31 results on '"John Barnard"'
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2. Whole Genome Sequence Analysis of the Plasma Proteome in Black Adults Provides Novel Insights Into Cardiovascular Disease
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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
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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.
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- 2022
3. COVID-19 and Cardiovascular Disease
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Tamanna Singh, John C. Tilton, Joseph Loscalzo, John Barnard, Emily J. Tsai, Scott J. Cameron, Mina K. Chung, Deborah H. Kwon, David A. Zidar, Nathan R. Tucker, Timothy A. Chan, Clifford V. Harding, and Michael R. Bristow
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0301 basic medicine ,medicine.medical_specialty ,Physiology ,business.industry ,Inflammation ,Disease ,030204 cardiovascular system & hematology ,medicine.disease ,Thrombosis ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Immune system ,Pandemic ,Epidemiology ,Immunology ,medicine ,Platelet activation ,medicine.symptom ,Cardiology and Cardiovascular Medicine ,Ventricular remodeling ,business - Abstract
A pandemic of historic impact, coronavirus disease 2019 (COVID-19) has potential consequences on the cardiovascular health of millions of people who survive infection worldwide. Severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2), the etiologic agent of COVID-19, can infect the heart, vascular tissues, and circulating cells through ACE2 (angiotensin-converting enzyme 2), the host cell receptor for the viral spike protein. Acute cardiac injury is a common extrapulmonary manifestation of COVID-19 with potential chronic consequences. This update provides a review of the clinical manifestations of cardiovascular involvement, potential direct SARS-CoV-2 and indirect immune response mechanisms impacting the cardiovascular system, and implications for the management of patients after recovery from acute COVID-19 infection.
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- 2021
4. MP41-18 DIFFICULT FOLEY? A LOOK INTO DIFFICULT FOLEY CONSULTS
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Katharina Mitchell, Amr Elbakry, Caitlyn Patton, John Barnard, and Chad Morley
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Urology - Published
- 2022
5. MP22-09 URETHRAL STRICTURE/STENOSIS AS A COMPLICATION OF HIGH INTENSITY FOCUSED ULTRASOUND OF THE PROSTATE: WHAT IS THE OVERALL PATIENT EXPERIENCE?
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David Barham, John Barnard, and Joel Gelman
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Urology - Published
- 2022
6. PD52-01 COMPLICATIONS OF THE PENUMA PENILE IMPLANT FOR GENITAL ENHANCEMENT
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David Barham, John Barnard, and Joel Gelman
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Urology - Published
- 2022
7. Abstract 14084: Computationally Identified Shape Differences In The Left Atrium On Pre-ablation Ct Scans Appear To Be Associated With Recurrence Of Atrial Fibrillation
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Golnoush Asaeikheybari, Amogh Hiremath, Rakesh Shiradkar, Majd El-harasis, M. Benjamin Shoemaker, John Barnard, Amit Gupta, Mina K Chung, and Anant Madabhushi
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Physiology (medical) ,Cardiology and Cardiovascular Medicine - Abstract
Introduction: Catheter-based ablation is an increasingly utilized management strategy for atrial fibrillation (AF); however, a major problem is AF recurrence post-ablation. There is increasing interest in the use of advanced image analysis to better understand differences in left atrial (LA) shape that may be associated with a higher recurrence risk and potential sites of recurrence. Hypothesis: Factors which lead to the post-ablation recurrence prompt LA differential remodeling. The significant shape difference regions among AF recurrence (AF+) and AF non-recurrence (AF-) patients can be identified from pre-ablation CT scans. Those regions could potentially represent future sites of recurrence and hence could be targets for ablation. Methods: This study included pre-ablation CT-scans of 51 AF+ and 51 AF- patients. Two separate atlases were created by registering Left atrial CT volumes of AF+ and AF- patients to their representative templates (T+ and T- respectively). The atlases were co-registered to a common canonical frame of reference (T-) and a non-parametric General Linear Model (GLM) based t-test with 500 permutations was used to identify the regions (Surface of interest (SOI)) that are statistically significant (p-value Results: The registration accuracy in the final common frame in terms of average Dice similarity coefficient was in the range of 0.85-0.94 over the 10 SOI constructions. The frequency map revealed the maximum overlap of SOIs in an area where left pulmonary veins enter the left atrium. This could potentially represent a new target for ablation. Conclusions: An ensemble atlas-based shape differentiation method revealed SOI regions that are structurally associated with recurrence and might potentially represent targets for ablation.
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- 2021
8. Abstract 11214: Ibrutinib Decreases Mitochondrial Oxidative Phosphorylation and Metabolic Gene Expression in Atrial-Like Engineered Heart Tissue
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Julie H Rennison, Beth Lovano, Laurie Castel, Cheryl R Lin, Feixong Cheng, Rohit Moudgil, Jonathan D Smith, John Barnard, Mina K Chung, and David R Van Wagoner
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Physiology (medical) ,Cardiology and Cardiovascular Medicine - Abstract
Introduction: Ibrutinib is a Bruton kinase inhibitor which treats many hematological malignancies, but also precipitates atrial fibrillation (AF). The precise mechanism(s) remain to be elucidated. Hypothesis: We hypothesized ibrutinib treatment would decrease mitochondrial function and metabolic gene expression in human inducible pluripotent stem cell-derived atrial cardiomyocytes grown as atrial-like engineered heart tissues (aEHTs). Methods: aEHTs were treated with vehicle or 1 μM ibrutinib daily, for 72 hours. Oxidative phosphorylation was assessed (n=5/group) using an Oroboros Oxygraph. Gene expression was evaluated by RNAseq (n=3/group). Results: Oxidative phosphorylation in the presence of complex I and complex II substrates, and maximal oxidative capacity, was decreased in ibrutinib-treated aEHTs compared to vehicle (Panel A). Subunit expression of complex I (NDUFA6, NDUFA9, NDUFS1, NDUFS2, NDUFS4, ND3, ND4, ND5, ND4L), complex II (SDHA, SDHB, SDHD), complex III (UQCR10, UQCRB, UQCRC1, UQCRC2, UQCRFS1), and complex IV (CO2, COX10, COX7A2, CYCS) was decreased. Ingenuity Pathway Analysis of genes differentially expressed identified TCA Cycle and Glycolysis I (Panel B), pathways that provide reducing equivalents to the electron transport chain, as pathways that were decreased by ibrutinib. These changes were accompanied by decreased AMPK Signaling, including key metabolic regulators (PRKAA2, PRKAB2, PRKAG2, SIRT1, and PPARGC1A), and Calcium Signaling. Tumor protein (TP53), nuclear protein 1 (NUPR1), and erb-B2 receptor tyrosine kinase (ERBB2) were identified as top upstream regulators. Conclusions: Ibrutinib treatment decreased oxidative phosphorylation and gene expression of electron transport chain subunits and key modulators of atrial metabolism. Together, these data identify metabolic pathways that are altered by ibrutinib in aEHTs and metabolic regulators that could be targeted for AF therapeutic intervention.
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- 2021
9. Abstract 11237: Expression of Mitochondrial, Contractile, and Calcium Regulatory Proteins is Altered in Patients with Atrial Fibrillation
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Julie H Rennison, Catherine C Cantlay, Ling Li, Cheryl R Lin, Beth S Lovano, Laurie Castel, Paul J Cantlay, A M Gillinov, Christine S Moravec, Belinda B Willard, Jonathan D Smith, Mina K Chung, John Barnard, and David R Van Wagoner
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Physiology (medical) ,Cardiology and Cardiovascular Medicine - Abstract
Introduction: Atrial fibrillation (AF) increases energy demand for contractile and electrical activity. Changes in left atrial (LA) protein expression of AF patients are poorly characterized. Hypothesis: Mitochondrial protein expression in patients with AF is altered in an attempt to meet increased energy demand. Methods: LA appendage tissue was obtained from 198 patients undergoing Maze surgery. At the time of surgery, 80 were in sinus rhythm (SR) (50 paroxysmal AF, 30 persistent AF) and 118 in AF (65 persistent AF, 53 permanent AF). Protein content was assessed by mass spectrometry and 2539 proteins were identified. Results: In AF compared to SR, 257 proteins were differentially expressed (q Conclusions: In one of the largest proteomic datasets in human LA to date, we find that expression of proteins in metabolic, myofibrillar, and calcium regulation pathways is altered in patients with AF. Additional metabolic changes were detected with progression to permanent AF. These data identify proteins that are altered in patients with AF providing insight into cellular pathways that may be targeted for AF prevention and therapy.
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- 2021
10. Abstract P382: Transcriptomic Analysis Of Human Left Atrial Tissue Reveals Mitochondrial Gene Co-expression
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Julie H. Rennison, A. Gillinov, John Barnard, Jeffrey Hsu, Sojin Y Wass, Han Sun, Mina K. Chung, Jonathan D. Smith, David R. Van Wagoner, Cheryl R Lin, Catherine Cantlay, Laurie Castel, Christine S. Moravec, Meghan McHale, and Beth Lovano
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Transcriptome ,Mitochondrial DNA ,Physiology ,Left atrial ,Biology ,Cardiology and Cardiovascular Medicine ,Cell biology - Abstract
Atrial fibrillation (AF) risk is heritable. High rate electrical activity in AF requires increased energy. Atrial mitochondrial structure and function are altered in AF patients in an effort to generate adequate ATP through oxidative phosphorylation. Genomic studies have identified putative AF risk genes, but the association of AF risk genes with expression of mitochondrial genes is unclear. We tested the hypothesis that putative AF risk genes are co-expressed with mitochondrial genes that play a role in atrial energy production. RNA-seq was performed on left atrial appendage (LAA) tissues obtained from 251 cardiac surgery patients. RNA coexpression profiles were evaluated for 222 putative AF risk genes. Genes encoding proteins that localize to the mitochondria were identified using MitoCarta 2.0. Changes in metabolic pathways were detected using Ingenuity Pathway Analysis (IPA). Our analysis identified 128 AF risk genes that coexpressed with at least one mitochondrial gene. The highest level of mitochondrial gene coexpression was evident with PCCB, in which 30% (253 of 848) of coexpressed genes were mitochondrial. CASQ2 (24%, 104 of 431) and ASAH1 (20%, 37 of 182) also showed high levels of mitochondrial gene coexpression. The IPA Oxidative Phosphorylation Pathway was significantly altered (p
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- 2021
11. MP56-16 ONE-STAGE URETHROPLASTY USING DORSAL-VENTRAL BUCCAL MUCOSAL GRAFT: LONG-TERM, VALIDATED PATIENT REPORTED OUTCOMES
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Joel Gelman and John Barnard
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Dorsal ventral ,medicine.medical_specialty ,Mucosal graft ,business.industry ,Urology ,Urethroplasty ,medicine.medical_treatment ,medicine ,One stage ,Buccal administration ,business ,Surgery - Published
- 2021
12. MP03-16 LONG-TERM FOLLOW-UP SUGGESTS HIGH SATISFACTION RATES FOR BULBOMEMBRANOUS RADIATION INDUCED URETHRAL STRICTURES TREATED WITH ANASTOMOTIC URETHROPLASTY
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Aron Liaw, John Barnard, and Joel Gelman
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medicine.medical_specialty ,Stenosis ,Long term follow up ,Urethral stricture ,business.industry ,Urology ,medicine ,Anastomotic urethroplasty ,Radiation induced ,medicine.disease ,business ,Surgery - Abstract
INTRODUCTION AND OBJECTIVE:Radiation-induced bulbomembranous urethral stricture/stenosis (RIS) is definitively treated by anastomotic urethroplasty in select patients. Prior studies have characteri...
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- 2021
13. MP57-16 IMMEDIATE SALVAGE WITH INFLATABLE PENILE PROSTHESIS IN AN INFECTED FIELD: A CONTEMPORARY MULTI-INSTITUTIONAL COHORT
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John Barnard, Koenraad van Renterghem, E. Choi, James Furr, Aaron C. Lentz, Daniel Jiang, Faysal A. Yafi, and Patrick Selph
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medicine.medical_specialty ,Inflatable penile prosthesis ,business.industry ,Urology ,Field (Bourdieu) ,Cohort ,medicine ,business ,Surgery - Published
- 2021
14. The relation between ABO blood types and clinical and platelet function parameters in patients who underwent percutaneous coronary intervention
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Kandice Kottke-Marchant, Gurunathan Murugesan, John Barnard, Sanjay Gandhi, Deepak L. Bhatt, and A. Anil Timur
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Adult ,Blood Platelets ,Male ,medicine.medical_specialty ,Platelet Aggregation ,Platelet Function Tests ,medicine.medical_treatment ,Coronary Artery Disease ,030204 cardiovascular system & hematology ,Gastroenterology ,ABO Blood-Group System ,03 medical and health sciences ,Percutaneous Coronary Intervention ,Postoperative Complications ,0302 clinical medicine ,P2Y12 ,Thromboembolism ,Internal medicine ,ABO blood group system ,medicine ,Humans ,Platelet ,Prospective Studies ,030212 general & internal medicine ,Myocardial infarction ,Aged ,Aged, 80 and over ,Blood type ,Aspirin ,business.industry ,Incidence ,Percutaneous coronary intervention ,General Medicine ,Middle Aged ,Clopidogrel ,medicine.disease ,United States ,Female ,Cardiology and Cardiovascular Medicine ,business ,Follow-Up Studies ,medicine.drug - Abstract
Background ABO blood groups have been associated with venous thromboembolism and arterial thrombosis. Although platelets play key roles in thrombogenesis, the relation between ABO groups and platelets is not well known and was investigated in this study. Patients and methods ABO blood type information was retrospectively obtained for 206 patients who underwent percutaneous coronary intervention (PCI) and received dual antiplatelet therapy with aspirin and clopidogrel. Platelet function was measured using VerifyNow system, light transmission aggregometry, thromboxane B2, urinary 11-dehydrothromboxane B2, and vasodilator-stimulated phosphoprotein phosphorylation assays. Samples were also tested following treatment with 10 and 30 µmol/l of aspirin or 30 and 100 µmol/l of P2Y12 inhibitor 2-methylthioadenosine 5'-monophosphate triethylammonium salt hydrate (2-MeSAMP). Forty-four clinical and 30 platelet function parameters were analyzed. Patients were categorized as aspirin or clopidogrel poor responder (PR) according to cutoff levels of each test. Results Blood type A was significantly associated with myocardial infarction (MI) history [odds ratio (OR)=2.50, 95% confidence interval (CI)=1.37-4.58, P=0.003], higher baseline troponin T and creatine kinase-MB (CK-MB) index, post-PCI CK-MB index, and platelet reactivity index (PRI), and being PR against 2-MeSAMP (OR=5.75, 95% CI=1.51-21.90, P=0.010). Blood type O was associated with higher arachidonic acid-induced platelet aggregation and negatively associated with MI history (OR=0.47, 95% CI=0.26-0.84, P=0.010), PRI and being PR against clopidogrel (OR=0.54, 95% CI=0.30-0.99, P=0.043) and 2-MeSAMP (OR=0.16, 95% CI=0.03-0.76, P=0.021). Conclusion Blood type A was found as a risk factor for MI. Higher arachidonic acid-induced aggregation in group O and higher PRI in group A against aspirin and P2Y12 inhibitor treatment, respectively, may suggest alternative antiplatelet therapies for PRs with these blood types.
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- 2019
15. Comorbidities in Childhood Celiac Disease: A Phenome Wide Association Study Using the Electronic Health Record
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Simon Lin, Brendan Boyle, Steve Rust, Ariana Prinzbach, John Barnard, Soheil Moosavinasab, and Yungui Huang
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0301 basic medicine ,medicine.medical_specialty ,business.industry ,Gastroenterology ,Disease ,Phenome ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Childhood celiac disease ,Electronic health record ,Internal medicine ,mental disorders ,Pediatrics, Perinatology and Child Health ,Medicine ,030211 gastroenterology & hepatology ,business - Abstract
Objectives:Celiac disease (CD) is associated with a variety of extraintestinal autoimmune and inflammatory findings that manifest clinically as symptoms and comorbidities. Understanding these comorbidities may improve identification of the disease and prevent sequelae. In this study, we use
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- 2018
16. Abstract 15509: SYNE2 Expression Regulates Calcium Cycling and Mitochondria Function in Cardiomyocytes: Implications for Association With Atrial Fibrillation
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John Barnard, Conner P Witherow, Mina K. Chung, Sathyamangla V. Naga Prasad, David R. Van Wagoner, Nana Liu, and Jonathan D. Smith
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business.industry ,Endoplasmic reticulum ,Atrial fibrillation ,Mitochondrion ,medicine.disease ,Cell biology ,medicine.anatomical_structure ,Physiology (medical) ,Gene expression ,Medicine ,Nuclear membrane ,Cardiology and Cardiovascular Medicine ,business ,Cytoskeleton ,Nucleus ,SYNE2 Gene - Abstract
Introduction: SYNE2 encodes a nuclear membrane protein that connects the nucleus with the cytoskeleton. rs1152591 is a common SNP in the SYNE2 gene that is associated with atrial fibrillation (AF) and with reduced expression of SYNE2α1 , a short isoform, in human left atrial appendage tissue. We previously found that SYNE2α1 over expression (OE) acts as a dominant negative for the nuclear phenotype, similar to the SYNE2 knockdown (KD), leading to enlarged nuclear size and decreased nuclear stiffness. Objectives: To determine if GFP- SYNE2α1 (OE) and KD of all SYNE2 isoforms show similar effects on gene expression and cell physiology in human induced pluripotent stem cell-derived cardiomyocytes (iCMs). Methods and Results: RNAseq after SYNE2α1 OE or SYNE2 KD revealed both congruent changes in expression of specific genes, supporting the dominant negative role of SYNE2α1 , but also divergent changes in expression of some genes, showing specific effects of the SYNE2α1 short isoform. We identified both mitochondrial function and sarcoplasmic reticulum (SR) function as differentially expressed pathways comparing OE vs. KD iCMs. Fura-2 photometry was used to study Ca 2+ cycling in beating iCMs, and revealed delayed calcium reuptake in the SYNE2 KD cells (15.9% increase in reuptake time as % of each contraction, pSYNE2α1 OE cells (not significant). Flow cytometry showed significantly lower SERCA2 expression in the SYNE2 KD cells but not in the SYNE2α1 OE cells (12% decrease, p=0.029). Immunofluorescence microscopy revealed that GFP-SYNE2α1 not only localized to the nuclear membrane but also to the SR, stained with anti-SERCA2. Flow cytometry after MitoTracker Orange staining, to monitor the cellular volume of functional mitochondria, was significantly increased in both the SYNE2α1 OE and SYNE2 KD iCMs vs. their respective controls. Thus, despite differential expression of mitochondrial pathway genes, SYNE2α1 mimics the KD of all SYNE2 isoforms in regard to mitochondrial function. Conclusions: SYNE2α1 OE, unlike KD of all SYNE2 isoforms, preserves SR Ca 2+ reuptake activity, and this may contribute to the mechanism by which the AF risk allele in the SYNE2 gene, associated with decreased expression of SYNE2α1, predisposes carriers to AF.
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- 2020
17. Abstract 17259: Identification of Biological Pathways of Candidate Atrial Fibrillation Risk Genes Through the Use of Weighted Gene Coexpression Network Analysis
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Meghan McHale, David R. Van Wagoner, Jonathan D. Smith, Christine S. Moravec, Jeffery Hsu, Erik Offerman, A. Gillinov, Sojin Y Wass, Han Sun, John Barnard, Mina K. Chung, Catherine Cantlay, and Julie H. Rennison
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Biological pathway ,business.industry ,Physiology (medical) ,medicine ,Atrial fibrillation ,Identification (biology) ,Computational biology ,Cardiology and Cardiovascular Medicine ,Gene coexpression ,medicine.disease ,business ,Gene ,Network analysis - Abstract
Introduction: Over 135 genetic loci have been linked to atrial fibrillation (AF), yet the biological pathways of AF pathophysiology remain elusive. Weighted gene coexpression network analysis (WGCNA) constructs gene modules within a network based on correlations in gene expression, and identifies mechanisms related to AF risk. Objective: To identify biological pathways of candidate AF risk genes that will advance our understanding of AF mechanisms. Methods: RNA-sequencing was performed on left atrial appendage tissue from 265 patients. RNA-seq data were adjusted for differences in AF rhythm state and other known AF risk factors. Correlations from adjusted data were further adjusted for latent factors then spatial quantile normalized to correct for mean-variance bias. WGCNA was applied to the resulting adjusted and normalized gene-gene correlations to identify gene modules. Ingenuity Pathway Analysis and gene set over representation analysis (GSOR) were applied to each module. Results: WGCNA identified 63 modules from 17,434 genes; 47 of these contained at least one candidate AF risk gene. AF risk genes were overrepresented in 7 modules (Table 1). Notable top pathways of AF overrepresented modules include apelin signaling, heme metabolism, intracellular ion homeostasis, and the unfolded protein response. These are known to be involved in calcium signaling, iron homeostasis, glucose regulation, heat shock response, and protein ubiquitination during states of high energy demand and stress. These pathways coincide with larger cellular processes of myocyte remodeling, apoptosis, and cell survival, which were also prominent. Conclusions: Biological pathways identified through WGCNA and GSOR suggest that sustained increases in energy demand during AF promotes stress-induced cellular remodeling. Changes in calcium signaling, iron homeostasis, the unfolded protein response and glucose regulation are likely primary mechanisms of AF pathophysiology.
- Published
- 2020
18. Abstract 262: Regional Transcriptomics of Left Atrial Cardiac Tissue in a Patient With Atrial Fibrillation
- Author
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John Barnard, Mina K. Chung, David R. Van Wagoner, Kenneth R. McCurry, Jonathan D. Smith, Toshihiro Okamoto, Han Sun, and Samuel Harwood
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medicine.medical_specialty ,Physiology ,business.industry ,Left atrial ,Internal medicine ,Cardiology ,medicine ,Atrial fibrillation ,Cardiology and Cardiovascular Medicine ,medicine.disease ,business - Abstract
Background: Common genetic variants and inflammatory factors are associated with atrial fibrillation (AF) risk. Although the top AF risk locus is near PITX2 (associated with pulmonary vein (PV) development), regional differential expression (DE) of AF risk genes in the left atrium (LA) and PVs is not well studied. While LAA and PV gene expression have been compared, transcriptome mapping of the entire LA has not been done. We tested the hypothesis that there is significant regional DE in LA structures. Methods: RNAseq was performed in 25 regions within the PVs (n=12), LA body (LAB) (n=10), and LA appendage (LAA) (n=3) from a 75 year old male with hypertension and AF who died of a stroke. DE analysis of regional clusters (R 3.6 Limma package) and gene set enrichment analysis (GSEA) (Broad Institute) were performed. Results: In full transcriptome (n=20664) sequencing, 118 genes were significantly (q < 0.05) upregulated in the LAA, including FOSB (fold change [FC] 67.0), IL6 (FC 15.4), TNF (FC 2.4) and NLRP3 (FC 2.4), and 56 downregulated, including developmental genes such as SHOX2 (FC -12.9) and HOXA4 (FC -4.1). LAA GSEA showed enrichment (FDR < 0.05) of inflammatory response genes and TNF-α, IL-2, IL-6, and IgG signaling pathways. 2454 genes were significantly upregulated and 3737 downregulated in the PVs while 4021 genes were upregulated and 2998 were downregulated in the LAB. In an AF implicated gene set (n=190), 28 genes were upregulated in the PVs, including SIRT1 (FC 1.7), and 31 downregulated, including PMNT (FC -2.1) and CGA (FC -3.2). NEURL1 was significantly upregulated in the inferior PV (n=4) compared to the superior PV (n=8) (FC 3.6). In the LAB, 33 genes were upregulated, including MYH7 (FC 2.2) and PMNT (FC 2.1) , and 38 downregulated including SIRT1 (FC -1.9). PITX2 did not show any significant DE in any gene set. Conclusions: This data shows that genes involved in AF pathogenesis can have substantial regional expression difference, particularly when comparing the LA body, PVs, and LAA. Inflammatory activation in the LAA may contribute to increased stroke risk.
- Published
- 2020
19. PD21-10 EVOKED EMG AS A METHOD FOR CONFIRMING TIBIAL NERVE RECRUITMENT IN SUBJECTS WITH OAB
- Author
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Mingming Zhang, Stanley Zaslau, John Barnard, Samir Arora, Jessica Spear, and Laura LeScoezec
- Subjects
medicine.medical_specialty ,business.industry ,Urology ,education ,urologic and male genital diseases ,medicine.disease ,female genital diseases and pregnancy complications ,humanities ,Neuromodulation (medicine) ,Overactive bladder ,Medicine ,business ,Tibial nerve - Abstract
INTRODUCTION AND OBJECTIVE:Neuromodulation of the tibial nerve has been found to be an effective therapy to treat overactive bladder (OAB) while eliminating all the systemic side effects found with...
- Published
- 2020
20. Common Coding Variants in SCN10A Are Associated With the Nav1.8 Late Current and Cardiac Conduction
- Author
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Alvaro Alonso, Donna M. Muzny, Moritz F. Sinner, Ching-Ti Liu, John Barnard, Eric Boerwinkle, David J. Milan, Thomas P. Cappola, Robert W. Mills, Alanna C. Morrison, Thomas Lumley, Colleen M. Sitlani, Dan E. Arking, Michael Morley, L. Adrienne Cupples, Nona Sotoodehnia, Rebecca D. Jackson, Mina K. Chung, Paul M.L. Janssen, Ning Li, Stephen S. Rich, Jerome I. Rotter, Christopher J. O'Donnell, David R. Van Wagoner, Kenneth B. Margulies, Xiaoyan Yin, Gus J. Vlahakes, Sara L. Pulit, Caroline N. Herndon, Vadim V. Fedorov, Joshua C. Bis, Susan R. Heckbert, Jared W. Magnani, Bruce M. Psaty, Steven A. Lubitz, Christopher Newton-Cheh, Honghuang Lin, Peter J. Mohler, Patrick T. Ellinor, Elena Dolmatova, Jonathan D. Smith, Vincenzo Macri, William J. Hucker, Emelia J. Benjamin, Richard A. Gibbs, and Jennifer A. Brody
- Subjects
0301 basic medicine ,medicine.medical_specialty ,education.field_of_study ,Haplotype ,Population ,Single-nucleotide polymorphism ,Locus (genetics) ,General Medicine ,030204 cardiovascular system & hematology ,Biology ,03 medical and health sciences ,QRS complex ,030104 developmental biology ,0302 clinical medicine ,Endocrinology ,Internal medicine ,Cardiac conduction ,medicine ,Missense mutation ,PR interval ,education - Abstract
Background: Genetic variants at the SCN5A / SCN10A locus are strongly associated with electrocardiographic PR and QRS intervals. While SCN5A is the canonical cardiac sodium channel gene, the role of SCN10A in cardiac conduction is less well characterized. Methods: We sequenced the SCN10A locus in 3699 European-ancestry individuals to identify variants associated with cardiac conduction, and replicated our findings in 21,000 individuals of European ancestry. We examined association with expression in human atrial tissue. We explored the biophysical effect of variation on channel function using cellular electrophysiology. Results: We identified 2 intronic single nucleotide polymorphisms in high linkage disequilibrium ( r 2 =0.86) with each other to be the strongest signals for PR (rs10428132, β=−4.74, P =1.52×10 −14 ) and QRS intervals (rs6599251, QRS β=−0.73; P =1.2×10 −4 ), respectively. Although these variants were not associated with SCN5A or SCN10A expression in human atrial tissue (n=490), they were in high linkage disequilibrium ( r 2 ≥0.72) with a common SCN10A missense variant, rs6795970 (V1073A). In total, we identified 7 missense variants, 4 of which (I962V, P1045T, V1073A, and L1092P) were associated with cardiac conduction. These 4 missense variants cluster in the cytoplasmic linker of the second and third domains of the SCN10A protein and together form 6 common haplotypes. Using cellular electrophysiology, we found that haplotypes associated with shorter PR intervals had a significantly larger percentage of late current compared with wild-type (I962V+V1073A+L1092P, 20.2±3.3%, P =0.03, and I962V+V1073A, 22.4±0.8%, P =0.0004 versus wild-type 11.7±1.6%), and the haplotype associated with the longest PR interval had a significantly smaller late current percentage (P1045T, 6.4±1.2%, P =0.03). Conclusions: Our findings suggest an association between genetic variation in SCN10A , the late sodium current, and alterations in cardiac conduction.
- Published
- 2018
21. Weighted Gene Coexpression Network Analysis of Human Left Atrial Tissue Identifies Gene Modules Associated With Atrial Fibrillation
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John Barnard, Mina K. Chung, Jeffrey Hsu, David Serre, David Newton, Jonathan D. Smith, Laurie Castel, Edward G. Soltesz, Gösta B. Pettersson, Nicholas Y. Tan, David R. Van Wagoner, and A. Marc Gillinov
- Subjects
Male ,medicine.medical_specialty ,Heart Valve Diseases ,Gene regulatory network ,Muscle Proteins ,Coronary Artery Disease ,Biology ,Bioinformatics ,Severity of Illness Index ,Article ,Coronary artery disease ,Gene Modules ,Left atrial ,Internal medicine ,Atrial Fibrillation ,Genetics ,medicine ,Cluster Analysis ,Humans ,Gene Regulatory Networks ,Heart Atria ,Genetics (clinical) ,Aged ,Oligonucleotide Array Sequence Analysis ,Calcineurin ,Intracellular Signaling Peptides and Proteins ,Atrial fibrillation ,Middle Aged ,medicine.disease ,Gene coexpression ,Phenotype ,DNA-Binding Proteins ,Cardiology ,Mitral Valve ,Regression Analysis ,Female ,DNA microarray ,T-Box Domain Proteins ,Cardiology and Cardiovascular Medicine ,Signal Transduction - Abstract
Background— Genetic mechanisms of atrial fibrillation (AF) remain incompletely understood. Previous differential expression studies in AF were limited by small sample size and provided limited understanding of global gene networks, prompting the need for larger-scale, network-based analyses. Methods and Results— Left atrial tissues from Cleveland Clinic patients who underwent cardiac surgery were assayed using Illumina Human HT-12 mRNA microarrays. The data set included 3 groups based on cardiovascular comorbidities: mitral valve (MV) disease without coronary artery disease (n=64), coronary artery disease without MV disease (n=57), and lone AF (n=35). Weighted gene coexpression network analysis was performed in the MV group to detect modules of correlated genes. Module preservation was assessed in the other 2 groups. Module eigengenes were regressed on AF severity or atrial rhythm at surgery. Modules whose eigengenes correlated with either AF phenotype were analyzed for gene content. A total of 14 modules were detected in the MV group; all were preserved in the other 2 groups. One module (124 genes) was associated with AF severity and atrial rhythm across all groups. Its top hub gene, RCAN1 , is implicated in calcineurin-dependent signaling and cardiac hypertrophy. Another module (679 genes) was associated with atrial rhythm in the MV and coronary artery disease groups. It was enriched with cell signaling genes and contained cardiovascular developmental genes including TBX5 . Conclusions— Our network-based approach found 2 modules strongly associated with AF. Further analysis of these modules may yield insight into AF pathogenesis by providing novel targets for functional studies.
- Published
- 2013
22. Abstract 470: Computational Identification of NKX2-5 Binding Sites and Downstream Gene Targets Using Transcription Factor Motif and Human Heart-specific Experimental Data
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John Barnard, David R. Van Wagoner, Jonathan D. Smith, Mina K. Chung, and Nicholas Y. Tan
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Gene targets ,Heart development ,Physiology ,Human heart ,Motif (music) ,Computational biology ,Biology ,Binding site ,Cardiology and Cardiovascular Medicine ,Transcription factor - Abstract
Background: While NKX2-5 plays pivotal roles in human cardiac development and disease, no ChIP-Seq studies of NKX2-5 in human cardiac tissues currently exist, resulting in an incomplete understanding of its direct gene targets. Modern computational methods which identify binding sites using transcription factor motif and tissue-specific experimental data can help to fill this knowledge gap. Objective: To use computational methods to identify likely NKX2-5 binding sites and downstream gene targets using human heart-specific experimental data. Methods: Human cardiomyocyte DNAse hypersensitivity data (2 replicates) were downloaded from the Encyclopedia of DNA Elements (ENCODE) database. The position weight matrix (PWM) representing the transcription factor motif of NKX2-5 was obtained from JASPAR. We applied the Protein Interaction Quantification (PIQ) algorithm to detect NKX2-5 binding sites using the PWM and DNAse hypersensitivity data as inputs. RNA-Seq data from 108 human heart-specific samples (atrial appendages and left ventricles) were downloaded from the Genotype-Tissue Expression (GTEx) database. Protein-coding genes significantly expressed in the heart (RPKM Results: 1283 binding sites for NKX2-5 were discovered by PIQ. Of 12698 protein-coding, heart-expressed genes, 625 were within 100kb of these binding sites. The identified genes were highly enriched in physiologic categories like “Vasculogenesis” and “Development of Cardiovascular Tissue” (p = 2.36x10-9 and 2.31x10-8 respectively). Notable genes included: cardiac transcription factors (MEF2A, TBX20); growth factors (TGFB2, BMP2); muscle and ion channel function (ACTA2, BIN1), and; calcium signaling (CALM2, CAMK2D). Conclusion: By using computational analyses of transcription factor motif and human heart-specific experimental data, we have identified candidate downstream targets of NKX2-5. Future work will include validation studies in an external cohort and analysis of associations between these candidate genes and cardiac disease.
- Published
- 2016
23. Abstract 244: Differential mRNA Expressions in Thoracic Aortic Aneurysm in Patients with Bicuspid and Tricuspid Aortic Valve
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Mariah Wright, John Barnard, Yuanjia Zhu, Andrea Hanick, Eric E. Roselli, and David R. Van Wagoner
- Subjects
Aortic valve ,medicine.medical_specialty ,Messenger RNA ,Physiology ,business.industry ,Mrna expression ,medicine.disease ,Thoracic aortic aneurysm ,medicine.anatomical_structure ,Bicuspid aortic valve ,Internal medicine ,medicine ,Cardiology ,In patient ,Cardiology and Cardiovascular Medicine ,business - Abstract
Objective: Bicuspid aortic valve (BAV), the most common congenital heart condition, is frequently associated with thoracic aortic aneurysm (TAA). Aortic mRNA expression patterns in BAV patients and expression differences between BAV and tricuspid aortic valve (TAV) patients are unclear. We sought to compare mRNA expressions in TAA in patients with BAV and TAV. Methods and Results: Ascending aorta tissue was obtained from 58 aortic aneurysm repair patients (31 BAV, 27 TAV) and from 8 heart transplant donors. Illumina Human HT-12v4 microarrays were used to assess mRNA expression. After standard QC and filtering, probes were analyzed using multivariable linear regression analysis, adjusting for age, gender, medication use (beta blockers, ACE-Is, ARBs), and 10 surrogate variables. Ingenuity Pathway Analysis (IPA) was used to identify pathways and top regulator effect networks that were differentially expressed in BAV vs. TAV and BAV vs. donors. In BAV vs. TAV, MMP9, ESM1 and IL1B were downregulated 0.63, 0.74 and 0.77 fold, whereas COMP was upregulated 2.29 fold (p < 0.05 for all). In BAV vs. donors, IL1R2, MCEMP1, IL18RAP and ACAN were downregulated 0.66, 0.2, 0.2 and 0.05 fold, while ADAMTS8, CCL21 and CIDEA were upregulated 6.97, 6.24 and 4.65 fold (p < 0.0001). IPA analysis showed P53 as the top upstream regulator for both BAV vs. TAV (p = 1.9e-8) and BAV vs. donors (p = 2.3e-25). IRF7, which protects against angiotensin II-induced hypertrophy in cardiomyocytes, was also a significant upstream regulator for BAV vs. TAV (p = 3.6e-7). Additionally, miR-124-3p in BAV vs. TAV (p = 6.3e-7) and BAV vs. donors (p = 1.7e-22), as well as miR-96-5p in BAV vs. TAV (p = 4e-7) were predicted significant upstream regulators. Immune response was shown to be the top regulator effect network in BAV vs. TAV, whereas perivascular fibrosis was shown to be an important regulator effect network in BAV vs. donors. Cell stress pathways were also activated in BAV vs. donors. Conclusions: Distinct pathways and regulator effect networks exist in TAA with BAV or TAV. TAV associated TAA is more associated with inflammatory responses, while BAV aortopathy is more associated with extracellular matrix remodelling and cell stress. MiRs may also play an important role in BAV aortopathy.
- Published
- 2016
24. PANCR, the PITX2 Adjacent Noncoding RNA, Is Expressed in Human Left Atria and Regulates PITX2c Expression
- Author
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Jonathan D. Smith, Mina K. Chung, John Barnard, Shamone R. Gore-Panter, Jeffrey Hsu, David R. Van Wagoner, and Christine S. Moravec
- Subjects
Male ,0301 basic medicine ,RNA, Untranslated ,Genotype ,Biology ,Transcriptome ,03 medical and health sciences ,Physiology (medical) ,Atrial Fibrillation ,Gene expression ,Humans ,Myocytes, Cardiac ,Heart Atria ,Aged ,Homeodomain Proteins ,Regulation of gene expression ,Gene knockdown ,Messenger RNA ,Reverse Transcriptase Polymerase Chain Reaction ,RNA ,Middle Aged ,Non-coding RNA ,Molecular biology ,Long non-coding RNA ,030104 developmental biology ,Gene Expression Regulation ,Female ,Cardiology and Cardiovascular Medicine ,Transcription Factors - Abstract
Background— Genome-wide studies reveal that genetic variants at chromosome 4q25 constitute the strongest locus associated with atrial fibrillation, the most frequent arrhythmia. However, the mechanisms underlying this association are unknown. Our goal is to find and characterize left atrial–expressed transcripts in the chromosome 4q25 atrial fibrillation risk locus that may play a role in atrial fibrillation pathogenesis. Methods and Results— RNA sequencing performed on human left/right pairs identified an intergenic long noncoding RNA adjacent to the PITX2 gene, which we have named PANCR ( PITX2 adjacent noncoding RNA). In a human tissue screen, PANCR was expressed specifically in the left atria and eye and in no other chambers of the heart. The levels of PANCR and PITX2c RNAs were highly correlated in 233 human left atrial appendage samples. PANCR levels were not associated with either atrial rhythm status or the genotypes of the chromosome 4q25 atrial fibrillation risk variants. Both PANCR and PITX2c RNAs were induced early during differentiation of human embryonic stem cells into cardiomyocytes. Because long noncoding RNAs often control gene expression, we performed siRNA-mediated knockdown of PANCR, and this treatment repressed PITX2c expression and mimicked the effects of PITX2c knockdown on global mRNA and miRNA expression. Cell fractionation studies demonstrate that PANCR is primarily localized in the cytoplasm. Conclusions— PANCR and PITX2c are coordinately expressed early during cardiomyocyte differentiation from stem cells. PANCR knockdown decreased PITX2c expression in differentiated cardiomyocytes, altering the transcriptome in a manner similar to PITX2c knockdown.
- Published
- 2016
25. Whole Genome Expression Differences in Human Left and Right Atria Ascertained by RNA Sequencing
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Mina K. Chung, John Barnard, Jonathan D. Smith, David R. Van Wagoner, Jeffrey Hsu, David Serre, and Peter Hanna
- Subjects
medicine.medical_specialty ,Sequence analysis ,Biology ,Bioinformatics ,Genome ,Article ,Internal medicine ,microRNA ,Gene expression ,Genetics ,medicine ,Humans ,Heart Atria ,RNA, Messenger ,Genetics (clinical) ,Atrium (architecture) ,Sequence Analysis, RNA ,Gene Expression Profiling ,RNA ,Arrhythmias, Cardiac ,Atrial fibrillation ,medicine.disease ,Gene expression profiling ,MicroRNAs ,Cardiology ,Cardiology and Cardiovascular Medicine - Abstract
Background— The left and right atria have different susceptibilities toward developing arrhythmias, with left atrial arrhythmias more commonly observed. To understand the molecular basis for such differences, we catalogued micro (mi)RNA and mRNA expression differences by next generation sequencing. Methods and Results— Four human left-right atrial pairs were subjected to whole-genome expression analyses via next-generation sequencing of small RNAs, including miRNAs, and poly-A–enriched mRNAs. Using a paired sample design, significant differences in the expression of 32 miRNAs were found in between the left and right atria at a probability value of Conclusions— There are significant differences in miRNA and mRNA expression profiles between the left and right atria, which may yield insight into increased the arrhythmogenesis of the left atria.
- Published
- 2012
26. Atherosclerosis Susceptibility Loci Identified From a Strain Intercross of Apolipoprotein E–Deficient Mice via a High-Density Genome Scan
- Author
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John Barnard, Jonathan D. Smith, Yaomin Xu, Julie Baglione, Megan Settle, and Jeffrey M. Bhasin
- Subjects
Genetic Markers ,Male ,Apolipoprotein E ,Genotype ,Quantitative Trait Loci ,Genome Scan ,Locus (genetics) ,Quantitative trait locus ,Biology ,Polymorphism, Single Nucleotide ,Genome ,Lesion ,Mice ,Mice, Inbred AKR ,Apolipoproteins E ,Species Specificity ,medicine ,Animals ,Genetic Predisposition to Disease ,Gene ,Aorta ,Genetics ,Genomics ,Atherosclerosis ,Mice, Mutant Strains ,Mice, Inbred C57BL ,Phenotype ,Mice, Inbred DBA ,Genetic marker ,Female ,Lod Score ,medicine.symptom ,Cardiology and Cardiovascular Medicine - Abstract
Objective— Apolipoprotein (apo) E-deficient mice are hypercholesterolemic and develop atherosclerosis on low-fat chow diets; however, the genetic background strain has a large effect on atherosclerosis susceptibility. This study aimed to determine the genetic regions associated with strain effects on lesion area. Methods and Results— We performed a strain intercross between atherosclerosis sensitive DBA/2 and atherosclerosis resistant AKR apoE-deficient mice. Aortic root lesion area, total cholesterol, body weights, and complete blood counts were ascertained for 114 male and 95 female F 2 progeny. A high-density genome scan was performed using a mouse single nucleotide polymorphism chip yielding 1967 informative polymorphic markers. Quantitative trait locus (QTL) statistical analyses were performed. Novel loci associated with lesion or log lesion area were identified for the female and male F 2 cohorts. The atherosclerosis QTLs in female mice reside on chromosomes 15, 5, 3, and 13, and in male mice on chromosomes 17, 18, and 2. QTL were also identified for body weight, total cholesterol, and blood count parameters. Conclusions— Loci were identified for atherosclerosis susceptibility in a strain intercross study. The identity of the responsible genes at these loci remains to be determined.
- Published
- 2006
27. Keys to Writing A Competitive Grant
- Author
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John Barnard
- Subjects
National Institutes of Health (U.S.) ,Research Design ,business.industry ,Data Collection ,Research Support as Topic ,Writing ,Pediatrics, Perinatology and Child Health ,Gastroenterology ,Humans ,Medicine ,business ,United States ,Management - Published
- 2002
28. Abstract 110: Noncoding RNAs: A Possible 'Linc' to Atrial Fibrillation
- Author
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Shamone R Gore, Jeffery Hsu, Peter Hanna, David R Van Wagoner, John Barnard, Mina K Chung, and Jonathan D Smith
- Subjects
Physiology ,Cardiology and Cardiovascular Medicine - Abstract
Atrial fibrillation (AF), the most common cardiac arrhythmia, is associated with a 2-fold increased risk of mortality and a ~5- fold increased risk of stroke. Genome wide association studies have identified a locus on chromosome 4q25 that has the strongest association with AF. The SNPs in this locus most strongly associated with AF are located in an intergenic region that is 78 to 157 kb distal to the closest gene PITX2. PITX2 is a candidate gene for AF, due to its role in left/right patterning during heart development and expression found only in the left vs. right atrium. Our lab performed RNA-seq on human atria and identified a long intergenic non-coding RNA (linc-RNA) adjacent to PITX2 that is expressed with the same left/right atrial asymmetry as PITX2. We hypothesized that there may be functional genetic variants in the 4q25 region that directly affect expression of PITX2 or the linc-RNA adjacent to PITX2. Further, we hypothesized that the linc-RNA may control in trans the expression of genes that can alter cellular electrophysiology and lead to AF susceptibility. First we used qPCR to determine whether the expression of PITX2 and this linc-RNA were correlated in 199 human left atria samples. We found the expression of these genes to be highly and positively correlated with an r2 value of 0.47 (p < .0001). We obtained genome-wide SNP information for each of these subjects using an Illumina SNP microarray. We determined the association of SNPs on chromosome 4 with the expression levels of PITX2 and the linc-RNA by performing expression QTL (eQTL) analysis. In the 4q25 region, common genetic variation was more strongly associated with expression of the linc-RNA than PITX2. Two of the strongest linc-RNA eQTL SNPs (p-value ~10-4) were associated with AF with a p-value of ~10 15. We are now starting functional studies to determine if this linc-RNA can modulate gene expression in trans by transfection of a linc-RNA expression plasmid into HEK-293 cells. We plan to determine the effects of over expression this linc-RNA on global gene expression profiles using expression arrays and RNA-seq
- Published
- 2012
29. Abstract 4403: Significant Single Nucleotide Polymorphism Associated with Atrial Fibrillation Located on Chromosome 4q25 in a Whole Genome Association Study and Association with Left Atrial Gene Expression
- Author
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Mina K Chung, David R Van Wagoner, Jonathan D Smith, Robert C Wirka, Eric J Topol, Milind Y Desai, Lisa Prcela, Stanley L Hazen, and John Barnard
- Subjects
Physiology (medical) ,Cardiology and Cardiovascular Medicine - Abstract
Introduction: Heritability studies of atrial fibrillation (AF) suggest a complex genetic basis for common AF. Recently a locus on chromosome 4q25 was associated with AF in a genome-wide association study (GWAS), but the mechanism by which this locus is associated with AF is unknown. Methods: To identify genetic variations associated with AF, we performed an analysis of AF as a secondary phenotype from a case-control GWAS of myocardial infarction. 210,178 autosomal SNPs of high quality were genotyped in 138 AF cases and 546 controls. Stratified score tests of the trend/additive model and general genotypic model were performed for each SNP. Genomic control and multidimensional scaling were used to control and assess population stratification. The SNP meeting genome-wide significance was genotyped in 46 left atrial appendage tissue samples for which we obtained expression levels for 22,184 transcripts. Cis expression traits within 1 megabase of the top SNP were tested for association with the SNP genotypes. Results: One SNP (rs4611994) met our per-SNP genome-wide significance thresholds (both a conservative Bonferroni threshold or a more liberal FDR-based threshold) for association with AF, which was in perfect linkage disequilibrium with the locus on chromosome 4q25 found in the deCODE genetics AF study (r 2 with SNP rs2200733=1.0). This SNP yielded an AF odds ratio of 2.28 under the additive model, with a p-value using genomic control/general genotype model of 5.0E-08, and a minor allele frequency 0.13 in controls and 0.25 in AF cases, and a genome-wide p-value of 0.046 by permutation analysis. In the 46 left atrial tissue samples, cis analysis demonstrated significant association between rs4611994 genotype and expression of LRIT3 (Leucine-rich repeat, immunoglobulin-like domain and transmembrane domain-containing protein 3) with q-value 2.22E-03 and the C isoform of PITX2 with q-value 7.50E-03. Conclusions: Our GWAS for common AF has replicated the AF-associated locus on chromosome 4q25. The genotype at this locus was correlated with cis regulation of the LRIT3 and PITX2C transcripts, suggesting these genes as candidates for mechanistic studies.
- Published
- 2008
30. Classification of Natalizumab Cases with Progressive Multifocal Leukoencephalopathy (P07.058)
- Author
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Sandra Richman, John Barnard, Tuan Dong-Si, Carmen Bozic, Thomas Weber, Gary Bloomgren, Nancy Richert, Mariska Kooijmans-Coutinho, Grainne Quinn, and David B. Clifford
- Subjects
Pathology ,medicine.medical_specialty ,Natalizumab ,business.industry ,Progressive multifocal leukoencephalopathy ,medicine ,Neurology (clinical) ,medicine.disease ,business ,medicine.drug - Published
- 2012
31. Propofol: Pro- or Anticonvulsant Drug?
- Author
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Jamie Sleigh, Logan Voss, John Barnard, and Heidi Kirsch
- Subjects
Anesthesiology and Pain Medicine - Published
- 2009
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