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Table of Contents

April 2019 | Volume 2, No. 2

Research Articles

  • FUS (fused in sarcoma) is a component of the cellular response to topoisomerase I–induced DNA breakage and transcriptional stress
    Open Access
    FUS (fused in sarcoma) is a component of the cellular response to topoisomerase I–induced DNA breakage and transcriptional stress

    Maria Isabel Martinez-Macias, Duncan AQ Moore, Ryan L Green, Fernando Gomez-Herreros, Marcel Naumann, Andreas Hermann, Philip Van Damme, Majid Hafezparast, Keith W Caldecott

    Maria Isabel Martinez-Macias ... Keith W Caldecott

    Published 26 February 2019

    This work shows that the ALS-associated protein FUS is a component of the cellular response to transcriptional stress induced by topoisomerase I–induced DNA breakage, thereby accumulating at sites of nucleolar rRNA synthesis.

  • Worldwide genetic variation of the IGHV and TRBV immune receptor gene families in humans
    Open Access
    Worldwide genetic variation of the IGHV and TRBV immune receptor gene families in humans

    Shishi Luo, Jane A Yu, Heng Li, Yun S Song

    Shishi Luo ... Yun S Song

    Published 26 February 2019

    This article presents a comprehensive study of the IGHV and TRBV gene families in a globally diverse sample of humans and shows that the two gene families exhibit starkly different patterns of variation.

  • Assessment and site-specific manipulation of DNA (hydroxy-)methylation during mouse corticogenesis
    Open Access
    Assessment and site-specific manipulation of DNA (hydroxy-)methylation during mouse corticogenesis

    Florian Noack, Abhijeet Pataskar, Martin Schneider, Frank Buchholz, Vijay K Tiwari, Federico Calegari

    Florian Noack ... Federico Calegari

    Published 27 February 2019

    This work describes the dynamics of DNA modifications in specific cell types of the developing mammalian cortex. By providing a new method to manipulate this process in vivo, it is shown how this process can influence brain formation.

  • Maternal circulating miRNAs that predict infant FASD outcomes influence placental maturation
    Open Access
    Maternal circulating miRNAs that predict infant FASD outcomes influence placental maturation

    Alexander M Tseng, Amanda H Mahnke, Alan B Wells, Nihal A Salem, Andrea M Allan, Victoria HJ Roberts, Natali Newman, Nicole AR Walter, Christopher D Kroenke, Kathleen A Grant, Lisa K Akison, Karen M Moritz, Christina D Chambers, Rajesh C Miranda, Collaborative Initiative on Fetal Alcohol Spectrum Disorders

    Alexander M Tseng ... Collaborative Initiative on Fetal Alcohol Spectrum Disorders

    Published 4 March 2019

    Maternal gestational circulating microRNAs, predictive of adverse infant outcomes, including growth deficits, following prenatal alcohol exposure, contribute to placental pathology by impairing the EMT pathway in trophoblasts.

  • The small and large ribosomal subunits depend on each other for stability and accumulation
    Open Access
    The small and large ribosomal subunits depend on each other for stability and accumulation

    Brian Gregory, Nusrat Rahman, Ananth Bommakanti, Md Shamsuzzaman, Mamata Thapa, Alana Lescure, Janice M Zengel, Lasse Lindahl

    Brian Gregory ... Lasse Lindahl

    Published 5 March 2019

    Stopping 60S assembly blocks accumulation of 40S by post-assembly turnover, whereas inhibiting 40S assembly allows 60S assembly but results in fragmentation of 25S rRNA.

  • Innate extracellular vesicles from melanoma patients suppress β-catenin in tumor cells by miRNA-34a
    Open Access
    Innate extracellular vesicles from melanoma patients suppress β-catenin in tumor cells by miRNA-34a

    Jung-Hyun Lee, Jochen Dindorf, Martin Eberhardt, Xin Lai, Christian Ostalecki, Nina Koliha, Stefani Gross, Katja Blume, Heiko Bruns, Stefan Wild, Gerold Schuler, Julio Vera, Andreas S Baur

    Jung-Hyun Lee ... Andreas S Baur

    Published 7 March 2019

    Operated cancer patients develop elevated levels of extracellular vesicles (EVs) in their blood stream, suppressing cancer cells through miRNA-34a.

  • <em>PISD</em> is a mitochondrial disease gene causing skeletal dysplasia, cataracts, and white matter changes
    Open Access
    PISD is a mitochondrial disease gene causing skeletal dysplasia, cataracts, and white matter changes

    Tian Zhao, Caitlin M Goedhart, Pingdewinde N Sam, Rasha Sabouny, Susanne Lingrell, Adam J Cornish, Ryan E Lamont, Francois P Bernier, David Sinasac, Jillian S Parboosingh, Care4Rare Canada Consortium, Jean E Vance, Steven M Claypool, A Micheil Innes, Timothy E Shutt

    Tian Zhao ... Timothy E Shutt

    Published 11 March 2019

    This work demonstrates that pathogenic variants in PISD cause mitochondrial disease and suggests a novel mechanistic link whereby impaired lipid content in the inner mitochondrial membrane alters the activity of inner mitochondrial membrane proteases.

  • Expanding the repertoire of glucocorticoid receptor target genes by engineering genomic response elements
    Open Access
    Expanding the repertoire of glucocorticoid receptor target genes by engineering genomic response elements

    Verena Thormann, Laura V Glaser, Maika C Rothkegel, Marina Borschiwer, Melissa Bothe, Alisa Fuchs, Sebastiaan H Meijsing

    Verena Thormann ... Sebastiaan H Meijsing

    Published 13 March 2019

    This study shows that addition of a single transcription factor binding site can be sufficient to convert a gene into a glucocorticoid receptor target.

  • Structural basis of guanine nucleotide exchange for Rab11 by SH3BP5
    Open Access
    Structural basis of guanine nucleotide exchange for Rab11 by SH3BP5

    Sakurako Goto-Ito, Nobukatsu Morooka, Atsushi Yamagata, Yusuke Sato, Ken Sato, Shuya Fukai

    Sakurako Goto-Ito ... Shuya Fukai

    Published 14 March 2019

    The structure of the SH3BP5–Rab11a complex and structure-based mutational analyses reveal structural basis of nucleotide exchange for Rab11 by its specific guanine nucleotide exchange factor.

  • Dependence on Myb expression is attenuated in myeloid leukaemia with N-terminal CEBPA mutations
    Open Access
    Dependence on Myb expression is attenuated in myeloid leukaemia with N-terminal CEBPA mutations

    Giacomo Volpe, Pierre Cauchy, David S Walton, Carl Ward, Daniel Blakemore, Rachael Bayley, Mary L Clarke, Luisa Schmidt, Claus Nerlov, Paloma Garcia, Stéphanie Dumon, Florian Grebien, Jon Frampton

    Giacomo Volpe ... Jon Frampton

    Published 15 March 2019

    We show that for acute myeloid leukaemias with CEBPA mutations, the dependency of leukaemia growth and differentiation on the Myb transcription factor is related to the combination of N- and C-terminal mutations involved and how this affects overall gene expression.

  • Human DNA polymerase delta is a pentameric holoenzyme with a dimeric p12 subunit
    Open Access
    Human DNA polymerase delta is a pentameric holoenzyme with a dimeric p12 subunit

    Prashant Khandagale, Doureradjou Peroumal, Kodavati Manohar, Narottam Acharya

    Prashant Khandagale ... Narottam Acharya

    Published 18 March 2019

    The subunit p12 of human DNA polymerase delta (hPolδ) can dimerize, facilitating its interaction with PCNA and suggesting that hPolδ exists in a pentameric form in the cell.

  • Sex-regulated gene dosage effect of PPARα on synaptic plasticity
    Open Access
    Sex-regulated gene dosage effect of PPARα on synaptic plasticity

    Nathalie Pierrot, Laurence Ris, Ilie-Cosmin Stancu, Anna Doshina, Floriane Ribeiro, Donatienne Tyteca, Eric Baugé, Fanny Lalloyer, Liza Malong, Olivier Schakman, Karelle Leroy, Pascal Kienlen-Campard, Philippe Gailly, Jean-Pierre Brion, Ilse Dewachter, Bart Staels, Jean-Noël Octave

    Nathalie Pierrot ... Jean-Noël Octave

    Published 20 March 2019

    Differences in PPARα expression between males and females affect the regulation of GluA1 expression and synaptic plasticity in mice.

  • Functional inhibition of acid sphingomyelinase disrupts infection by intracellular bacterial pathogens
    Open Access
    Functional inhibition of acid sphingomyelinase disrupts infection by intracellular bacterial pathogens

    Chelsea L Cockburn, Ryan S Green, Sheela R Damle, Rebecca K Martin, Naomi N Ghahrai, Punsiri M Colonne, Marissa S Fullerton, Daniel H Conrad, Charles E Chalfant, Daniel E Voth, Elizabeth A Rucks, Stacey D Gilk, Jason A Carlyon

    Chelsea L Cockburn ... Jason A Carlyon

    Published 22 March 2019

    Many intracellular pathogens hijack cholesterol. Inhibiting acid sphingomyelinase alters cholesterol traffic to target different intracellular bacteria, signifying a host-directed approach for treating infectious disease.

  • Drug screening with human SMN2 reporter identifies SMN protein stabilizers to correct SMA pathology
    Open Access
    Drug screening with human SMN2 reporter identifies SMN protein stabilizers to correct SMA pathology

    Yiran Wang, Chongchong Xu, Lin Ma, Yongchao Mou, Bowen Zhang, Shanshan Zhou, Yue Tian, Jessica Trinh, Xiaoqing Zhang, Xue-Jun Li

    Yiran Wang ... Xue-Jun Li

    Published 25 March 2019

    This study has established a versatile human SMN2 reporter line for drug screening and identified a novel strategy of targeting cysteine proteases for rescuing SMA pathological phenotypes.

  • <em>let-7</em> coordinates the transition to adulthood through a single primary and four secondary targets
    Open Access
    let-7 coordinates the transition to adulthood through a single primary and four secondary targets

    Florian Aeschimann, Anca Neagu, Magdalene Rausch, Helge Großhans

    Florian Aeschimann ... Helge Großhans

    Published 25 March 2019

    Although miRNAs may act through regulation of numerous targets, this study shows that the Caenorhabditis elegans let-7 miRNA promotes the juvenile-to-adult transition through repression of LIN41 alone, thereby activating four LIN41 targets that function in pairs to execute distinct developmental functions.

  • Location-dependent maintenance of intrinsic susceptibility to mTORC1-driven tumorigenesis
    Open Access
    Location-dependent maintenance of intrinsic susceptibility to mTORC1-driven tumorigenesis

    Gabrielle V Rushing, Asa A Brockman, Madelyn K Bollig, Nalin Leelatian, Bret C Mobley, Jonathan M Irish, Kevin C Ess, Cary Fu, Rebecca A Ihrie

    Gabrielle V Rushing ... Rebecca A Ihrie

    Published 25 March 2019

    Per-cell quantification of mTORC1 signaling activity in neural stem/progenitor cells reveals differential signaling, proliferative, and tumor-forming capability between dorsal and ventral cells within a single niche.

  • A dual role for SAMHD1 in regulating HBV cccDNA and RT-dependent particle genesis
    Open Access
    A dual role for SAMHD1 in regulating HBV cccDNA and RT-dependent particle genesis

    Peter AC Wing, Tamara Davenne, Jochen Wettengel, Alvina G Lai, Xiaodong Zhuang, Anindita Chakraborty, Valentina D’Arienzo, Catharina Kramer, Chunkyu Ko, James M Harris, Sabrina Schreiner, Martin Higgs, Stephanie Roessler, Joanna L Parish, Ulrike Protzer, Peter Balfe, Jan Rehwinkel, Jane A McKeating

    Peter AC Wing ... Jane A McKeating

    Published 27 March 2019

    Our study highlights a dual role for SAMHD1 in regulating hepatitis B virus cccDNA levels and reverse transcriptase–dependent particle genesis.

  • Epidermal development requires ninein for spindle orientation and cortical microtubule organization
    Open Access
    Epidermal development requires ninein for spindle orientation and cortical microtubule organization

    Nicolas Lecland, Chiung-Yueh Hsu, Cécile Chemin, Andreas Merdes, Christiane Bierkamp

    Nicolas Lecland ... Christiane Bierkamp

    Published 28 March 2019

    In the epidermis, ninein affects spindle orientation of progenitor cells, as well as cortical microtubule organization, desmosome assembly, and lamellar body secretion in differentiating cells.

  • The PI3K and MAPK/p38 pathways control stress granule assembly in a hierarchical manner
    Open Access
    The PI3K and MAPK/p38 pathways control stress granule assembly in a hierarchical manner

    Alexander Martin Heberle, Patricia Razquin Navas, Miriam Langelaar-Makkinje, Katharina Kasack, Ahmed Sadik, Erik Faessler, Udo Hahn, Philip Marx-Stoelting, Christiane A Opitz, Christine Sers, Ines Heiland, Sascha Schäuble, Kathrin Thedieck

    Alexander Martin Heberle ... Kathrin Thedieck

    Published 28 March 2019

    PI3K and p38 act in a hierarchical manner to enhance mTORC1 activity and stress granule formation; although PI3K is the main driver, the impact of p38 gets apparent as PI3K activity declines.

  • BZLF1 interacts with chromatin remodelers promoting escape from latent infections with EBV
    Open Access
    BZLF1 interacts with chromatin remodelers promoting escape from latent infections with EBV

    Marisa Schaeffner, Paulina Mrozek-Gorska, Alexander Buschle, Anne Woellmer, Takanobu Tagawa, Filippo M. Cernilogar, Gunnar Schotta, Nils Krietenstein, Corinna Lieleg, Philipp Korber, Wolfgang Hammerschmidt

    Marisa Schaeffner ... Wolfgang Hammerschmidt

    Published 29 March 2019

    How herpesviruses escape from their latent states is enigmatic, but BZLF1, an important transcription factor of EBV, recruits cellular chromatin remodelers to viral DNA to overcome its epigenetic repression and initiate viral transcription.

  • Human NK cell development in hIL-7 and hIL-15 knockin NOD/SCID/IL2rgKO mice
    Open Access
    Human NK cell development in hIL-7 and hIL-15 knockin NOD/SCID/IL2rgKO mice

    Masashi Matsuda, Rintaro Ono, Tomonori Iyoda, Takaho Endo, Makoto Iwasaki, Mariko Tomizawa-Murasawa, Yoriko Saito, Akiko Kaneko, Kanako Shimizu, Daisuke Yamada, Narumi Ogonuki, Takashi Watanabe, Manabu Nakayama, Yoko Koseki, Fuyuko Kezuka-Shiotani, Takanori Hasegawa, Hiromasa Yabe, Shunichi Kato, Atsuo Ogura, Leonard D Shultz, Osamu Ohara, Masaru Taniguchi, Haruhiko Koseki, Shin-ichiro Fujii, Fumihiko Ishikawa

    Masashi Matsuda ... Fumihiko Ishikawa

    Published 1 April 2019

    A new humanized mouse expressing human IL-7 and IL-15 facilitates development and maturation of human NK cells and can be useful as a preclinical in vivo model for testing new treatment modalities.

  • Intra-individual methylomics detects the impact of early-life adversity
    Open Access
    Intra-individual methylomics detects the impact of early-life adversity

    Shan Jiang, Noriko Kamei, Jessica L Bolton, Xinyi Ma, Hal S Stern, Tallie Z Baram, Ali Mortazavi

    Shan Jiang ... Ali Mortazavi

    Published 1 April 2019

    This study shows that methylation profile changes across time in the same individual distinguish a stressful experience from typical infancy, providing a potential predictive marker of vulnerability to disease.

  • ROS amplification drives mouse spermatogonial stem cell self-renewal
    Open Access
    ROS amplification drives mouse spermatogonial stem cell self-renewal

    Hiroko Morimoto, Mito Kanastu-Shinohara, Narumi Ogonuki, Satoshi Kamimura, Atsuo Ogura, Chihiro Yabe-Nishimura, Yoshifumi Mori, Takeshi Morimoto, Satoshi Watanabe, Kinya Otsu, Takuya Yamamoto, Takashi Shinohara

    Hiroko Morimoto ... Takashi Shinohara

    Published 2 April 2019

    Although reactive oxygen species (ROS) are required for spermatogonial stem cell (SSC) self-renewal, the mechanism has remained unknown. We show that SSC self-renewal signals activate MAPK14/MAPK7 pathway to induce nuclear translocation of BCL6B and activation of NOX1.

  • Constitutive STAT5 activation regulates Paneth and Paneth-like cells to control <em>Clostridium difficile</em> colitis
    Open Access
    Constitutive STAT5 activation regulates Paneth and Paneth-like cells to control Clostridium difficile colitis

    Ruixue Liu, Richard Moriggl, Dongsheng Zhang, Haifeng Li, Rebekah Karns, Hai-Bin Ruan, Haitao Niu, Christopher Mayhew, Carey Watson, Hansraj Bangar, Sang-wook Cha, David Haslam, Tongli Zhang, Shila Gilbert, Na Li, Michael Helmrath, James Wells, Lee Denson, Xiaonan Han

    Ruixue Liu ... Xiaonan Han

    Published 4 April 2019

    STAT5 controls the intestinal epithelial stem cell niche by regulating Wnt/β-catenin signaling, and lack of active pYSTAT5 induces Clostridium difficile infection. STAT5 may be a transcription factor that restricts niche cell differentiation.

  • m<sup>6</sup>A-mRNA methylation regulates cardiac gene expression and cellular growth
    Open Access
    m6A-mRNA methylation regulates cardiac gene expression and cellular growth

    Vivien Kmietczyk, Eva Riechert, Laura Kalinski, Etienne Boileau, Ellen Malovrh, Brandon Malone, Agnieszka Gorska, Christoph Hofmann, Eshita Varma, Lonny Jürgensen, Verena Kamuf-Schenk, Janine Altmüller, Rewati Tappu, Martin Busch, Patrick Most, Hugo A Katus, Christoph Dieterich, Mirko Völkers

    Vivien Kmietczyk ... Mirko Völkers

    Published 9 April 2019

    This study provides evidence that m6A methylation is dynamically regulated during human and murine cardiac disease and highlights an important role of the m6A methylase Mettl3 in regulating cardiac growth by gene expression control.

  • CXXC5 mediates growth plate senescence and is a target for enhancement of longitudinal bone growth
    Open Access
    CXXC5 mediates growth plate senescence and is a target for enhancement of longitudinal bone growth

    Sehee Choi, Hyun-Yi Kim, Pu-Hyeon Cha, Seol Hwa Seo, Chulho Lee, Yejoo Choi, Wookjin Shin, Yunseok Heo, Gyoonhee Han, Weontae Lee, Kang-Yell Choi

    Sehee Choi ... Kang-Yell Choi

    Published 10 April 2019

    Inhibition of the CXXC5–DVL interaction is a potential therapeutic strategy for height enhancement of children with growth retardation.

  • Mitotic replisome disassembly depends on TRAIP ubiquitin ligase activity
    Open Access
    Mitotic replisome disassembly depends on TRAIP ubiquitin ligase activity

    Sara Priego Moreno, Rebecca M Jones, Divyasree Poovathumkadavil, Shaun Scaramuzza, Agnieszka Gambus

    Sara Priego Moreno ... Agnieszka Gambus

    Published 12 April 2019

    Analysis of the mitotic replisome disassembly pathway in X. laevis egg extract shows that any replisomes retained on chromatin past S-phase are unloaded through formation of K6- and K63-linked ubiquitin chains on Mcm7 by TRAIP ubiquitin ligase and p97/VCP activity.

  • A network of human functional gene interactions from knockout fitness screens in cancer cells
    Open Access
    A network of human functional gene interactions from knockout fitness screens in cancer cells

    Eiru Kim, Merve Dede, Walter F Lenoir, Gang Wang, Sanjana Srinivasan, Medina Colic, Traver Hart

    Eiru Kim ... Traver Hart

    Published 12 April 2019

    The function of human genes can be strongly inferred from their knockout fitness profiles across hundreds of CRISPR screens, illuminating the modular organization of the cell.

  • Human CST suppresses origin licensing and promotes AND-1/Ctf4 chromatin association
    Open Access
    Human CST suppresses origin licensing and promotes AND-1/Ctf4 chromatin association

    Yilin Wang, Kathryn S Brady, Benjamin P Caiello, Stephanie M Ackerson, Jason A Stewart

    Yilin Wang ... Jason A Stewart

    Published 12 April 2019

    This study suggests a novel role of the telomere-associated human CST complex in suppressing origin licensing, through interactions with MCM, while promoting the recruitment of AND-1 and DNA polymerase alpha for replisome formation.

  • An extracellular matrix protein promotes anillin-dependent processes in the <em>Caenorhabditis elegans</em> germline
    Open Access
    An extracellular matrix protein promotes anillin-dependent processes in the Caenorhabditis elegans germline

    Hongxia Lan, Xinyan Wang, Ling Jiang, Jianjian Wu, Xuan Wan, Lidan Zeng, Dandan Zhang, Yiyan Lin, Chunhui Hou, Shian Wu, Yu Chung Tse

    Hongxia Lan ... Yu Chung Tse

    Published 15 April 2019

    The extracellular matrix protein Hemicentin (HIM-4) is an extracellular factor that regulates anillin (ANI-1) for germ cell membrane stabilization and contractile ring formation in C. elegans germline cells.

  • Competition in the chaperone-client network subordinates cell-cycle entry to growth and stress
    Open Access
    Competition in the chaperone-client network subordinates cell-cycle entry to growth and stress

    David F Moreno, Eva Parisi, Galal Yahya, Federico Vaggi, Attila Csikász-Nagy, Martí Aldea

    David F Moreno ... Martí Aldea

    Published 15 April 2019

    Growth and cell-cycle entry compete for multifunctional chaperones subjugating the critical size and proliferation to the growth potential of the cell.

  • Inhibition of the deubiquitinase USP8 corrects a Drosophila PINK1 model of mitochondria dysfunction
    Open Access
    Inhibition of the deubiquitinase USP8 corrects a Drosophila PINK1 model of mitochondria dysfunction

    Sophia von Stockum, Alvaro Sanchez-Martinez, Samantha Corrà, Joy Chakraborty, Elena Marchesan, Lisa Locatello, Caterina Da Rè, Paola Cusumano, Federico Caicci, Vanni Ferrari, Rodolfo Costa, Luigi Bubacco, Maria Berica Rasotto, Ildiko Szabo, Alexander J Whitworth, Luca Scorrano, Elena Ziviani

    Sophia von Stockum ... Elena Ziviani

    Published 15 April 2019

    Aberrant mitochondrial dynamics contribute to disease conditions. Genetic and pharmacological inhibition of USP8 ameliorates mitochondrial phenotypes deriving from loss of function of Drosophila PINK1 and Parkin.

  • The impact of poly-A microsatellite heterologies in meiotic recombination
    Open Access
    The impact of poly-A microsatellite heterologies in meiotic recombination

    Angelika Heissl, Andrea J Betancourt, Philipp Hermann, Gundula Povysil, Barbara Arbeithuber, Andreas Futschik, Thomas Ebner, Irene Tiemann-Boege

    Angelika Heissl ... Irene Tiemann-Boege

    Published 25 April 2019

    Meiosis strongly influences the transmission and evolution of heterozygous poly-A repeats as measured experimentally in a large collection of single recombination products in a human hotspot.

Resources

  • Gene editing enables T-cell engineering to redirect antigen specificity for potent tumor rejection
    Open Access
    Gene editing enables T-cell engineering to redirect antigen specificity for potent tumor rejection

    Julian J Albers, Tim Ammon, Dario Gosmann, Stefan Audehm, Silvia Thoene, Christof Winter, Ramona Secci, Anja Wolf, Anja Stelzl, Katja Steiger, Jürgen Ruland, Florian Bassermann, Christian Kupatt, Martina Anton, Angela M Krackhardt

    Julian J Albers ... Angela M Krackhardt

    Published 15 March 2019

    Targeted integration of a tumor-reactive T-cell receptor into the TRAC locus using CRISPR-Cas9 and AAV6 redirects primary human T cells against tumor cells in vitro and in vivo.

  • Sequence and expression levels of circular RNAs in progenitor cell types during mouse corticogenesis
    Open Access
    Sequence and expression levels of circular RNAs in progenitor cell types during mouse corticogenesis

    Martina Dori, Leila Haj Abdullah Alieh, Daniel Cavalli, Simone Massalini, Mathias Lesche, Andreas Dahl, Federico Calegari

    Martina Dori ... Federico Calegari

    Published 29 March 2019

    This study identifies circular RNAs (circRNAs) in specific cell types of the developing mammalian cortex. This resource addresses the complexity and potential significance of this elusive class of transcripts.

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Volume 2, No. 2
April 2019
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