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From the Cover

3457 Bison arrival in North America 3297 Collaboration between psychologists and economists 3328 Properties of glasses 3397 New Middle Pleistocene hominin cranium 3491 Chromosome Y and susceptibility to influenza

Contents

THIS WEEK IN PNAS Cover image: Pictured is a modern 3265 In This Issue plains bison cow from Elk Island National Park, Alberta, Canada. Duane Froese et al. report on the oldest well-dated LETTERS (ONLINE ONLY) bison fossils in North America, including E2545 Relevance of the alternate conductance states of anthrax toxin channel a steppe bison (Bison priscus) from Goli Yamini and Ekaterina M. Nestorovich northern Yukon and a giant long-horned bison (Bison latifrons) from Colorado. E2547 Reply to Yamini and Nestorovich: Alternate clamped states of the anthrax toxin Based on ancient bison mitochondrial protective antigen channel genomes, the study finds that all Bryan A. Krantz modern bison are descended from a dispersal of bison between 195,000 INNER WORKINGS—An over-the-shoulder look at scientists at work and 135,000 years ago from Eurasia via the Bering Land Bridge and a subsequent 3266 SMART collars help track and conserve wildlife dispersal approximately 45,000 and Leslie Willoughby 21,000 years ago. See the article by – Froese et al. on pages 3457 3462. Image CORE CONCEPTS—A brief introduction to emerging topics in science courtesy of John W. Ives (University of Alberta, Edmonton, Canada). 3269 Unraveling the enigma of fast radio bursts Adam Mann

QNAS 3272 QnAs with Marcia McNutt Prashant Nair

RETROSPECTIVE 3275 George Klein: 1925–2016 Klaus Rajewsky

COMMENTARIES 3278 Manipulating molecules with quantum light Markus Kowalewski and Shaul Mukamel See companion article on page 3026 in issue 12 of volume 114 3281 Can self-awareness be taught? Monkeys pass the mirror test—again Annamarie W. Huttunen, Geoffrey K. Adams, and Michael L. Platt See companion article on page 3258 in issue 12 of volume 114

Free online through the PNAS open access option. PNAS u March 28, 2017 u vol. 114 u no. 13 u iii–vii 3284 Rationally designed PPARδ-specific agonists and their BIOPHYSICS AND COMPUTATIONAL BIOLOGY therapeutic potential for metabolic syndrome E2644 Phosphorylation-induced conformational dynamics in Rebecca L. Cox an intrinsically disordered protein and potential role See companion article on page E2563 in phenotypic heterogeneity 3286 Collaboration, conflict, and disconnect between Prakash Kulkarni, Mohit Kumar Jolly, Dongya Jia, Steven M. psychologists and economists Mooney, Ajay Bhargava, Luciane T. Kagohara, Yihong Chen, Pengyu Hao, Yanan He, Robert W. Veltri, Alexander Grishaev, Charles F. Manski Keith Weninger, Herbert Levine, and John Orban See companion article on page 3297 E2654 Bacterial proteostasis balances energy and chaperone 3289 Glass transition imminent, resistance is futile utilization efficiently Vassiliy Lubchenko Mantu Santra, Daniel W. Farrell, and Ken A. Dill See companion article on page 3328

PNAS PLUS CHEMISTRY E2556 Electron transfer between anatase TiO and an 3292 Significance Statements 2 O2 molecule directly observed by atomic Brief statements written by the authors about the significance of their force microscopy papers. Martin Setvin, Jan Hulva, Gareth S. Parkinson, Michael Schmid, and Ulrike Diebold PERSPECTIVE E2563 Structural basis for specific ligation of the peroxisome 3297 Eliciting probabilistic expectations: Collaborations proliferator-activated receptor δ between psychologists and economists Chyuan-Chuan Wu, Thomas J. Baiga, Michael Downes, James J. Wa¨ndi Bruine de Bruin and Baruch Fischhoff La Clair, Annette R. Atkins, Stephane B. Richard, Weiwei Fan, See Commentary on page 3286 Theresa A. Stockley-Noel, Marianne E. Bowman, Joseph P. Noel, and Ronald M. Evans INAUGURAL ARTICLE See Commentary on page 3284 3305 Experimental comparison of two quantum 3334 Diagnosis of prostate cancer by desorption electrospray computing architectures ionization mass spectrometric imaging of small Norbert M. Linke, Dmitri Maslov, Martin Roetteler, Shantanu metabolites and lipids Debnath, Caroline Figgatt, Kevin A. Landsman, Kenneth Wright, Shibdas Banerjee, Richard N. Zare, Robert J. Tibshirani, and Christopher Monroe Christian A. Kunder, Rosalie Nolley, Richard Fan, James D. Brooks, and Geoffrey A. Sonn 3451 Volatile secondary metabolites as aposematic PHYSICAL SCIENCES olfactory signals and defensive weapons in aquatic environments APPLIED MATHEMATICS Giuseppe Giordano, Marianna Carbone, Maria Letizia Ciavatta, 3415 Topological knots and links in proteins Eleonora Silvano, Margherita Gavagnin, Mary J. Garson, Pawel Dabrowski-Tumanski and Joanna I. Sulkowska Karen L. Cheney, I Wayan Mudianta, Giovanni Fulvio Russo, Guido Villani, Laura Magliozzi, Gianluca Polese, Christian 3521 Overcoming catastrophic forgetting in Zidorn, Adele Cutignano, Angelo Fontana, Michael T. Ghiselin, neural networks and Ernesto Mollo James Kirkpatrick, Razvan Pascanu, Neil Rabinowitz, Joel 3469 Storage and release of hydrogen cyanide in Veness, Guillaume Desjardins, Andrei A. Rusu, Kieran Milan, a chelicerate (Oribatula tibialis) John Quan, Tiago Ramalho, Agnieszka Grabska-Barwinska, Adrian Bru¨ckner, Gu¨nther Raspotnig, Katja Wehner, Reinhard , Claudia Clopath, Dharshan Kumaran, Meusinger, Roy A. Norton, and Michael Heethoff and Raia Hadsell

APPLIED PHYSICAL SCIENCES COMPUTER SCIENCES E2548 Effect of material flexibility on the thermodynamics 3305 Experimental comparison of two quantum and kinetics of hydrophobically induced computing architectures evaporation of water Norbert M. Linke, Dmitri Maslov, Martin Roetteler, Shantanu Y. Elia Altabet, Amir Haji-Akbari ( ), Debnath, Caroline Figgatt, Kevin A. Landsman, Kenneth Wright, and Pablo G. Debenedetti and Christopher Monroe 3311 Eradicating catastrophic collapse in interdependent networks via reinforced nodes EARTH, ATMOSPHERIC, AND PLANETARY SCIENCES Xin Yuan, Yanqing Hu, H. Eugene Stanley, and Shlomo Havlin E2571 Biological regulation of atmospheric chemistry en 3316 Computational investigation of surface freezing in route to planetary oxygenation a molecular model of water Gareth Izon, Aubrey L. Zerkle, Kenneth H. Williford, James Amir Haji-Akbari ( ) and Pablo G. Debenedetti Farquhar, Simon W. Poulton, and Mark W. Claire 3322 Dynamic cross-correlations between entangled 3340 Pacific North American circulation pattern links biofilaments as they diffuse external forcing and North American hydroclimatic Boyce Tsang, Zachary E. Dell, Lingxiang Jiang, Kenneth S. change over the past millennium Schweizer, and Steve Granick Zhongfang Liu, Yanlin Tang, Zhimin Jian, Christopher J. Poulsen, 3328 Real space renormalization group theory of Jeffrey M. Welker, and Gabriel J. Bowen disordered models of glasses 3346 Sediment supply controls equilibrium channel Maria Chiara Angelini and Giulio Biroli geometry in gravel rivers See Commentary on page 3289 Allison M. Pfeiffer, Noah J. Finnegan, and Jane K. Willenbring

iv u www.pnas.org Contents 3352 Deep-sea coral evidence for lower Southern Ocean BIOLOGICAL SCIENCES surface nitrate concentrations during the last ice age AGRICULTURAL SCIENCES Xingchen Tony Wang, Daniel M. Sigman, Maria G. Prokopenko, 3393 In vivo diagnostics of early abiotic plant stress Jess F. Adkins, Laura F. Robinson, Sophia K. Hines, Junyi Chai, Anja S. Studer, Alfredo Martı´nez-Garcı´a, Tianyu Chen, response via Raman spectroscopy and Gerald H. Haug Narangerel Altangerel, Gombojav O. Ariunbold, Connor Gorman, Masfer H. Alkahtani, Eli J. Borrego, Dwight Bohlmeyer, Philip 3457 Fossil and genomic evidence constrains the timing of Hemmer, Michael V. Kolomiets, Joshua S. Yuan, and Marlan O. Scully bison arrival in North America Duane Froese, Mathias Stiller, Peter D. Heintzman, Alberto V. ANTHROPOLOGY Reyes, Grant D. Zazula, Andre´ E. R. Soares, Matthias Meyer, E2590 Cross-cousin marriage among the Yanomamö shows Elizabeth Hall, Britta J. L. Jensen, Lee J. Arnold, Ross D. E. – MacPhee, and Beth Shapiro evidence of parent offspring conflict and mate competition between brothers Napoleon A. Chagnon, Robert F. Lynch, Mary K. Shenk, ENGINEERING Raymond Hames, and Mark V. Flinn 3358 Wettability effect on nanoconfined water flow 3397 New Middle Pleistocene hominin cranium from Keliu Wu, Zhangxin Chen, Jing Li, Xiangfang Li, Jinze Xu, Gruta da Aroeira (Portugal) and Xiaohu Dong Joan Daura, Montserrat Sanz, Juan Luis Arsuaga, Dirk L. Hoffmann, Rolf M. Quam, Marı´a Cruz Ortega, Elena Santos, PHYSICS Sandra Go´mez, Angel Rubio, Lucı´a Villaescusa, Pedro Souto, – Joa˜o Mauricio, Filipa Rodrigues, Artur Ferreira, Paulo Godinho, E2580 Optimal run-and-tumble based transportation of Erik Trinkaus, and Joa˜o Zilha˜o a Janus particle with active steering Tomoyuki Mano, Jean-Baptiste Delfau, Junichiro Iwasawa, APPLIED BIOLOGICAL SCIENCES and Masaki Sano E2598 Morphological features of IFN-γ–stimulated E2662 Large-scale identification of coevolution signals across mesenchymal stromal cells predict overall homo-oligomeric protein interfaces by direct immunosuppressive capacity coupling analysis Matthew W. Klinker, Ross A. Marklein, Jessica L. Lo Surdo, Guido Uguzzoni, Shalini John Lovis, Francesco Oteri, Alexander Cheng-Hong Wei, and Steven R. Bauer Schug, Hendrik Szurmant, and Martin Weigt 3364 Tunable moiré bands and strong correlations in BIOCHEMISTRY small-twist-angle bilayer graphene E2608 Photocyclic behavior of rhodopsin induced by an Kyounghwan Kim, Ashley DaSilva, Shengqiang Huang, Babak atypical isomerization mechanism Fallahazad, Stefano Larentis, Takashi Taniguchi, Kenji ´ 渡邊賢司 Sahil Gulati, Beata Jastrzebska, Surajit Banerjee, Angel L. Watanabe ( ), Brian J. LeRoy, Allan H. MacDonald, Placeres, Przemyslaw Miszta, Songqi Gao, Karl Gunderson, and Emanuel Tutuc Gregory P. Tochtrop, Sławomir Filipek, Kota Katayama, 3370 Coarse graining from variationally enhanced sampling Philip D. Kiser, Muneto Mogi, Phoebe L. Stewart, applied to the Ginzburg–Landau model and Krzysztof Palczewski Michele Invernizzi, Omar Valsson, and Michele Parrinello E2616 Phytosphingosine degradation pathway includes fatty 3375 Deep melting reveals liquid structural memory and acid α-oxidation reactions in the anomalous ferromagnetism in bismuth endoplasmic reticulum Yu Shu, Dongli Yu, Wentao Hu, Yanbin Wang, Guoyin Shen, Takuya Kitamura, Naoya Seki, and Akio Kihara Yoshio Kono, Bo Xu, Julong He, Zhongyuan Liu, E2624 Structure-guided SCHEMA recombination generates and Yongjun Tian diverse chimeric channelrhodopsins 3381 Electron–hole asymmetry of the topological surface Claire N. Bedbrook, Austin J. Rice, Kevin K. Yang, Xiaozhe Ding, states in strained HgTe Siyuan Chen, Emily M. LeProust, Viviana Gradinaru, Andreas Jost, Michel Bendias, Jan Bo¨ttcher, Ewelina and Frances H. Arnold Hankiewicz, Christoph Bru¨ne, Hartmut Buhmann, Laurens W. E2634 Multisite aggregation of p53 and implications for Molenkamp, Jan C. Maan, Uli Zeitler, Nigel Hussey, drug rescue and Steffen Wiedmann GuoZhen Wang and Alan R. Fersht 3387 Monostable superrepellent materials 3403 Distinct recognition of complement iC3b by integrins Yanshen Li, David Que´re´, Cunjing Lv, and Quanshui Zheng αXβ2 and αMβ2 3393 In vivo diagnostics of early abiotic plant stress Shutong Xu, Jianchuan Wang, Jia-Huai Wang, response via Raman spectroscopy and Timothy A. Springer Narangerel Altangerel, Gombojav O. Ariunbold, Connor Gorman, 3409 Persistence of the mitochondrial permeability transition Masfer H. Alkahtani, Eli J. Borrego, Dwight Bohlmeyer, Philip in the absence of subunit c of human ATP synthase Hemmer, Michael V. Kolomiets, Joshua S. Yuan, and Marlan O. Scully Jiuya He, Holly C. Ford, Joe Carroll, Shujing Ding, Ian M. Fearnley, and John E. Walker

SOCIAL SCIENCES BIOPHYSICS AND COMPUTATIONAL BIOLOGY E2644 Phosphorylation-induced conformational dynamics in ANTHROPOLOGY an intrinsically disordered protein and potential role E2590 Cross-cousin marriage among the Yanomamö shows in phenotypic heterogeneity evidence of parent–offspring conflict and mate Prakash Kulkarni, Mohit Kumar Jolly, Dongya Jia, Steven M. competition between brothers Mooney, Ajay Bhargava, Luciane T. Kagohara, Yihong Chen, Napoleon A. Chagnon, Robert F. Lynch, Mary K. Shenk, Pengyu Hao, Yanan He, Robert W. Veltri, Alexander Grishaev, Raymond Hames, and Mark V. Flinn Keith Weninger, Herbert Levine, and John Orban

Contents PNAS u March 28, 2017 u vol. 114 u no. 13 u v E2654 Bacterial proteostasis balances energy and chaperone 3451 Volatile secondary metabolites as aposematic utilization efficiently olfactory signals and defensive weapons in Mantu Santra, Daniel W. Farrell, and Ken A. Dill aquatic environments E2662 Large-scale identification of coevolution signals across Giuseppe Giordano, Marianna Carbone, Maria Letizia Ciavatta, homo-oligomeric protein interfaces by direct Eleonora Silvano, Margherita Gavagnin, Mary J. Garson, Karen L. Cheney, I Wayan Mudianta, Giovanni Fulvio Russo, coupling analysis Guido Villani, Laura Magliozzi, Gianluca Polese, Christian Guido Uguzzoni, Shalini John Lovis, Francesco Oteri, Alexander Zidorn, Adele Cutignano, Angelo Fontana, Michael T. Ghiselin, Schug, Hendrik Szurmant, and Martin Weigt and Ernesto Mollo 3415 Topological knots and links in proteins 3457 Fossil and genomic evidence constrains the timing of Pawel Dabrowski-Tumanski and Joanna I. Sulkowska bison arrival in North America Duane Froese, Mathias Stiller, Peter D. Heintzman, Alberto V. 3421 Ligand-induced allostery in the interaction of the Reyes, Grant D. Zazula, Andre´ E. R. Soares, Matthias Meyer, Pseudomonas aeruginosa heme binding protein Elizabeth Hall, Britta J. L. Jensen, Lee J. Arnold, Ross D. E. with heme oxygenase MacPhee, and Beth Shapiro Daniel J. Deredge, Weiliang Huang, Colleen Hui, Hirotoshi 3463 Flowering phenology shifts in response to Matsumura, Zhi Yue, Pierre Moe¨nne-Loccoz, Jana Shen, Patrick L. Wintrode, and Angela Wilks biodiversity loss Amelia A. Wolf, Erika S. Zavaleta, and Paul C. Selmants 3427 Steady-state EB cap size fluctuations are determined by stochastic microtubule growth and maturation EVOLUTION Jamie Rickman, Christian Duellberg, Nicholas I. Cade, Lewis D. Griffin, and Thomas Surrey E2729 Osmolality/salinity-responsive enhancers (OSREs) control induction of osmoprotective genes in CELL BIOLOGY euryhaline fish

E2672 Fission yeast myosin I facilitates PI(4,5)P2-mediated Xiaodan Wang and Dietmar Ku¨ltz anchoring of cytoplasmic dynein to the cortex 3469 Storage and release of hydrogen cyanide in Jerrin Mathew Thankachan, Stephen Sukumar Nuthalapati, a chelicerate (Oribatula tibialis) Nireekshit Addanki Tirumala, and Vaishnavi Ananthanarayanan Adrian Bru¨ckner, Gu¨nther Raspotnig, Katja Wehner, Reinhard 3433 Conserved role for Gga proteins in phosphatidylinositol Meusinger, Roy A. Norton, and Michael Heethoff 4-kinase localization to the trans-Golgi network Lydia Daboussi, Giancarlo Costaguta, Razmik Ghukasyan, GENETICS and Gregory S. Payne E2739 Loss of LMOD1 impairs smooth muscle cytocontractility 3439 Parasitophorous vacuole poration precedes its rupture and causes megacystis microcolon intestinal and rapid host erythrocyte cytoskeleton collapse hypoperistalsis syndrome in humans and mice in Plasmodium falciparum egress Danny Halim, Michael P. Wilson, Daniel Oliver, Erwin Brosens, Victoria L. Hale, Jean M. Watermeyer, Fiona Hackett, Gema Joke B. G. M. Verheij, Yu Han, Vivek Nanda, Qing Lyu, Michael Vizcay-Barrena, Christiaan van Ooij, James A. Thomas, Doukas, Hans Stoop, Rutger W. W. Brouwer, Wilfred F. J. van Matthew C. Spink, Maria Harkiolaki, Elizabeth Duke, Roland A. IJcken, Orazio J. Slivano, Alan J. Burns, Christine K. Christie, Fleck, Michael J. Blackman, and Helen R. Saibil Karen L. de Mesy Bentley, Alice S. Brooks, Dick Tibboel, Suowen Xu, Zheng Gen Jin, Tono Djuwantono, Wei Yan, Maria M. Alves, DEVELOPMENTAL BIOLOGY Robert M. W. Hofstra, and Joseph M. Miano E2682 Toll pathway is required for wound-induced 3473 Transcriptional landscape of the human cell cycle expression of barrier repair genes in the Yin Liu, Sujun Chen, Su Wang, Fraser Soares, Martin Fischer, Drosophila epidermis Feilong Meng, Zhou Du, Charles Lin, Clifford Meyer, James A. Amalia Capilla, Dmitry Karachentsev, Rachel A. Patterson, Anita DeCaprio, Myles Brown, X. Shirley Liu, and Housheng Hansen He Hermann, Michelle T. Juarez, and William McGinnis 3479 Gentamicin B1 is a minor gentamicin component with E2689 AMPK blocks starvation-inducible transgenerational major nonsense mutation suppression activity defects in Alireza Baradaran-Heravi, Ju¨rgen Niesser, Aruna D. Balgi, Emilie Demoinet, Shaolin Li, and Richard Roy Kunho Choi, Carla Zimmerman, Andrew P. South, Hilary J. Anderson, Natalie C. Strynadka, Marcel B. Bally, E2699 Injury-stimulated and self-restrained BMP signaling and Michel Roberge dynamically regulates stem cell pool size during Drosophila midgut regeneration IMMUNOLOGY AND INFLAMMATION Aiguo Tian, Bing Wang, and Jin Jiang E2748 Cathepsin S is the major activator of the E2709 Hormone and receptor interplay in the regulation of psoriasis-associated proinflammatory mosquito lipid metabolism cytokine IL-36γ Xueli Wang, Yuan Hou, Tusar T. Saha, Gaofeng Pei, Alexander S. Joseph S. Ainscough, Tom Macleod, Dennis McGonagle, Raikhel, and Zhen Zou Rosella Brakefield, Jens M. Baron, Ade Alase, Miriam 3445 Specific deletion of LKB1/Stk11 in the Müllerian duct Wittmann, and Martin Stacey mesenchyme drives hyperplasia of the periurethral E2758 Receptor Mincle promotes skin allergies and is stroma and tumorigenesis in male mice capable of recognizing cholesterol sulfate Jitu W. George, Amanda L. Patterson, Pradeep S. Tanwar, Alexey V. Kostarnoy, Petya G. Gancheva, Bernd Lepenies, Andre´ Kajdacsy-Balla, Gail S. Prins, and Jose M. Teixeira Amir I. Tukhvatulin, Alina S. Dzharullaeva, Nikita B. Polyakov, Daniil A. Grumov, Daria A. Egorova, Andrey Y. Kulibin, ECOLOGY Maxim A. Bobrov, Ekaterina A. Malolina, Pavel A. Zykin, E2719 Multitrait successional forest dynamics enable diverse Andrey I. Soloviev, Evgeniy Riabenko, Diana V. Maltseva, competitive coexistence Dmitry A. Sakharov, Alexander G. Tonevitsky, Lyudmila V. Daniel S. Falster, A˚ke Bra¨nnstro¨m, Mark Westoby, Verkhovskaya, Denis Y. Logunov, Boris S. Naroditsky, and Ulf Dieckmann and Alexander L. Gintsburg

vi u www.pnas.org Contents E2766 Inhibition of atherogenesis by the COP9 signalosome NEUROSCIENCE subunit 5 in vivo 3521 Overcoming catastrophic forgetting in Yaw Asare, Miriam Ommer, Florence. A. Azombo, Setareh neural networks Alampour-Rajabi, Marieke Sternkopf, Maryam Sanati, Marion J. James Kirkpatrick, Razvan Pascanu, Neil Rabinowitz, Joel Gijbels, Corinna Schmitz, Dzmitry Sinitski, Pathricia V. Tilstam, Veness, Guillaume Desjardins, Andrei A. Rusu, Kieran Milan, Hongqi Lue, Andre´ Gessner, Denise Lange, Johannes A. Schmid, John Quan, Tiago Ramalho, Agnieszka Grabska-Barwinska, Christian Weber, Martin Dichgans, Joachim Jankowski, Ruggero Demis Hassabis, Claudia Clopath, Dharshan Kumaran, Pardi,MennoP.J.deWinther,HeidiNoels,andJu¨rgen Bernhagen and Raia Hadsell + E2776 Exhaustion-associated regulatory regions in CD8 3527 Patterns of coordinated cortical remodeling during tumor-infiltrating T cells adolescence and their associations with functional Giuliana P. Mognol, Roberto Spreafico, Victor Wong, James P. specialization and evolutionary expansion Scott-Browne, Susan Togher, Alexander Hoffmann, Patrick G. Aristeidis Sotiras, Jon B. Toledo, Raquel E. Gur, Ruben C. Gur, Hogan, Anjana Rao, and Sara Trifari Theodore D. Satterthwaite, and Christos Davatzikos 3485 Modulating IgG effector function by Fc glycan engineering PLANT BIOLOGY Tiezheng Li, David J. DiLillo, Stylianos Bournazos, John P. 3533 BRASSINOSTEROID INSENSITIVE2 negatively Giddens, Jeffrey V. Ravetch, and Lai-Xi Wang regulates cellulose synthesis in Arabidopsis 3491 Genetic variation in chromosome Y regulates by phosphorylating cellulose synthase 1 susceptibility to influenza A virus Clara Sa´nchez-Rodrı´guez, KassaDee Ketelaar, Rene Schneider, Dimitry N. Krementsov, Laure K. Case, Oliver Dienz, Abbas Jose A. Villalobos, Chris R. Somerville, Staffan Persson, Raza, Qian Fang, Jennifer L. Ather, Matthew E. Poynter, and Ian S. Wallace Jonathan E. Boyson, Janice Y. Bunn, and Cory Teuscher 3539 Noncanonical role of Arabidopsis COP1/SPA complex in repressing BIN2-mediated PIF3 phosphorylation MEDICAL SCIENCES and degradation in darkness 3497 Small molecule selectively suppresses MYC Jun-Jie Ling, Jian Li, Danmeng Zhu, and Xing Wang Deng transcription in cancer cells Claire Bouvard, Sang Min Lim, John Ludka, Nahid Yazdani, Ashley K. Woods, Arnab K. Chatterjee, Peter G. Schultz, and Shoutian Zhu CORRECTIONS (ONLINE ONLY)

3503 B vitamins attenuate the epigenetic effects of ambient OPINION fine particles in a pilot human intervention trial E2796 Opinion: Gender diversity leads to better science Jia Zhong, Oskar Karlsson, Guan Wang, Jun Li, Yichen Guo, Xinyi Lin, Michele Zemplenyi, Marco Sanchez-Guerra, Letizia Mathias Wullum Nielsen, Sharla Alegria, Love Bo¨rjeson, Henry Trevisi, Bruce Urch, Mary Speck, Liming Liang, Brent A. Coull, Etzkowitz, Holly J. Falk-Krzesinski, Aparna Joshi, Erin Petros Koutrakis, Frances Silverman, Diane R. Gold, Tangchun Leahey, Laurel Smith-Doerr, Anita Williams Woolley, Wu, and Andrea A. Baccarelli and Londa Schiebinger 3509 Selective dietary supplementation in early postpartum is associated with high resilience against COMMENTARY depressed mood E2797 Crystals creeping out of cracks Yekta Dowlati, Arun V. Ravindran, Zindel V. Segal, Donna E. Thomas Koop Stewart, Meir Steiner, and Jeffrey H. Meyer

MICROBIOLOGY BIOPHYSICS AND COMPUTATIONAL BIOLOGY E2786 Mouse cytomegalovirus M36 and M45 death E2798 Insights into immune system development and suppressors cooperate to prevent inflammation function from mouse T-cell repertoires resulting from antiviral programmed cell Zachary Sethna, Yuval Elhanati, Chrissy S. Dudgeon, death pathways Curtis G. Callan Jr., Arnold J. Levine, Thierry Mora, Lisa P. Daley-Bauer, Linda Roback, Lynsey N. Crosby, and Aleksandra M. Walczak A. Louise McCormick, Yanjun Feng, William J. Kaiser, and Edward S. Mocarski NEUROSCIENCE 3515 Host immunity to Plasmodium falciparum and the E2799 Homeostatic regulation of AMPA receptor expression assessment of emerging artemisinin resistance at single hippocampal synapses in a multinational cohort Qingming Hou, Dawei Zhang, Larissa Jarzylo, Richard L. Ricardo Ataide, Elizabeth A. Ashley, Rosanna Powell, Jo-Anne Huganir, and Heng-Ye Man Chan, Michael J. Malloy, Katherine O’Flaherty, Eizo Takashima, Christine Langer, Takafumi Tsuboi, Arjen M. Dondorp, Nicholas P. Day, Mehul Dhorda, Rick M. Fairhurst, Pharath Lim, Chanaki Amaratunga, Sasithon Pukrittayakamee, Tran Tinh Hien, Ye Htut, Mayfong Mayxay, M. Abul Faiz, James G. Beeson, Francois Nosten, Julie A. Simpson, NicholasJ.White,andFreyaJ.I.Fowkes ix Subscription Form

Contents PNAS u March 28, 2017 u vol. 114 u no. 13 u vii Loss of LMOD1 impairs smooth muscle cytocontractility PNAS PLUS and causes megacystis microcolon intestinal hypoperistalsis syndrome in humans and mice

Danny Halima,1, Michael P. Wilsonb,1, Daniel Oliverc, Erwin Brosensa, Joke B. G. M. Verheijd, Yu Hanb, Vivek Nandab, Qing Lyub, Michael Doukase, Hans Stoope, Rutger W. W. Brouwerf, Wilfred F. J. van IJckenf, Orazio J. Slivanob, Alan J. Burnsa,g, Christine K. Christieb, Karen L. de Mesy Bentleyh, Alice S. Brooksa, Dick Tibboeli, Suowen Xub, Zheng Gen Jinb, Tono Djuwantonoj, Wei Yanc, Maria M. Alvesa, Robert M. W. Hofstraa,g,2, and Joseph M. Mianob,2 aDepartment of Clinical Genetics, Erasmus University Medical Center, 3015 CN Rotterdam, The Netherlands; bAab Cardiovascular Research Institute, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642; cDepartment of Physiology and Cell Biology, University of Nevada School of Medicine, Reno, NV 89557; dDepartment of Genetics, University Medical Center, University of Groningen, 9700 RB Groningen, The Netherlands; eDepartment of Pathology, Erasmus University Medical Center, 3015 CN Rotterdam, The Netherlands; fCenter for Biomics, Erasmus University Medical Center, 3015 CN Rotterdam, The Netherlands; gStem Cells and Regenerative Medicine, Birth Defects Research Centre, University College London Institute of Child Health, London WC1N 1EH, United Kingdom; hDepartment of Pathology and Laboratory Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642; iDepartment of Pediatric Surgery, Erasmus University Medical Center, 3015 CN Rotterdam, The Netherlands; and jDepartment of Obstetrics and Gynecology, Faculty of Medicine, Universitas Padjadjaran, Bandung, Indonesia

Edited by Eric N. Olson, University of Texas Southwestern Medical Center, Dallas, TX, and approved February 21, 2017 (received for review December 13, 2016) Megacystis microcolon intestinal hypoperistalsis syndrome (MMIHS) is lacking (6, 7). Heterozygous mutations in ACTG2 are also ob- a congenital visceral myopathy characterized by severe dilation of the served in patients with autosomal dominant MMIHS (6, 8), but urinary bladder and defective intestinal motility. The genetic basis of there is emerging evidence for a recessive mode of inheritance. MMIHS has been ascribed to spontaneous and autosomal dominant For example, a homozygous loss-of-function variant in the my- mutations in actin gamma 2 (ACTG2), a smooth muscle contractile osin heavy chain 11 (MYH11) gene, which is another highly GENETICS gene. However, evidence suggesting a recessive origin of the disease specific contractile gene for smooth muscle lineages (9), was also exists. Using combined homozygosity mapping and whole reported in a patient with MMIHS from a consanguineous (i.e., exome sequencing, a genetically isolated family was found to carry genetically related) couple (10). To date, no other smooth a premature termination codon in Leiomodin1 (LMOD1),agenepref- muscle-restricted contractile genes have been linked to MMIHS. erentially expressed in vascular and visceral smooth muscle cells. Par- In this report, a patient with MMIHS is described from a ents heterozygous for the mutation exhibited no abnormalities, but consanguineous couple in whom no variants of ACTG2 or a child homozygous for the premature termination codon dis- played symptoms consistent with MMIHS. We used CRISPR-Cas9 MYH11 were found. Rather, an autosomal recessive inherited (CRISPR-associated protein) genome editing of Lmod1 to generate subtype of MMIHS has been discovered involving a homozygous a similar premature termination codon. Mice homozygous for the nonsense mutation in Leiomodin1 (LMOD1), an understudied mutation showed loss of LMOD1 protein and pathology consistent smooth muscle-restricted gene (11) that is a direct target of the with MMIHS, including late gestation expansion of the bladder, hydronephrosis, and rapid demise after parturition. Loss of Significance LMOD1 resulted in a reduction of filamentous actin, elongated cytoskeletal dense bodies, and impaired intestinal smooth muscle Rare recessive monogenic diseases are often found in isolated contractility. These results define LMOD1 as a disease gene for populations. In one such population, we identified a child car- MMIHS and suggest its role in establishing normal smooth muscle rying a homozygous nonsense mutation in an understudied cytoskeletal–contractile coupling. smooth muscle-restricted gene called Leiomodin1 (LMOD1). Heterozygous parents showed no disease; however, the child CRISPR-Cas9 | genetics | Leiomodin | myopathy | smooth muscle died shortly after birth from a rare condition known as mega- cystis microcolon intestinal hypoperistalsis syndrome. A mouse egacystis microcolon intestinal hypoperistalsis syndrome model with a similar Lmod1 mutation, engineered with CRISPR- M(MMIHS) (MIM155310) is a rare congenital defect of Cas9 genome editing, exhibited the same gastrointestinal and visceral smooth muscle, primarily affecting females who present urinary bladder phenotypes as seen in the newborn child. Phe- at birth with functional obstruction of intestine, microcolon, di- notyping revealed insights into the underlying cause of the dis- lation of bladder, and secondary hydronephrosis. More than ease. Results demonstrate the conserved function of LMOD1 in 250 cases have been reported since the initial description of human and mice and the importance of this protein in the mo- MMIHS in five young girls in 1976 (1–3). Total parenteral nu- lecular regulation of contractility in visceral smooth muscle cells. trition (TPN), adequate intermittent catheterization of bladder, and surgical corrections for intestinal malrotation are frequent Author contributions: D.H., M.P.W., D.O., Y.H., V.N., T.D., W.Y., M.M.A., R.M.W.H., and J.M.M. designed research; D.H., M.P.W., D.O., E.B., J.B.G.M.V., Y.H., Q.L., H.S., R.W.W.B., modes of treatment for this disease without which rapid death W.F.J.v.I., O.J.S., C.C., K.L.d.M.B., S.X., W.Y., M.M.A., and J.M.M. performed research; D.H., ensues. In some instances, multivisceral organ transplantation M.P.W., E.B., J.B.G.M.V., M.D., A.J.B., K.L.d.M.B., A.S.B., D.T., Z.G.J., T.D., M.M.A., R.M.W.H., and has been indicated with some success. Despite these clinical in- J.M.M. analyzed data; and D.H., M.P.W., R.M.W.H., and J.M.M. wrote the paper. terventions, MMIHS often leads to premature death due to The authors declare no conflict of interest. complications of therapy (3, 4). This article is a PNAS Direct Submission. The majority of MMIHS cases are sporadic, stemming from de Freely available online through the PNAS open access option. novo, heterozygous missense mutations in the smooth muscle- 1D.H. and M.P.W. contributed equally to this work. restricted ACTG2 gene (5, 6). These mutations are thought to 2To whom correspondence may be addressed. Email: [email protected] or r.hofstra@ render the ACTG2 protein defective for normal actin polymer- erasmusmc.nl. ization and contractile activity in visceral smooth muscle organs This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. although formal in vivo proof for this ACTG2 loss of function is 1073/pnas.1620507114/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1620507114 PNAS | Published online March 14, 2017 | E2739–E2747