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1. Whole Genome Sequence Analysis of the Plasma Proteome in Black Adults Provides Novel Insights Into Cardiovascular Disease

Author

Daniel H. Katz, Usman A. Tahir, Alexander G. Bick, Akhil Pampana, Debby Ngo, Mark D. Benson, Zhi Yu, Jeremy M. Robbins, Zsu-Zsu Chen, Daniel E. Cruz, Shuliang Deng, Laurie Farrell, Sumita Sinha, Alec A. Schmaier, Dongxiao Shen, Yan Gao, Michael E. Hall, Adolfo Correa, Russell P. Tracy, Peter Durda, Kent D. Taylor, Yongmei Liu, W. Craig Johnson, Xiuqing Guo, Jie Yao, Yii-Der Ida Chen, Ani W. Manichaikul, Deepti Jain, Claude Bouchard, Mark A. Sarzynski, Stephen S. Rich, Jerome I. Rotter, Thomas J. Wang, James G. Wilson, Pradeep Natarajan, Robert E. Gerszten, Namiko Abe, Gonçalo Abecasis, Francois Aguet, Christine Albert, Laura Almasy, Alvaro Alonso, Seth Ament, Peter Anderson, Pramod Anugu, Deborah Applebaum-Bowden, Kristin Ardlie, Dan Arking, Donna K. Arnett, Allison Ashley-Koch, Stella Aslibekyan, Tim Assimes, Paul Auer, Dimitrios Avramopoulos, Najib Ayas, Adithya Balasubramanian, John Barnard, Kathleen Barnes, R. Graham Barr, Emily Barron-Casella, Lucas Barwick, Terri Beaty, Gerald Beck, Diane Becker, Lewis Becker, Rebecca Beer, Amber Beitelshees, Emelia Benjamin, Takis Benos, Marcos Bezerra, Larry Bielak, Joshua Bis, Thomas Blackwell, John Blangero, Eric Boerwinkle, Donald W. Bowden, Russell Bowler, Jennifer Brody, Ulrich Broeckel, Jai Broome, Deborah Brown, Karen Bunting, Esteban Burchard, Carlos Bustamante, Erin Buth, Brian Cade, Jonathan Cardwell, Vincent Carey, Julie Carrier, April Carson, Cara Carty, Richard Casaburi, Juan P. Casas Romero, James Casella, Peter Castaldi, Mark Chaffin, Christy Chang, Yi-Cheng Chang, Daniel Chasman, Sameer Chavan, Bo-Juen Chen, Wei-Min Chen, Michael Cho, Seung Hoan Choi, Lee-Ming Chuang, Mina Chung, Ren-Hua Chung, Clary Clish, Suzy Comhair, Matthew Conomos, Elaine Cornell, Carolyn Crandall, James Crapo, L. Adrienne Cupples, Joanne Curran, Jeffrey Curtis, Brian Custer, Coleen Damcott, Dawood Darbar, Sean David, Colleen Davis, Michelle Daya, Mariza de Andrade, Lisa de las Fuentes, Paul de Vries, Michael DeBaun, Ranjan Deka, Dawn DeMeo, Scott Devine, Huyen Dinh, Harsha Doddapaneni, Qing Duan, Shannon Dugan-Perez, Ravi Duggirala, Jon Peter Durda, Susan K. Dutcher, Charles Eaton, Lynette Ekunwe, Adel El Boueiz, Patrick Ellinor, Leslie Emery, Serpil Erzurum, Charles Farber, Jesse Farek, Tasha Fingerlin, Matthew Flickinger, Myriam Fornage, Nora Franceschini, Chris Frazar, Mao Fu, Stephanie M. Fullerton, Lucinda Fulton, Stacey Gabriel, Weiniu Gan, Shanshan Gao, Margery Gass, Heather Geiger, Bruce Gelb, Mark Geraci, Soren Germer, Robert Gerszten, Auyon Ghosh, Richard Gibbs, Chris Gignoux, Mark Gladwin, David Glahn, Stephanie Gogarten, Da-Wei Gong, Harald Goring, Sharon Graw, Kathryn J. Gray, Daniel Grine, Colin Gross, C. Charles Gu, Yue Guan, Namrata Gupta, David M. Haas, Jeff Haessler, Michael Hall, Yi Han, Patrick Hanly, Daniel Harris, Nicola L. Hawley, Jiang He, Ben Heavner, Susan Heckbert, Ryan Hernandez, David Herrington, Craig Hersh, Bertha Hidalgo, James Hixson, Brian Hobbs, John Hokanson, Elliott Hong, Karin Hoth, Chao (Agnes) Hsiung, Jianhong Hu, Yi-Jen Hung, Haley Huston, Chii Min Hwu, Marguerite Ryan Irvin, Rebecca Jackson, Cashell Jaquish, Jill Johnsen, Andrew Johnson, Craig Johnson, Rich Johnston, Kimberly Jones, Hyun Min Kang, Robert Kaplan, Sharon Kardia, Shannon Kelly, Eimear Kenny, Michael Kessler, Alyna Khan, Ziad Khan, Wonji Kim, John Kimoff, Greg Kinney, Barbara Konkle, Charles Kooperberg, Holly Kramer, Christoph Lange, Ethan Lange, Leslie Lange, Cathy Laurie, Cecelia Laurie, Meryl LeBoff, Jiwon Lee, Sandra Lee, Wen-Jane Lee, Jonathon LeFaive, David Levine, Dan Levy, Joshua Lewis, Xiaohui Li, Yun Li, Henry Lin, Honghuang Lin, Xihong Lin, Simin Liu, Yu Liu, Ruth J.F. Loos, Steven Lubitz, Kathryn Lunetta, James Luo, Ulysses Magalang, Michael Mahaney, Barry Make, Ani Manichaikul, Alisa Manning, JoAnn Manson, Lisa Martin, Melissa Marton, Susan Mathai, Rasika Mathias, Susanne May, Patrick McArdle, Merry-Lynn McDonald, Sean McFarland, Stephen McGarvey, Daniel McGoldrick, Caitlin McHugh, Becky McNeil, Hao Mei, James Meigs, Vipin Menon, Luisa Mestroni, Ginger Metcalf, Deborah A. Meyers, Emmanuel Mignot, Julie Mikulla, Nancy Min, Mollie Minear, Ryan L. Minster, Braxton D. Mitchell, Matt Moll, Zeineen Momin, May E. Montasser, Courtney Montgomery, Donna Muzny, Josyf C. Mychaleckyj, Girish Nadkarni, Rakhi Naik, Take Naseri, Sergei Nekhai, Sarah C. Nelson, Bonnie Neltner, Caitlin Nessner, Deborah Nickerson, Osuji Nkechinyere, Kari North, Jeff O’Connell, Tim O’Connor, Heather Ochs-Balcom, Geoffrey Okwuonu, Allan Pack, David T. Paik, Nicholette Palmer, James Pankow, George Papanicolaou, Cora Parker, Gina Peloso, Juan Manuel Peralta, Marco Perez, James Perry, Ulrike Peters, Patricia Peyser, Lawrence S. Phillips, Jacob Pleiness, Toni Pollin, Wendy Post, Julia Powers Becker, Meher Preethi Boorgula, Michael Preuss, Bruce Psaty, Pankaj Qasba, Dandi Qiao, Zhaohui Qin, Nicholas Rafaels, Laura Raffield, Mahitha Rajendran, Vasan S. Ramachandran, D.C. Rao, Laura Rasmussen-Torvik, Aakrosh Ratan, Susan Redline, Robert Reed, Catherine Reeves, Elizabeth Regan, Alex Reiner, Muagututi’a Sefuiva Reupena, Ken Rice, Stephen Rich, Rebecca Robillard, Nicolas Robine, Dan Roden, Carolina Roselli, Jerome Rotter, Ingo Ruczinski, Alexi Runnels, Pamela Russell, Sarah Ruuska, Kathleen Ryan, Ester Cerdeira Sabino, Danish Saleheen, Shabnam Salimi, Sejal Salvi, Steven Salzberg, Kevin Sandow, Vijay G. Sankaran, Jireh Santibanez, Karen Schwander, David Schwartz, Frank Sciurba, Christine Seidman, Jonathan Seidman, Frédéric Sériès, Vivien Sheehan, Stephanie L. Sherman, Amol Shetty, Aniket Shetty, Wayne Hui-Heng Sheu, M. Benjamin Shoemaker, Brian Silver, Edwin Silverman, Robert Skomro, Albert Vernon Smith, Jennifer Smith, Josh Smith, Nicholas Smith, Tanja Smith, Sylvia Smoller, Beverly Snively, Michael Snyder, Tamar Sofer, Nona Sotoodehnia, Adrienne M. Stilp, Garrett Storm, Elizabeth Streeten, Jessica Lasky Su, Yun Ju Sung, Jody Sylvia, Adam Szpiro, Daniel Taliun, Hua Tang, Margaret Taub, Matthew Taylor, Simeon Taylor, Marilyn Telen, Timothy A. Thornton, Machiko Threlkeld, Lesley Tinker, David Tirschwell, Sarah Tishkoff, Hemant Tiwari, Catherine Tong, Russell Tracy, Michael Tsai, Dhananjay Vaidya, David Van Den Berg, Peter VandeHaar, Scott Vrieze, Tarik Walker, Robert Wallace, Avram Walts, Fei Fei Wang, Heming Wang, Jiongming Wang, Karol Watson, Jennifer Watt, Daniel E. Weeks, Joshua Weinstock, Bruce Weir, Scott T. Weiss, Lu-Chen Weng, Jennifer Wessel, Cristen Willer, Kayleen Williams, L. Keoki Williams, Carla Wilson, James Wilson, Lara Winterkorn, Quenna Wong, Joseph Wu, Huichun Xu, Lisa Yanek, Ivana Yang, Ketian Yu, Seyedeh Maryam Zekavat, Yingze Zhang, Snow Xueyan Zhao, Wei Zhao, Xiaofeng Zhu, Michael Zody, and Sebastian Zoellner

Subjects
Adult, Male, Proteomics, Aging, Whole genome sequence analysis, Proteome, Clinical Sciences, Black People, Disease, Computational biology, race and ethnicity, Cardiorespiratory Medicine and Haematology, Cardiovascular, Article, proteomics, cardiovascular disease, Physiology (medical), Genetics, 2.1 Biological and endogenous factors, Humans, Medicine, Aetiology, Lung, Heart Disease - Coronary Heart Disease, and Blood Institute TOPMed (Trans-Omics for Precision Medicine) Consortium†, business.industry, Prevention, Human Genome, National Heart, Genomics, Blood proteins, Genetic architecture, Heart Disease, Good Health and Well Being, Cardiovascular System & Hematology, Cardiovascular Diseases, Public Health and Health Services, Female, Cardiology and Cardiovascular Medicine, business, Biotechnology, Genome-Wide Association Study
Abstract

Background: Plasma proteins are critical mediators of cardiovascular processes and are the targets of many drugs. Previous efforts to characterize the genetic architecture of the plasma proteome have been limited by a focus on individuals of European descent and leveraged genotyping arrays and imputation. Here we describe whole genome sequence analysis of the plasma proteome in individuals with greater African ancestry, increasing our power to identify novel genetic determinants. Methods: Proteomic profiling of 1301 proteins was performed in 1852 Black adults from the Jackson Heart Study using aptamer-based proteomics (SomaScan). Whole genome sequencing association analysis was ascertained for all variants with minor allele count ≥5. Results were validated using an alternative, antibody-based, proteomic platform (Olink) as well as replicated in the Multi-Ethnic Study of Atherosclerosis and the HERITAGE Family Study (Health, Risk Factors, Exercise Training and Genetics). Results: We identify 569 genetic associations between 479 proteins and 438 unique genetic regions at a Bonferroni-adjusted significance level of 3.8×10 -11 . These associations include 114 novel locus-protein relationships and an additional 217 novel sentinel variant-protein relationships. Novel cardiovascular findings include new protein associations at the APOE gene locus including ZAP70 (sentinel single nucleotide polymorphism [SNP] rs7412-T, β=0.61±0.05, P =3.27×10 -30 ) and MMP-3 (β=-0.60±0.05, P =1.67×10 -32 ), as well as a completely novel pleiotropic locus at the HPX gene, associated with 9 proteins. Further, the associations suggest new mechanisms of genetically mediated cardiovascular disease linked to African ancestry; we identify a novel association between variants linked to APOL1-associated chronic kidney and heart disease and the protein CKAP2 (rs73885319-G, β=0.34±0.04, P =1.34×10 -17 ) as well as an association between ATTR amyloidosis and RBP4 levels in community-dwelling individuals without heart failure. Conclusions: Taken together, these results provide evidence for the functional importance of variants in non-European populations, and suggest new biological mechanisms for ancestry-specific determinants of lipids, coagulation, and myocardial function.

Published
2022

2. Sequencing of a central nervous system tumor demonstrates cancer transmission in an organ transplant

Author

Qingchang Meng, Harshavardhan Doddapaneni, Sadhna Dhingra, Maria F. Cardenas, Lesette Perez, Marie-Claude Gingras, Xiuping Liu, Hsu Chao, Caitlin Nessner, Richard A. Gibbs, Abbas Rana, John A. Goss, Aniko Sabo, Donna M. Muzny, Jianhong Hu, and Viktoriya Korchina

Subjects
Adult, Male, 0301 basic medicine, medicine.medical_specialty, Adolescent, Somatic cell, Biopsy, Health, Toxicology and Mutagenesis, DNA Mutational Analysis, Transplants, Plant Science, Biology, Biochemistry, Genetics and Molecular Biology (miscellaneous), DNA sequencing, Organ transplantation, Central Nervous System Neoplasms, Young Adult, 03 medical and health sciences, 0302 clinical medicine, INDEL Mutation, CDKN2A, Exome Sequencing, Biomarkers, Tumor, medicine, Humans, Gene, Research Articles, Chromosomal Deletion, Ecology, Cancer, Organ Transplantation, Sequence Analysis, DNA, Middle Aged, Prognosis, medicine.disease, Tissue Donors, Transplant Recipients, Transplantation, surgical procedures, operative, 030104 developmental biology, 030220 oncology & carcinogenesis, Mutation, Cancer research, Female, Research Article
Abstract

This study uses DNA sequencing to trace a donor organ transplant–mediated cancer transmission and illustrates how precise molecular pathology profiles might reduce future risk for transplant recipients., Four organ transplant recipients from an organ donor diagnosed with anaplastic pleomorphic xanthoastrocytoma developed fatal malignancies for which the origin could not be confirmed by standard methods. We identified the somatic mutational profiles of the neoplasms using next-generation sequencing technologies and tracked the relationship between the different samples. The data were consistent with the presence of an aggressive clonal entity in the donor and the subsequent proliferation of descendent tumors in each recipient. Deleterious mutations in BRAF, PIK3CA, SDHC, DDR2, and FANCD2, and a chromosomal deletion spanning the CDKN2A/B genes, were shared between the recipients’ lesions. In addition to demonstrating that DNA sequencing tracked a donor/recipient cancer transmission, this study established that the genetic profile of a donor tumor and its potential aggressive phenotype could have been determined before transplantation was considered. As the genetic correlates of tumor invasion and metastases become better known, adding genetic profiling by DNA sequencing to the data considered for transplant safety should be considered.

Published
2021

3. Beliefs in vaccine as causes of autism among SPARK cohort caregivers

Author

Eric Fombonne, Robin P. Goin-Kochel, Brian J. O'Roak, Leonard Abbeduto, Gabriella Aberbach, John Acampado, Andrea J. Ace, Charles Albright, Michael Alessandri, David G. Amaral, Alpha Amatya, Claudine Anglo, Robert D. Annett, Ivette Arriaga, Raven Ashley, Irina Astrovskaya, Kelly Baalman, Melissa Baer, Ethan Bahl, Adithya Balasubramanian, Gabrielle Baraghoshi, Nicole Bardett, Rebecca A. Barnard, Asif Bashar, Arthur Beaudet, Malia Beckwith, Landon Beeson, Dawn Bentley, Raphael A. Bernier, Elizabeth Berry-Kravis, Sarah Boland, Stephanie Booker, Catherine Bradley, Stephanie J. Brewster, Elizabeth Brooks, Melissa Brown, Leo Brueggeman, Martin E. Butler, Eric M. Butter, Kristen Callahan, Alexies Camba, Paul Carbone, Laura Carpenter, Sarah Carpenter, Nicholas Carriero, Lindsey A. Cartner, Lucas Casten, Ahmad S. Chatha, Wubin Chin, Sharmista Chintalapalli, Daniel Cho, Wendy K. Chung, Renee D. Clark, Cheryl Cohen, Kendra Coleman, Costanza Columbi, Leigh Coppola, Eric Courchesne, Joseph F. Cubells, Mary Hannah Currin, Amy M. Daniels, Giancarla David, Lindsey DeMarco, Megan Y. Dennis, Kate Dent, Gabriel S. Dichter, Yan Ding, Huyen Dinh, Ryan Doan, HarshaVardhan Doddapaneni, Evan E. Eichler, Sara Eldred, Christine Eng, Craig A. Erickson, Amy Esler, Ali Fatemi, Pamela Feliciano, Gregory Fischer, Angela Fish, Ian Fisk, Eric J. Fombonne, Margaret Foster, Emily A. Fox, Sunday Francis, Sandra L. Friedman, Swami Ganesan, Michael Garrett, Vahid Gazestani, Madeleine R. Geisheker, Jennifer A. Gerdts, Daniel H. Geschwind, Mohammad Ghaziuddin, Richard A. Gibbs, Natalia Gonzalez, Lindsey Goudreau, Anthony J. Griswold, Luke P. Grosvenor, Angela J. Gruber, Amanda C. Gulsrud, Jaclyn Gunderson, Chris Gunter, Abha Gupta, Anibal Gutierrez, Melissa N. Hale, Monica Haley, Jacob B. Hall, Kira E. Hamer, Bing Han, Nathan Hanna, Antonio Hardan, Christina Harkins, Gloria Harrington, Jill Harris, Nina Harris, Brenda Hauf, Caitlin Hayes, Kathryn Heerwagen, Susan L. Hepburn, Lynette M. Herbert, Michelle Heyman, Lorrin Higgins, Brittani A. Hilscher, Eugenia Hofammann, Margaret Hojlo, Susannah Horner, Alexander Hsieh, Jianhong Hu, Lark Y. Huang-Storms, Samantha Hunter, Hanna Hutter, Dalia Istephanous, Suma Jacob, Nancy Jaramillo, Anna Jelinek, William Jensen, Mark Jones, Michelle Jordy, Alissa Jorgenson, Roger Jou, A. Pablo Juarez, Jessyca Judge, Jane Jurayj, Taylor Kalmus, Stephen Kanne, Hannah E. Kaplan, Lauren Kasparson, Matt Kent, So Hyun Kim, Alex Kitaygorodsky, Hope Koene, Tanner Koomar, Viktoriya Korchina, Anthony D. Krentz, Hoa Lam Schneider, Elena Lamarche, Erica Lampert, Rebecca J. Landa, Alex E. Lash, J. Kiely Law, Noah Lawson, Kevin Layman, Holly Lechniak, Sandra Lee, Soo J. Lee, Daniel Lee Coury, Christa Lese Martin, Laurie Lesher, Hai Li, Deana Li, Natasha Lillie, Xiuping Liu, Marilyn Lopez, Catherine Lord, Kathryn Lowe, Malcolm D. Mallardi, Patricia Manning, Julie Manoharan, Richard Marini, Christa Martin, Gabriela Marzano, Andrew Mason, Sarah Mastel, Emily T. Matthews, James T. McCracken, Alexander P. McKenzie, Alexandra Miceli, Jacob J. Michaelson, Anna Milliken, Sarah Mohiuddin, Zeineen Momin, Michael J. Morrier, Stewart Mostofsky, Shwetha Murali, Donna Muzny, Vincent J. Myers, Jason Neely, Caitlin Nessner, Amy Nicholson, Melanie Niederhouser, Kaela O'Brien, Eirene O'Connor, Molly O'Neil, Cesar Ochoa-Lubinoff, Jessica Orobio, Libby Orrick, Crissy Ortiz, Opal Y. Ousley, Lillian D. Pacheco, Samiza Palmer, Juhi Pandey, Anna Marie Paolicelli, Katherine G. Pawlowski, Karen L. Pierce, Joseph Piven, Samantha Plate, Jose Polanco, Marc Popp, Natalie Pottschmidt, Tiziano Pramparo, Lisa M. Prock, Hongjian Qi, Shanping Qiu, Angela L. Rachubinski, Kshitij Rajbhandari, Rishiraj Rana, Vai Ranganathan, Laurie Raymond, Rick Remington, Catherine E. Rice, Chris Rigby, Beverly E. Robertson, Nicki Rodriguez, Barbara Rodriguez, Katherine Roeder, Cordelia R. Rosenberg, Nicole Russo-Ponsaran, Elizabeth Ruzzo, Aniko Sabo, Mustafa Sahin, Andrei Salomatov, Sophia Sandhu, Susan Santangelo, Dustin E. Sarver, Jessica Scherr, Robert T. Schultz, Kathryn A. Schweers, Rebecca Shaffer, Swapnil Shah, Tamim Shaikh, Yufeng Shen, Amanda D. Shocklee, Lisa Shulman, Matthew Siegel, Andrea R. Simon, Laura Simon, Vini Singh, Steve Skinner, Christopher J. Smith, Kaitlin Smith, LeeAnne G. Snyder, Latha V. Soorya, Aubrie Soucy, Danielle Stamps, Morgan Steele, Alexandra N. Stephens, Colleen M. Stock, Catherine Sullivan, James S. Sutcliffe, Amy Swanson, Maira Tafolla, Nicole Takahashi, Cora Taylor, Carrie Thomas, Taylor Thomas, Samantha Thompson, Jennifer Tjernagel, Tychele N. Turner, Maria Valicenti-McDermott, Bonnie Van Metre, Candace Van Wade, Jeremy Veenstra-Vanderweele, Mary Verdi, Brianna M. Vernoia, Natalia Volfovsky, Jermel Wallace, Corrie H. Walston, Jiayao Wang, Tianyun Wang, Zachary Warren, Lucy Wasserburg, Sabrina White, L. Casey White-Lehman, Ericka L. Wodka, Simon Xu, Wha S. Yang, Meredith Yinger, Sarah Youngkin, Timothy Yu, Lan Zang, Hana Zaydens, Haicang Zhang, Haoquan Zhao, Xueya Zhou, and Allyson Zick

Subjects
Causes of autism, Male, Health Knowledge, Attitudes, Practice, Adolescent, Language delay, Autism Spectrum Disorder, Ethnic group, behavioral disciplines and activities, 03 medical and health sciences, 0302 clinical medicine, 030225 pediatrics, mental disorders, Intellectual disability, medicine, Ethnicity, Humans, 030212 general & internal medicine, Autistic Disorder, Child, Minority Groups, Vaccines, General Veterinary, General Immunology and Microbiology, business.industry, Vaccination, Public Health, Environmental and Occupational Health, medicine.disease, Infectious Diseases, Caregivers, Autism spectrum disorder, Child, Preschool, Cohort, Molecular Medicine, Autism, Female, business, Developmental regression, Clinical psychology
Abstract

Background Fear of autism has led to a decline in childhood-immunization uptake and to a resurgence of preventable infectious diseases. Identifying characteristics of parents who believe in a causal role of vaccines for autism spectrum disorder (ASD) in their child may help targeting educational activities and improve adherence to the immunization schedule. Objectives To compare caregivers of children with ASD who agree or disagree that vaccines play an etiological role in autism for 1) socio-demographics characteristics and 2) developmental and clinical profiles of their children. Methods Data from 16,525 participants with ASD under age 18 were obtained from SPARK, a national research cohort started in 2016. Caregivers completed questionnaires at registration that included questions on beliefs about the etiologic role of childhood immunizations and other factors in ASD. Data were available about family socio-demographic characteristics, first symptoms of autism, developmental regression, co-occurring psychiatric disorders, seizures, and current levels of functioning. Results Participants with ASD were 80.4% male with a mean age of 8.1 years (SD = 4.1). Overall, 16.5% of caregivers endorsed immunizations as perceived causes of autism. Compared to caregivers who disagreed with vaccines as a cause for ASD, those who believed in vaccine causation came disproportionately from ethnic minority, less educated, and less wealthy backgrounds. More often their children had experienced developmental regression involving language and other skills, were diagnosed earlier, had lost skills during the second year of life, and had worse language, adaptive, and cognitive outcomes. Conclusion One in six caregivers who participate in a national research cohort believe that child immunizations could be a cause of autism in their child. Parent social background (non-White, less educated) and child developmental features (regression in second year, poorer language skills, and worse adaptive outcomes) index caregivers who are more likely to harbor these beliefs and could benefit from targeted educational activities.

Published
2019

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