic resonance imaging to the atomic scale has been a long-standing aspiration, driven by the prospect of directly mapping atomic positions in molecules with three-dimensional spatial resolution. We report detection of individual, isolated proton spins by a nitrogen-vacancy (NV) center in a diamond chip covered by an inorganic salt. The single-proton identity was confirmed by the Zeeman effect and by a quantum coherent rotation of the weakly coupled nuclear spin. Using the hyperfine field of the NV center as an imaging gradient, we determined proton-NV distances of less than 1 nm.
Genetic Signatures of Exceptional Longevity in Humans Science (IF 37.205) Pub Date : 2010-07-01 Paola Sebastiani, Nadia Solovieff, Annibale Puca, Stephen W. Hartley, Efthymia Melista, Stacy Andersen, Daniel A. Dworkis, Jemma B. Wilk, Richard H. Myers, Martin H. Steinberg, Monty Montano, Clinton T. Baldwin, Thomas T. Perls
Healthy aging is thought to reflect the combined influence of environmental factors (lifestyle choices) and genetic factors. To explore the genetic contribution, we undertook a genome-wide association study of exceptional longevity (EL) in 1055 centenarians and 1267 controls. Using these data, we built a genetic model that includes 150 single-nucleotide polymorphisms (SNPs) and found that it could predict EL with 77% accuracy in an independent set of centenarians and controls. Further in silico analysis revealed that 90% of centenarians can be grouped into 19 clusters characterized by different combinations of SNP genotypes—or genetic signatures—of varying predictive value. The different signatures, which attest to the genetic complexity of EL, correlated with differences in the prevalence and age of onset of age-associated diseases (e.g., dementia, hypertension, and cardiovascular disease) and may help dissect this complex phenotype into subphenotypes of healthy aging.
Some contents have been Reproduced by permission of The Royal Society of Chemistry.
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