Digital Commons Network^™

High-Resolution Metabolomics Of Exposure To Tobacco Smoke During Pregnancy And Adverse Birth Outcomes In The Atlanta African American Maternal-Child Cohort, Youran Tan, Dana Boyd Barr, P Barry Ryan, Veronika Fedirko, Jeremy A Sarnat, Audrey J Gaskins, Che-Jung Chang, Ziyin Tang, Carmen J Marsit, Elizabeth J Corwin, Dean P Jones, Anne L Dunlop, Donghai Liang

Faculty, Staff and Student Publications

Exposure to tobacco smoke during pregnancy has been associated with a series of adverse reproductive outcomes; however, the underlying molecular mechanisms are not well-established. We conducted an untargeted metabolome-wide association study to identify the metabolic perturbations and molecular mechanisms underlying the association between cotinine, a widely used biomarker of tobacco exposure, and adverse birth outcomes. We collected early and late pregnancy urine samples for cotinine measurement and serum samples for high-resolution metabolomics (HRM) profiling from 105 pregnant women from the Atlanta African American Maternal-Child cohort (2014-2016). Maternal metabolome perturbations mediating prenatal tobacco smoke exposure and adverse birth outcomes were assessed …

A Narrative Review On Invasive Brain Stimulation For Treatment-Resistant Depression, Manoj P Dandekar, Alexandre P Diaz, Ziaur Rahman, Ritele H Silva, Ziad Nahas, Scott Aaronson, Sudhakar Selvaraj, Albert J Fenoy, Marsal Sanches, Jair C Soares, Patricio Riva-Posse, Joao Quevedo

Faculty, Staff and Student Publications

While most patients with depression respond to pharmacotherapy and psychotherapy, about one-third will present treatment resistance to these interventions. For patients with treatment-resistant depression (TRD), invasive neurostimulation therapies such as vagus nerve stimulation, deep brain stimulation, and epidural cortical stimulation may be considered. We performed a narrative review of the published literature to identify papers discussing clinical studies with invasive neurostimulation therapies for TRD. After a database search and title and abstract screening, relevant English-language articles were analyzed. Vagus nerve stimulation, approved by the U.S. Food and Drug Administration as a TRD treatment, may take several months to show therapeutic …

Clinical Implementation And Initial Experience With A 15 Tesla Mr-Linac For Mr-Guided Radiation Therapy For Gynecologic Cancer: An R-Ideal Stage 1 And 2a First In Humans Feasibility Study Of New Technology Implementation, David S Lakomy, Jinzhong Yang, Sastry Vedam, Jihong Wang, Belinda Lee, Angela Sobremonte, Pamela Castillo, Neil Hughes, Mustefa Mohammedsaid, Anuja Jhingran, Ann H Klopp, Seungtaek Choi, C David Fuller, Lilie L Lin

Faculty, Staff and Student Publications

PURPOSE: Magnetic resonance imaging-guided linear accelerator systems (MR-linacs) can facilitate the daily adaptation of radiation therapy plans. Here, we report our early clinical experience using a MR-linac for adaptive radiation therapy of gynecologic malignancies.

METHODS AND MATERIALS: Treatments were planned with an Elekta Monaco v5.4.01 and delivered by a 1.5 Tesla Elekta Unity MR-linac. The system offers a choice of daily adaptation based on either position (ATP) or shape (ATS) of the tumor and surrounding normal structures. The ATS approach has the option of manually editing the contours of tumors and surrounding normal structures before the plan is adapted. Here, …

Multiplexed Engineering And Precision Gene Editing In Cellular Immunotherapy, Alexander Biederstädt, Gohar Shahwar Manzar, May Daher

Faculty, Staff and Student Publications

The advent of cellular immunotherapy in the clinic has entirely redrawn the treatment landscape for a growing number of human cancers. Genetically reprogrammed immune cells, including chimeric antigen receptor (CAR)-modified immune effector cells as well as T cell receptor (TCR) therapy, have demonstrated remarkable responses across different hard-to-treat patient populations. While these novel treatment options have had tremendous success in providing long-term remissions for a considerable fraction of treated patients, a number of challenges remain. Limited

Translating Mentoring Interventions Research Into Practice: Evaluation Of An Evidence-Based Workshop For Research Mentors On Developing Trainees’ Scientific Communication Skills, Erin K Dahlstrom, Christine Bell, Shine Chang, Hwa Young Lee, Cheryl B Anderson, Annie Pham, Christine Maidl Pribbenow, Carrie A Cameron

Faculty, Staff and Student Publications

A key part of keeping doctoral and postdoctoral trainees in STEM research careers is mentoring. Our previous research indicates that mentoring trainees in scientific communication (SC) skill development increases research career intention through two social-cognitive constructs, self-efficacy in and outcome expectations for acquiring SC skills, as well as science identity. While many mentor training interventions exist, no programs focus on developing SC skills specifically. The "Scientific Communication Advances Research Excellence" (SCOARE) program trains mentors to address trainee scientific communication (SC) skill development as an innovative approach to increase trainee research career persistence. The SCOARE training is a half-day workshop for …

Pathogenic Tau Accelerates Aging-Associated Activation Of Transposable Elements In The Mouse Central Nervous System, Paulino Ramirez, Gabrielle Zuniga, Wenyan Sun, Adrian Beckmann, Elizabeth Ochoa, Sarah L Devos, Bradley Hyman, Gabriel Chiu, Ethan R Roy, Wei Cao, Miranda Orr, Virginie Buggia-Prevot, William J Ray, Bess Frost

Faculty, Staff and Student Publications

Transposable elements comprise almost half of the mammalian genome. A growing body of evidence suggests that transposable element dysregulation accompanies brain aging and neurodegenerative disorders, and that transposable element activation is neurotoxic. Recent studies have identified links between pathogenic forms of tau, a protein that accumulates in Alzheimer's disease and related "tauopathies," and transposable element-induced neurotoxicity. Starting with transcriptomic analyses, we find that age- and tau-induced transposable element activation occurs in the mouse brain. Among transposable elements that are activated at the RNA level in the context of brain aging and tauopathy, we find that the endogenous retrovirus (ERV) class …

Transcriptomic-Assisted Immune And Neoantigen Profiling In Premalignancy, Kyle Chang, Florencia Mcallister, Eduardo Vilar

Faculty, Staff and Student Publications

Immune-based cancer therapies such as checkpoint inhibitors (CPI) and vaccines have been increasingly studied across different cancer types. Response to such therapies depends on a number of factors such as mutational burden, neoantigen load, presence of tumor infiltrating lymphocytes, among others. Next-generation sequencing (NGS) technologies are particularly attractive to interrogate the immune response compared to traditional assays such as qRT-PCR and immunohistochemistry (IHC) because they enable the discovery of neoantigens and simultaneous profiling of immune infiltration using gene expression on a large scale. Current approaches in immune profiling utilizes whole-exome sequencing (WES) for human leukocyte allele (HLA) typing and neoantigen …

Epigenome-Wide Association Study Of Mitochondrial Genome Copy Number, Penglong Wang, Christina A Castellani, Jie Yao, Tianxiao Huan, Lawrence F Bielak, Wei Zhao, Jeffrey Haessler, Roby Joehanes, Xianbang Sun, Xiuqing Guo, Ryan J Longchamps, Joann E Manson, Megan L Grove, Jan Bressler, Kent D Taylor, Tuuli Lappalainen, Silva Kasela, David J Van Den Berg, Lifang Hou, Alexander Reiner, Yongmei Liu, Eric Boerwinkle, Jennifer A Smith, Patricia A Peyser, Myriam Fornage, Stephen S Rich, Jerome I Rotter, Charles Kooperberg, Dan E Arking, Daniel Levy, Chunyu Liu

Faculty, Staff and Student Publications

We conducted cohort- and race-specific epigenome-wide association analyses of mitochondrial deoxyribonucleic acid (mtDNA) copy number (mtDNA CN) measured in whole blood from participants of African and European origins in five cohorts (n = 6182, mean age = 57-67 years, 65% women). In the meta-analysis of all the participants, we discovered 21 mtDNA CN-associated DNA methylation sites (CpG) (P < 1 × 10-7), with a 0.7-3.0 standard deviation increase (3 CpGs) or decrease (18 CpGs) in mtDNA CN corresponding to a 1% increase in DNA methylation. Several significant CpGs have been reported to be associated with at least two risk factors (e.g. chronological age or smoking) for cardiovascular disease (CVD). Five genes [PR/SET domain 16, nuclear receptor subfamily 1 group H member 3 (NR1H3), DNA repair protein, DNA polymerase kappa and decaprenyl-diphosphate synthase subunit 2], which harbor nine significant CpGs, are known to be involved in mitochondrial biosynthesis and functions. For example, NR1H3 encodes a transcription factor that is differentially expressed during an adipose tissue transition. The methylation level of cg09548275 in NR1H3 was negatively associated with mtDNA CN (effect size = -1.71, P = 4 × 10-8) and was positively associated with the NR1H3 expression level (effect size = 0.43, P = 0.0003), which indicates that the methylation level in NR1H3 may underlie the relationship between mtDNA CN, the NR1H3 transcription factor and energy expenditure. In summary, the study results suggest that mtDNA CN variation in whole blood is associated with DNA methylation levels in genes that are involved in a wide range of mitochondrial activities. These findings will help reveal molecular mechanisms between mtDNA CN and CVD.

Trial Of Spesolimab For Generalized Pustular Psoriasis, Hervé Bachelez, Milan J Anadkat, Et Al

Open Access Publications

BACKGROUND: Generalized pustular psoriasis (GPP) is a rare, life-threatening, inflammatory skin disease characterized by widespread eruption of sterile pustules. Interleukin-36 signaling is involved in the pathogenesis of this disorder. Spesolimab, a humanized anti-interleukin-36 receptor monoclonal antibody, is being studied for the treatment of GPP flares.

METHODS: In a phase 2 trial, we randomly assigned patients with a GPP flare in a 2:1 ratio to receive a single 900-mg intravenous dose of spesolimab or placebo. Patients in both groups could receive an open-label dose of spesolimab on day 8, an open-label dose of spesolimab as a rescue medication after day 8, …

A Next Generation Sequencing-Based Protocol For Screening Of Variants Of Concern In Autism Spectrum Disorder, Jie Huang, Jun Liu, Ruiyi Tian, Kevin Liu, Patrick Zhuang, Hannah Tayla Sherman, Christoph Budjan, Michelle Fong, Min-Seo Jeong, Xue-Jun Kong

2020-Current year OA Pubs

Autism spectrum disorder (ASD) is a neurodevelopmental disorder with strong genetic influences. There is an increasing demand for ASD genetic testing beyond the traditionally recommended microarray and syndromic autism testing; however, the current whole genome sequencing (WGS) and whole exome sequencing (WES) methods are lacking an academic standard for WGS variant annotation, reporting, and interpretation, tailored towards patients with ASD and offer very limited interpretation for clinical significance. Using WGS data from six family trios, we demonstrate the clinical feasibility and technical implementation of an evidence-based, fully transparent bioinformatics pipeline and report framework for an ASD-focused WGS genetic report. We …

Myeloid-Derived Suppressor Cells Mediate T Cell Dysfunction In Nonhuman Primate Tb Granulomas, Bindu Singh, Dhiraj K Singh, Shashank R Ganatra, Ruby A Escobedo, Shabaana Khader, Larry S Schlesinger, Deepak Kaushal, Smriti Mehra

Open Access Publications

Myeloid-derived suppressor cells (MDSCs) represent an innate immune cell population comprised of immature myeloid cells and myeloid progenitors with very potent immunosuppressive potential. MDSCs are reported to be abundant in the lungs of active tuberculosis (TB) patients. We sought to perform an in-depth study of MDSCs during latent TB infection (LTBI) and active TB (ATB) using the nonhuman primate (NHP) model of pulmonary TB. We found a higher proportion of granulocytic, polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) in the lungs of ATB animals compared to those with LTBI or naive control animals. Active disease in the lung, but not LTBI, was …

Recurrent High-Impact Mutations At Cognate Structural Positions In Class A G Protein-Coupled Receptors Expressed In Tumors, Eunna Huh, Jonathan Gallion, Melina A Agosto, Sara J Wright, Theodore G Wensel, Olivier Lichtarge

Faculty, Staff and Students Publications

G protein-coupled receptors (GPCRs) are the largest family of human proteins. They have a common structure and, signaling through a much smaller set of G proteins, arrestins, and effectors, activate downstream pathways that often modulate hallmark mechanisms of cancer. Because there are many more GPCRs than effectors, mutations in different receptors could perturb signaling similarly so as to favor a tumor. We hypothesized that somatic mutations in tumor samples may not be enriched within a single gene but rather that cognate mutations with similar effects on GPCR function are distributed across many receptors. To test this possibility, we systematically aggregated …

Skin Bacterial Metacommunities Of San Francisco Bay Area Salamanders Are Structured By Host Genus And Habitat Quality., Shannon Buttimer, Obed Hernandez-Gomez, Erica Bree Rosenblum

Natural Sciences and Mathematics | Faculty Scholarship

Host-associated microbial communities can influence physiological processes of macroorganisms, including contributing to infectious disease resistance. For instance, some bacteria that live on amphibian skin produce antifungal compounds that inhibit two lethal fungal pathogens, Batrachochytrium dendrobatidis (Bd) and Batrachochytrium salamandrivorans (Bsal). Therefore, differences in microbiome composition among host species or populations within a species can contribute to variation in susceptibility to Bd/Bsal. This study applies 16S rRNA sequencing to characterize the skin bacterial microbiomes of three widespread terrestrial salamander genera native to the western United States. Using a metacommunity structure analysis, we identified dispersal barriers for these influential bacteria between salamander …

Multicenter Randomized Phase Ii Trial Of Atezolizumab With Or Without Cobimetinib In Biliary Tract Cancers, Mark Yarchoan, Andrea Wang-Gillam, Et Al

Open Access Publications

BACKGROUNDMEK inhibitors have limited activity in biliary tract cancers (BTCs) as monotherapy but are hypothesized to enhance responses to programmed death ligand 1 (PD-L1) inhibition.METHODSThis open-label phase II study randomized patients with BTC to atezolizumab (anti-PD-L1) as monotherapy or in combination with cobimetinib (MEK inhibitor). Eligible patients had unresectable BTC with 1 to 2 lines of prior therapy in the metastatic setting, measurable disease, and Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to 1. The primary endpoint was progression-free survival (PFS).RESULTSSeventy-seven patients were randomized and received study therapy. The trial met its primary endpoint, with a …

Transcriptional Reprogramming Differentiates Active From Inactive Esr1 Fusions In Endocrine Therapy-Refractory Metastatic Breast Cancer, Xuxu Gou, Shunqiang Li, Et Al.

2020-Current year OA Pubs

Genomic analysis has recently identified multiple

Acculturation Strategies And Pap Screening Uptake Among Sub-Saharan African Immigrants (Sais), Adebola Adegboyega, Jia-Rong Wu, Gia Mudd-Martin

Nursing Faculty Publications

Although regular cervical cancer screening can prevent cervical cancer, screening utilization remains low among immigrant population including sub-Saharan African immigrants (SAIs). Acculturation is a complex process, which can lead to adoption of positive or negative health behaviors from the dominant culture. Acculturation strategies are the varying ways in which individuals seek to go about their acculturation by either maintaining or rejecting their own cultural values ip or accepting or rejecting the host culture's cultural values. Cervical cancer screening behaviors among SAI women may be influenced by their acculturation strategies. We conducted a secondary analysis of data to examine the relationship …

The Five Ds Of Outpatient Antibiotic Stewardship For Urinary Tract Infections, Melanie C Goebel, Barbara W Trautner, Larissa Grigoryan

Faculty, Staff and Students Publications

Urinary tract infections (UTI) are one of the most common indications for antibiotic prescriptions in the outpatient setting. Given rising rates of antibiotic resistance among uropathogens, antibiotic stewardship is critically needed to improve outpatient antibiotic use, including in outpatient clinics (primary care and specialty clinics) and emergency departments. Outpatient clinics are in general a neglected practice area in antibiotic stewardship programs, yet most antibiotic use in the United States is in the outpatient setting. This article provides a comprehensive review of antibiotic stewardship strategies for outpatient UTI in the adult population, with a focus on the "five Ds" of stewardship …

A Case Of Unintentional Isopropanol Poisoning Via Transdermal Absorption Delayed By Weekly Hemodialysis, Andrew R. Chavez, Michael T. Sweeney, Peter Akpunonu

Emergency Medicine Faculty Publications

BACKGROUND Isopropanol toxicity is the most common reported toxic alcohol ingestion in the United States and is well known to emergency physicians. Most toxicities result from unintentional ingestion of rubbing alcohol; however, an under-recognized mechanism of unintentional toxicity is transdermal absorption. Additionally, hemodialysis effectively removes isopropanol and its metabolites from circulation, so that in patients receiving regular hemodialysis, the manifestation of toxicity can be delayed.

CASE REPORT A 67-year-old woman with end-stage renal disease secondary to insulin-dependent type II diabetes on once-weekly hemodialysis presented to the Emergency Department via the Emergency Medical Service with acute encephalopathy, severe hypoglycemia, and hypothermia. …

Polatuzumab Vedotin In Previously Untreated Diffuse Large B-Cell Lymphoma, Hervé Tilly, Neha Mehta-Shah, Et Al

Open Access Publications

BACKGROUND: Diffuse large B-cell lymphoma (DLBCL) is typically treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). However, only 60% of patients are cured with R-CHOP. Polatuzumab vedotin is an antibody-drug conjugate targeting CD79b, which is ubiquitously expressed on the surface of malignant B cells.

METHODS: We conducted a double-blind, placebo-controlled, international phase 3 trial to evaluate a modified regimen of R-CHOP (pola-R-CHP), in which vincristine was replaced with polatuzumab vedotin, as compared with standard R-CHOP, in patients with previously untreated intermediate-risk or high-risk DLBCL. Patients 18 to 80 years of age were randomly assigned in a 1:1 ratio to …

Inhibition Of Nadph Oxidase Blocks Netosis And Reduces Thrombosis In Heparin-Induced Thrombocytopenia, Halina H L Leung, Jose Perdomo, Zohra Ahmadi, Feng Yan, Steven E. Mckenzie, Beng H Chong

Department of Medicine Faculty Papers

Heparin-induced thrombocytopenia (HIT) is associated with severe and potentially lethal thrombotic complications. NETosis was recently shown to be an important driver of thrombosis in HIT. We investigated the role of reactive oxygen species (ROS) and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 2 (NOX2) and their contributions to thrombus development in HIT. We showed that neutrophil activation by HIT immune complexes induced ROS-dependent NETosis. Analysis of thrombi formed in a microfluidics system showed ROS production in both platelets and neutrophils, and abundant neutrophil extracellular traps (NETs) and ROS distributed throughout the clot. Neutrophil-targeted ROS inhibition was sufficient to block HIT-induced NETosis …

Defining The Transcriptional Control Of Pediatric Aml Highlights Rara As A Superenhancer-Regulated Druggable Dependency, Monika W Perez, Oscar Sias-Garcia, Alfred Daramola, Helen Wei, Maci Terrell, Raushan Rashid, Woojun D Park, Kevin Duong, Terzah M Horton, Feng Li, Nikitha Cherayil, Jost Vrabic Koren, Vincent U Gant, Jacob J Junco, Choladda V Curry, Alexandra M Stevens, Charles Y Lin, Joanna S Yi

Faculty, Staff and Students Publications

Somatic mutations are rare in pediatric acute myeloid leukemia (pAML), indicating that alternate strategies are needed to identify targetable dependencies. We performed the first enhancer mapping of pAML in 22 patient samples. Generally, pAML samples were distinct from adult AML samples, and MLL (KMT2A)-rearranged samples were also distinct from non-KMT2A-rearranged samples. Focusing specifically on superenhancers (SEs), we identified SEs associated with many known leukemia regulators. The retinoic acid receptor alpha (RARA) gene was differentially regulated in our cohort, and a RARA-associated SE was detected in 64% of the study cohort across all cytogenetic and molecular subtypes tested. RARA SE+ pAML …

Peroxisomal Β-Oxidation Acts As A Sensor For Intracellular Fatty Acids And Regulates Lipolysis, Lianggong Ding, Wenfei Sun, Miroslav Balaz, Anyuan He, Manuel Klug, Stefan Wieland, Robert Caiazzo, Violeta Raverdy, Francois Pattou, Philippe Lefebvre, Irfan J Lodhi, Bart Staels, Markus Heim, Christian Wolfrum

Open Access Publications

To liberate fatty acids (FAs) from intracellular stores, lipolysis is regulated by the activity of the lipases adipose triglyceride lipase (ATGL), hormone-sensitive lipase and monoacylglycerol lipase. Excessive FA release as a result of uncontrolled lipolysis results in lipotoxicity, which can in turn promote the progression of metabolic disorders. However, whether cells can directly sense FAs to maintain cellular lipid homeostasis is unknown. Here we report a sensing mechanism for cellular FAs based on peroxisomal degradation of FAs and coupled with reactive oxygen species (ROS) production, which in turn regulates FA release by modulating lipolysis. Changes in ROS levels are sensed …

Axicabtagene Ciloleucel As Second-Line Therapy For Large B-Cell Lymphoma, Frederick L Locke, Armin Ghobadi, Et Al

Open Access Publications

BACKGROUND: The prognosis of patients with early relapsed or refractory large B-cell lymphoma after the receipt of first-line chemoimmunotherapy is poor.

METHODS: In this international, phase 3 trial, we randomly assigned, in a 1:1 ratio, patients with large B-cell lymphoma that was refractory to or had relapsed no more than 12 months after first-line chemoimmunotherapy to receive axicabtagene ciloleucel (axi-cel, an autologous anti-CD19 chimeric antigen receptor T-cell therapy) or standard care (two or three cycles of investigator-selected, protocol-defined chemoimmunotherapy, followed by high-dose chemotherapy with autologous stem-cell transplantation in patients with a response to the chemoimmunotherapy). The primary end point was …

Evaluation Of Pediatric Rheumatology Telehealth Satisfaction During The Covid-19 Pandemic, Lindsay N Waqar-Cowles, John Chuo, Pamela F Weiss, Sabrina Gmuca, Marianna Lanoue, Jon M Burnham

College of Population Health Faculty Papers

Background: During the Coronavirus disease 2019 pandemic, ambulatory pediatric rheumatology healthcare rapidly transformed to a mainly telehealth model. However, pediatric patient and caregiver satisfaction with broadly deployed telehealth programs remains largely unknown. This study aimed to evaluate patient/caregiver satisfaction with telehealth and identify the factors associated with satisfaction in a generalizable sample of pediatric rheumatology patients.

Methods: Patients with an initial telehealth video visit with a rheumatology provider between April and June 2020 were eligible. All patients/caregivers were sent a post-visit survey to assess a modified version of the Telehealth Usability Questionnaire (TUQ) and demographic and clinical characteristics. TUQ total …

Meta-Analyses Identify Dna Methylation Associated With Kidney Function And Damage, Pascal Schlosser, Adrienne Tin, Pamela R Matias-Garcia, Chris H L Thio, Roby Joehanes, Hongbo Liu, Antoine Weihs, Zhi Yu, Anselm Hoppmann, Franziska Grundner-Culemann, Josine L Min, Adebowale A Adeyemo, Charles Agyemang, Johan Ärnlöv, Nasir A Aziz, Andrea Baccarelli, Murielle Bochud, Hermann Brenner, Monique M B Breteler, Cristian Carmeli, Layal Chaker, John C Chambers, Shelley A Cole, Josef Coresh, Tanguy Corre, Adolfo Correa, Simon R Cox, Niek De Klein, Graciela E Delgado, Arce Domingo-Relloso, Kai-Uwe Eckardt, Arif B Ekici, Karlhans Endlich, Kathryn L Evans, James S Floyd, Myriam Fornage, Lude Franke, Eliza Fraszczyk, Xu Gao, Xīn Gào, Mohsen Ghanbari, Sahar Ghasemi, Christian Gieger, Philip Greenland, Megan L Grove, Sarah E Harris, Gibran Hemani, Peter Henneman, Christian Herder, Steve Horvath, Lifang Hou, Mikko A Hurme, Shih-Jen Hwang, Marjo-Riitta Jarvelin, Sharon L R Kardia, Silva Kasela, Marcus E Kleber, Wolfgang Koenig, Jaspal S Kooner, Holly Kramer, Florian Kronenberg, Brigitte Kühnel, Terho Lehtimäki, Lars Lind, Dan Liu, Yongmei Liu, Donald M Lloyd-Jones, Kurt Lohman, Stefan Lorkowski, Ake T Lu, Riccardo E Marioni, Winfried März, Daniel L Mccartney, Karlijn A C Meeks, Lili Milani, Pashupati P Mishra, Matthias Nauck, Ana Navas-Acien, Christoph Nowak, Annette Peters, Holger Prokisch, Bruce M Psaty, Olli T Raitakari, Scott M Ratliff, Alex P Reiner, Sylvia E Rosas, Ben Schöttker, Joel Schwartz, Sanaz Sedaghat, Jennifer A Smith, Nona Sotoodehnia, Hannah R Stocker, Silvia Stringhini, Johan Sundström, Brenton R Swenson, Maria Tellez-Plaza, Joyce B J Van Meurs, Jana V Van Vliet-Ostaptchouk, Andrea Venema, Niek Verweij, Rosie M Walker, Matthias Wielscher, Juliane Winkelmann, Bruce H R Wolffenbuttel, Wei Zhao, Yinan Zheng, Marie Loh, Harold Snieder, Daniel Levy, Melanie Waldenberger, Katalin Susztak, Anna Köttgen, Alexander Teumer

Faculty, Staff and Student Publications

Chronic kidney disease is a major public health burden. Elevated urinary albumin-to-creatinine ratio is a measure of kidney damage, and used to diagnose and stage chronic kidney disease. to extend the knowledge on regulatory mechanisms related to kidney function and disease, we conducted a blood-based epigenome-wide association study for estimated glomerular filtration rate (n = 33,605) and urinary albumin-to-creatinine ratio (n = 15,068) and detected 69 and seven CpG sites where DNA methylation was associated with the respective trait. The majority of these findings showed directionally consistent associations with the respective clinical outcomes chronic kidney disease and moderately increased albuminuria. …

Epigenome-Wide Association Study Of Serum Urate Reveals Insights Into Urate Co-Regulation And The Slc2a9 Locus, Adrienne Tin, Pascal Schlosser, Pamela R Matias-Garcia, Chris H L Thio, Roby Joehanes, Hongbo Liu, Zhi Yu, Antoine Weihs, Anselm Hoppmann, Franziska Grundner-Culemann, Josine L Min, Victoria L Halperin Kuhns, Adebowale A Adeyemo, Charles Agyemang, Johan Ärnlöv, Nasir A Aziz, Andrea Baccarelli, Murielle Bochud, Hermann Brenner, Jan Bressler, Monique M B Breteler, Cristian Carmeli, Layal Chaker, Josef Coresh, Tanguy Corre, Adolfo Correa, Simon R Cox, Graciela E Delgado, Kai-Uwe Eckardt, Arif B Ekici, Karlhans Endlich, James S Floyd, Eliza Fraszczyk, Xu Gao, Xīn Gào, Allan C Gelber, Mohsen Ghanbari, Sahar Ghasemi, Christian Gieger, Philip Greenland, Megan L Grove, Sarah E Harris, Gibran Hemani, Peter Henneman, Christian Herder, Steve Horvath, Lifang Hou, Mikko A Hurme, Shih-Jen Hwang, Sharon L R Kardia, Silva Kasela, Marcus E Kleber, Wolfgang Koenig, Jaspal S Kooner, Florian Kronenberg, Brigitte Kühnel, Christine Ladd-Acosta, Terho Lehtimäki, Lars Lind, Dan Liu, Donald M Lloyd-Jones, Stefan Lorkowski, Ake T Lu, Riccardo E Marioni, Winfried März, Daniel L Mccartney, Karlijn A C Meeks, Lili Milani, Pashupati P Mishra, Matthias Nauck, Christoph Nowak, Annette Peters, Holger Prokisch, Bruce M Psaty, Olli T Raitakari, Scott M Ratliff, Alex P Reiner, Ben Schöttker, Joel Schwartz, Sanaz Sedaghat, Jennifer A Smith, Nona Sotoodehnia, Hannah R Stocker, Silvia Stringhini, Johan Sundström, Brenton R Swenson, Joyce B J Van Meurs, Jana V Van Vliet-Ostaptchouk, Andrea Venema, Uwe Völker, Juliane Winkelmann, Bruce H R Wolffenbuttel, Wei Zhao, Yinan Zheng, Marie Loh, Harold Snieder, Melanie Waldenberger, Daniel Levy, Shreeram Akilesh, Owen M Woodward, Katalin Susztak, Alexander Teumer, Anna Köttgen

Faculty, Staff and Student Publications

Elevated serum urate levels, a complex trait and major risk factor for incident gout, are correlated with cardiometabolic traits via incompletely understood mechanisms. DNA methylation in whole blood captures genetic and environmental influences and is assessed in transethnic meta-analysis of epigenome-wide association studies (EWAS) of serum urate (discovery, n = 12,474, replication, n = 5522). The 100 replicated, epigenome-wide significant (p < 1.1E-7) CpGs explain 11.6% of the serum urate variance. At SLC2A9, the serum urate locus with the largest effect in genome-wide association studies (GWAS), five CpGs are associated with SLC2A9 gene expression. Four CpGs at SLC2A9 have significant causal effects on serum urate levels and/or gout, and two of these partly mediate the effects of urate-associated GWAS variants. In other genes, including SLC7A11 and PHGDH, 17 urate-associated CpGs are associated with conditions defining metabolic syndrome, suggesting that these CpGs may represent a blood DNA methylation signature of cardiometabolic risk factors. This study demonstrates that EWAS can provide new insights into GWAS loci and the correlation of serum urate with other complex traits.

Practical Considerations Of Dissolved Oxygen Levels For Platelet Function Under Hypoxia, Branden Kusanto, Andrew Gordon, Leigh Naylor-Adamson, Lloyd Atkinson, Charlie Coupland, Zoe Booth, Yusra Ahmed, Isabel M Pires, Graeme J Stasiuk, Roger Sturmey, Simon D J Calaminus, Mònica Arman

Faculty, Staff and Student Publications

Investigating human platelet function in low-oxygen environments is important in multiple settings, including hypobaric hypoxia (e.g., high altitude), sea level hypoxia-related disease, and thrombus stability. These studies often involve drawing blood from which platelets are isolated and analysed at atmospheric conditions or re-exposed to low oxygen levels in hypoxia chambers before testing. However, it remains unknown how the in vitro handling of the samples itself changes their dissolved oxygen concentration, which might affect platelet function and experimental results. Here, we prepared healthy donor platelet-rich plasma and washed platelet (WP) suspensions and exposed them to 2% oxygen. We found that the …

Hypothalamic Steroid Receptor Coactivator-2 Regulates Adaptations To Fasting And Overnutrition, Yongjie Yang, Yanlin He, Hailan Liu, Wenjun Zhou, Chunmei Wang, Pingwen Xu, Xing Cai, Hesong Liu, Kaifan Yu, Zhou Pei, Ilirjana Hyseni, Makoto Fukuda, Qingchun Tong, Jianming Xu, Zheng Sun, Bert W O'Malley, Yong Xu

Faculty, Staff and Students Publications

The neuroendocrine system coordinates metabolic and behavioral adaptations to fasting, including reducing energy expenditure, promoting counterregulation, and suppressing satiation and anxiety to engage refeeding. Here, we show that steroid receptor coactivator-2 (SRC-2) in pro-opiomelanocortin (POMC) neurons is a key regulator of all these responses to fasting. POMC-specific deletion of SRC-2 enhances the basal excitability of POMC neurons; mutant mice fail to efficiently suppress energy expenditure during food deprivation. SRC-2 deficiency blunts electric responses of POMC neurons to glucose fluctuations, causing impaired counterregulation. When food becomes available, these mutant mice show insufficient refeeding associated with enhanced satiation and discoordination of anxiety …

High-Throughput Functional Analysis Of Cftr And Other Apically Localized Proteins In Ipsc-Derived Human Intestinal Organoids, Sunny Xia, Zoltán Bozóky, Michelle Di Paola, Onofrio Laselva, Saumel Ahmadi, Jia Xin Jiang, Amy L Pitstick, Chong Jiang, Daniela Rotin, Christopher N Mayhew, Nicola L Jones, Christine E Bear

Open Access Publications

Induced Pluripotent Stem Cells (iPSCs) can be differentiated into epithelial organoids that recapitulate the relevant context for CFTR and enable testing of therapies targeting Cystic Fibrosis (CF)-causing mutant proteins. However, to date, CF-iPSC-derived organoids have only been used to study pharmacological modulation of mutant CFTR channel activity and not the activity of other disease-relevant membrane protein constituents. In the current work, we describe a high-throughput, fluorescence-based assay of CFTR channel activity in iPSC-derived intestinal organoids and describe how this method can be adapted to study other apical membrane proteins. Specifically, we show how this assay can be employed to study …

Association Of Low-Frequency And Rare Coding Variants With Information Processing Speed, Jan Bressler, Gail Davies, Albert V Smith, Yasaman Saba, Joshua C Bis, Xueqiu Jian, Caroline Hayward, Lisa Yanek, Jennifer A Smith, Saira S Mirza, Ruiqi Wang, Hieab H H Adams, Diane Becker, Eric Boerwinkle, Archie Campbell, Simon R Cox, Gudny Eiriksdottir, Chloe Fawns-Ritchie, Rebecca F Gottesman, Megan L Grove, Xiuqing Guo, Edith Hofer, Sharon L R Kardia, Maria J Knol, Marisa Koini, Oscar L Lopez, Riccardo E Marioni, Paul Nyquist, Alison Pattie, Ozren Polasek, David J Porteous, Igor Rudan, Claudia L Satizabal, Helena Schmidt, Reinhold Schmidt, Stephen Sidney, Jeannette Simino, Blair H Smith, Stephen T Turner, Sven J Van Der Lee, Erin B Ware, Rachel A Whitmer, Kristine Yaffe, Qiong Yang, Wei Zhao, Vilmundur Gudnason, Lenore J Launer, Annette L Fitzpatrick, Bruce M Psaty, Myriam Fornage, M Arfan Ikram, Cornelia M Van Duijn, Sudha Seshadri, Thomas H Mosley, Ian J Deary

Faculty, Staff and Student Publications

Measures of information processing speed vary between individuals and decline with age. Studies of aging twins suggest heritability may be as high as 67%. The Illumina HumanExome Bead Chip genotyping array was used to examine the association of rare coding variants with performance on the Digit-Symbol Substitution Test (DSST) in community-dwelling adults participating in the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. DSST scores were available for 30,576 individuals of European ancestry from nine cohorts and for 5758 individuals of African ancestry from four cohorts who were older than 45 years and free of dementia and …