Medicine and Health Sciences Commons^™

Distinct Murine Pancreatic Transcriptomic Signatures During Chronic Pancreatitis Recovery, Yinjie Zhang, Baibing Yang, Joy M. Davis, Madeline M. Drake, Mamoun Younes, Qiang Shen, Zhongming Zhao, Yanna Cao, Tien C. Ko

School of Medicine Faculty Publications

We have previously demonstrated that the pancreas can recover from chronic pancreatitis (CP) lesions in the cerulein-induced mouse model. To explore how pancreatic recovery is achieved at the molecular level, we used RNA-sequencing (seq) and profiled transcriptomes during CP transition to recovery. CP was induced by intraperitoneally injecting cerulein in C57BL/6 mice. Time-matched controls (CON) were given normal saline. Pancreata were harvested from mice 4 days after the final injections (designated as CP and CON) or 4 weeks after the final injections (designated as CP recovery (CPR) and control recovery (CONR)). Pancreatic RNAs were extracted for RNA-seq and quantitative (q) …

A Screen Of Fda-Approved Drugs Identifies Inhibitors Of Protein Tyrosine Phosphatase 4a3 (Ptp4a3 Or Prl-3), Dylan R. Rivas, Mark Vincent C. Dela Cerna, Caroline N. Smith, Shilpa Sampathi, Blaine G. Patty, Donghan Lee, Jessica S. Blackburn

Molecular and Cellular Biochemistry Faculty Publications

Protein tyrosine phosphatase 4A3 (PTP4A3 or PRL-3) is highly expressed in a variety of cancers, where it promotes tumor cell migration and metastasis leading to poor prognosis. Despite its clinical significance, small molecule inhibitors of PRL-3 are lacking. Here, we screened 1443 FDA-approved drugs for their ability to inhibit the activity of the PRL phosphatase family. We identified five specific inhibitors for PRL-3 as well as one selective inhibitor of PRL-2. Additionally, we found nine drugs that broadly and significantly suppressed PRL activity. Two of these broad-spectrum PRL inhibitors, Salirasib and Candesartan, blocked PRL-3-induced migration in human embryonic kidney cells …

Factors Associated With Mutations: Their Matching Rates To Cardiovascular And Neurological Diseases, Hannah B. Lucas, Ian Mcknight, Regan Raines, Abdullah Hijazi, Christoph Hart, Chan Lee, Do-Gyoon Kim, Wei Li, Peter H. U. Lee, Joon W. Shim

Biomedical Engineering Faculty Research

Monogenic hypertension is rare and caused by genetic mutations, but whether factors associated with mutations are disease-specific remains uncertain. Given two factors associated with high mutation rates, we tested how many previously known genes match with (i) proximity to telomeres or (ii) high adenine and thymine content in cardiovascular diseases (CVDs) related to vascular stiffening. We extracted genomic information using a genome data viewer. In human chromosomes, 64 of 79 genetic loci involving >25 rare mutations and single nucleotide polymorphisms satisfied (i) or (ii), resulting in an 81% matching rate. However, this high matching rate was no longer observed as …

The Effects Of Mapk Signaling On The Development Of Cerebellar Granule Cells, Kerry Morgan

Honors Scholar Theses

The granule cells are the most abundant neuronal type in the human brain. Rapid proliferation of granule cell progenitors results in dramatic expansion and folding of the cerebellar cortex during postnatal development. Mis-regulation of this proliferation process causes medulloblastoma, the most prevalent childhood brain tumor. In the developing cerebellum, granule cells are derived from Atoh1-expressing cells, which arise from the upper rhombic lip (the interface between the roof plate and neuroepithelium). In addition to granule cells, the Atoh1 lineage also gives rise to different types of neurons including cerebellar nuclei neurons. In the current study, I have investigated the …

Spinal Muscular Atrophy Carrier Screening: Current Practice And Perceived Barriers In A Midwestern Women’S Health Care Clinic, Elyssa Gray Lewis, Heather Said, Kaeli Samson, Sara Fisher

Capstones: Genetic Counseling

Purpose: Spinal muscular atrophy (SMA) carrier screening has been universally recommended to be offered to all women of reproductive age by the American College of Obstetricians and Gynecologists since 2017. This quality improvement study surveyed women's healthcare providers at a single clinic within an academic institution to evaluate practices and assess barriers to offering SMA carrier screening to patients. Methods: Certified nurse midwife, internal medicine, obstetrician/gynecologists, nurse practitioners, residents, and maternal fetal medicine providers were invited to participate in a survey comprised of multiple choice, Likert scale, and open-ended questions. Full participation included 26 out of 54 providers in …

Genetics In The Nicu: Nurses’ Perceived Knowledge And Desired Education, Kathleen Shields

Dissertations and Theses (Open Access)

A large proportion of infants admitted to neonatal intensive care units (NICUs) have genetic conditions. NICU nurses play an important role in providing comprehensive care to these patients and their families. Previous research has demonstrated gaps exist in the genetics knowledge of nurses and that they lack comfort applying genetics information to clinical practice, but no research has been done assessing the knowledge of or comfort with genetics of NICU nurses specifically. NICU nurses (n=122) completed an online survey assessing their perceived knowledge of genetics, comfort with clinical scenarios involving genetics, and desired genetics education. Participants reported the highest levels …

Investigation Of Alpl Variant States And Clinical Outcomes: An Analysis Of Adults And Adolescents With Hypophosphatasia Treated With Asfotase Alfa., Priya S. Kishnani, Guillermo Del Angel, Shanggen Zhou, Eric T. Rush

Manuscripts, Articles, Book Chapters and Other Papers

Background: Hypophosphatasia (HPP), a rare metabolic disease, can be inherited in an autosomal recessive (biallelic) or an autosomal dominant (monoallelic) manner. Most of the severe, early-onset, frequently lethal HPP in infants is acquired through recessive inheritance; less severe, later-onset, typically nonlethal HPP phenotypes are acquired through either dominant or recessive inheritance. HPP's variable clinical presentation arises from >400 identified ALPL pathogenic variants with likely variable penetrance, especially with autosomal dominant inheritance. This post hoc analysis investigated the relationship between ALPL variant state (biallelic and monoallelic) and clinical outcomes with asfotase alfa in HPP.

Methods: Data were pooled from two phase …

Epigenome-Wide Association Study Of Kidney Function Identifies Trans-Ethnic And Ethnic-Specific Loci, Charles E. Breeze, Anna Batorsky, Mi Kyeong Lee, Mindy D. Szeto, Xiaoguang Xu, Daniel L. Mccartney, Rong Jiang, Amit Patki, Holly J. Kramer, James M. Eales, Laura Raffield, Leslie Lange, Ethan Lange, Peter Durda, Yongmei Liu, Russ P. Tracy, David Van Den Berg, Nhlbi Trans-Omics For Precision Medicine (Topmed) Consortium, Topmed Mesa Multi-Omics Working Group, Kathryn L. Evans, William E. Kraus, Donna K. Arnett

Epidemiology and Environmental Health Faculty Publications

BACKGROUND: DNA methylation (DNAm) is associated with gene regulation and estimated glomerular filtration rate (eGFR), a measure of kidney function. Decreased eGFR is more common among US Hispanics and African Americans. The causes for this are poorly understood. We aimed to identify trans-ethnic and ethnic-specific differentially methylated positions (DMPs) associated with eGFR using an agnostic, genome-wide approach.

METHODS: The study included up to 5428 participants from multi-ethnic studies for discovery and 8109 participants for replication. We tested the associations between whole blood DNAm and eGFR using beta values from Illumina 450K or EPIC arrays. Ethnicity-stratified analyses were performed using linear …

Use Of Antisense Oligonucleotides To Target Notch2 In Mouse Chondrocytes, Gabrielle Viviana Lanza

Honors Scholar Theses

NOTCH2 is a transmembrane receptor that is part of the Notch receptor family, known for controlling cell differentiation and function. Notch receptors play a crucial role in skeletal development and bone homeostasis. Hajdu Cheney Syndrome (HCS) is a rare monogenic disorder affecting the skeleton caused by a gain-of-function mutation in NOTCH2. Antisense oligonucleotides (ASO) are sequence-specific single-stranded nucleic acids that bind to target mRNA and initiate mRNA degradation. While previous work has explored the role of Notch2 ASOs in osteoblasts and osteoclasts, this paper explores the role of Notch2 and Notch2 ASOs in cells of cartilage tissue. The effect of …

Ciliary Extracellular Vesicles Are Distinct From The Cytosolic Extracellular Vesicles, Ashraf M. Mohieldin, Rajasekharreddy Pala, Richard Beuttler, James J. Moresco, John R. Yates Iii, Surya M. Nauli

Pharmacy Faculty Articles and Research

Extracellular vesicles (EVs) are cell‐derived membrane vesicles that are released into the extracellular space. EVs encapsulate key proteins and mediate intercellular signalling pathways. Recently, primary cilia have been shown to release EVs under fluid‐shear flow, but many proteins encapsulated in these vesicles have never been identified. Primary cilia are ubiquitous mechanosensory organelles that protrude from the apical surface of almost all human cells. Primary cilia also serve as compartments for signalling pathways, and their defects have been associated with a wide range of human genetic diseases called ciliopathies. To better understand the mechanism of ciliopathies, it is imperative to know …

Cyclin G2, A Novel Target Of Sulindac To Inhibit Cell Cycle Progression In Colorectal Cancer, Hongyou Zhao, Bin Yi, Zhipin Liang, Ches'nique N. Phillips, Hui Yi Lin, Adam I. Riker, Yaguang Xi

School of Medicine Faculty Publications

Sulindac has shown significant clinical benefit in preventing colorectal cancer progression, but its mechanism of action has not been fully elucidated. We have found that sulindac sulfide (SS) is able to inhibit cell cycle progression in human colorectal cancer cells, particularly through G1 arrest. To understand the underlying mechanisms of sulindac inhibitory activity, we have demonstrated that Cyclin G2 up-regulation upon SS treatment can substantially delay cell cycle progression by enhancing the transcriptional activity of FOXO3a in human colorectal tumor cells. MiR-182, an oncogenic microRNA known to inhibit FOXO3a gene expression, is also involved in the suppressive effect of SS …

Rare Deleterious Mutations Of Hnrnp Genes Result In Shared Neurodevelopmental Disorders., Madelyn A. Gillentine, Tianyun Wang, Kendra Hoekzema, Jill Rosenfeld, Pengfei Liu, Hui Guo, Chang N. Kim, Bert B A De Vries, Lisenka E L M Vissers, Magnus Nordenskjold, Malin Kvarnung, Anna Lindstrand, Ann Nordgren, Jozef Gecz, Maria Iascone, Anna Cereda, Agnese Scatigno, Silvia Maitz, Ginevra Zanni, Enrico Bertini, Christiane Zweier, Sarah Schuhmann, Antje Wiesener, Micah Pepper, Heena Panjwani, Erin Torti, Farida Abid, Irina Anselm, Siddharth Srivastava, Paldeep Atwal, Carlos A. Bacino, Gifty Bhat, Katherine Cobian, Lynne M. Bird, Jennifer Friedman, Meredith S. Wright, Bert Callewaert, Florence Petit, Sophie Mathieu, Alexandra Afenjar, Celenie K. Christensen, Kerry M. White, Orly Elpeleg, Itai Berger, Edward J. Espineli, Christina Fagerberg, Charlotte Brasch-Andersen, Lars Kjærsgaard Hansen, Timothy Feyma, Susan Starling Hughes, Isabelle Thiffault, Bonnie Sullivan, Shuang Yan, Kory Keller, Boris Keren, Cyril Mignot, Frank Kooy, Marije Meuwissen, Alice Basinger, Mary Kukolich, Meredith Philips, Lucia Ortega, Margaret Drummond-Borg, Mathilde Lauridsen, Kristina Sorensen, Anna Lehman, Causes Study, Elena Lopez-Rangel, Paul Levy, Davor Lessel, Timothy Lotze, Suneeta Madan-Khetarpal, Jessica Sebastian, Jodie Vento, Divya Vats, L Manace Benman, Shane Mckee, Ghayda M. Mirzaa, Candace Muss, John Pappas, Hilde Peeters, Corrado Romano, Maurizio Elia, Ornella Galesi, Marleen E H Simon, Koen L I Van Gassen, Kara Simpson, Robert Stratton, Sabeen Syed, Julien Thevenon, Irene Valenzuela Palafoll, Antonio Vitobello, Marie Bournez, Laurence Faivre, Kun Xia, Spark Consortium, Rachel K. Earl, Tomasz Nowakowski, Raphael A. Bernier, Evan E. Eichler

Manuscripts, Articles, Book Chapters and Other Papers

BACKGROUND: With the increasing number of genomic sequencing studies, hundreds of genes have been implicated in neurodevelopmental disorders (NDDs). The rate of gene discovery far outpaces our understanding of genotype-phenotype correlations, with clinical characterization remaining a bottleneck for understanding NDDs. Most disease-associated Mendelian genes are members of gene families, and we hypothesize that those with related molecular function share clinical presentations.

METHODS: We tested our hypothesis by considering gene families that have multiple members with an enrichment of de novo variants among NDDs, as determined by previous meta-analyses. One of these gene families is the heterogeneous nuclear ribonucleoproteins (hnRNPs), which …

Somatic Cag Expansion In Huntington's Disease Is Dependent On The Mlh3 Endonuclease Domain, Which Can Be Excluded Via Splice Redirection, Jennie C.L. Roy, Antonia Vitalo, Marissa A. Andrew, Eduarda Mota-Silva, Marina Kovalenko, Zoe Burch, Anh M. Nhu, Paula E. Cohen, Ed Grabczyk, Vanessa C. Wheeler, Ricardo Mouro Pinto

School of Medicine Faculty Publications

Somatic expansion of the CAG repeat tract that causes Huntington's disease (HD) is thought to contribute to the rate of disease pathogenesis. Therefore, factors influencing repeat expansion are potential therapeutic targets. Genes in the DNA mismatch repair pathway are critical drivers of somatic expansion in HD mouse models. Here, we have tested, using genetic and pharmacological approaches, the role of the endonuclease domain of the mismatch repair protein MLH3 in somatic CAG expansion in HD mice and patient cells. A point mutation in the MLH3 endonuclease domain completely eliminated CAG expansion in the brain and peripheral tissues of a HD …

Genetic Perturbation Of Pu.1 Binding And Chromatin Looping At Neutrophil Enhancers Associates With Autoimmune Disease., Stephen Watt, Louella Vasquez, Klaudia Walter, Alice L. Mann, Kousik Kundu, Lu Chen, Ying Sims, Simone Ecker, Frances Burden, Samantha Farrow, Ben Farr, Valentina Iotchkova, Heather Elding, Daniel Mead, Manuel Tardaguila, Hannes Ponstingl, David Richardson, Avik Datta, Paul Flicek, Laura Clarke, Kate Downes, T Pastinen, Peter Fraser, Mattia Frontini, Biola-Maria Javierre, Mikhail Spivakov, Nicole Soranzo

Manuscripts, Articles, Book Chapters and Other Papers

Neutrophils play fundamental roles in innate immune response, shape adaptive immunity, and are a potentially causal cell type underpinning genetic associations with immune system traits and diseases. Here, we profile the binding of myeloid master regulator PU.1 in primary neutrophils across nearly a hundred volunteers. We show that variants associated with differential PU.1 binding underlie genetically-driven differences in cell count and susceptibility to autoimmune and inflammatory diseases. We integrate these results with other multi-individual genomic readouts, revealing coordinated effects of PU.1 binding variants on the local chromatin state, enhancer-promoter contacts and downstream gene expression, and providing a functional interpretation for …

Understanding The Effect Of Adaptive Mutations On The Three-Dimensional Structure Of Rna, Justin Cook

Undergraduate Research and Scholarship Symposium

Single-nucleotide polymorphisms (SNPs) are variations in the genome where one base pair can differ between individuals.¹ SNPs occur throughout the genome and can correlate to a disease-state if they occur in a functional region of DNA.¹According to the central dogma of molecular biology, any variation in the DNA sequence will have a direct effect on the RNA sequence and will potentially alter the identity or conformation of a protein product. A single RNA molecule, due to intramolecular base pairing, can acquire a plethora of 3-D conformations that are described by its structural ensemble. One SNP, rs12477830, which …

Obstructive Sleep Apnea And Dementia-Common Gene Associations Through Network-Based Identification Of Common Driver Genes, Hyun-Hwan Jeong, Arvind Chandrakantan, Adam C Adler

Faculty, Staff and Students Publications

BACKGROUND: Obstructive Sleep Apnea (OSA) occurs in 7% of the adult population. The relationship between neurodegenerative diseases such as dementia and sleep disorders have long attracted clinical attention; however, no comprehensive data exists elucidating common gene expression between the two diseases. The objective of this study was to (1) demonstrate the practicability and feasibility of utilizing a systems biology approach called network-based identification of common driver genes (NICD) to identify common genomic features between two associated diseases and (2) utilize this approach to identify genes associated with both OSA and dementia.

METHODS: This study utilized 2 public databases (PCNet, DisGeNET) …

Delta-Like 4 Is Required For Pulmonary Vascular Arborization And Alveolarization In The Developing Lung., Sheng Xia, Heather Menden, Nick Townley, Sherry M. Mabry, Jeffrey J. Johnston, Michael F. Nyp, Daniel P. Heruth, Thomas Korfhagen, Venkatesh Sampath

Manuscripts, Articles, Book Chapters and Other Papers

The molecular mechanisms by which endothelial cells (ECs) regulate pulmonary vascularization and contribute to alveolar epithelial cell development during lung morphogenesis remain unknown. We tested the hypothesis that delta-like 4 (DLL4), an EC Notch ligand, is critical for alveolarization by combining lung mapping and functional studies in human tissue and DLL4-haploinsufficient mice (Dll4+/lacz). DLL4 expressed in a PECAM-restricted manner in capillaries, arteries, and the alveolar septum from the canalicular to alveolar stage in mice and humans. Dll4 haploinsufficiency resulted in exuberant, nondirectional vascular patterning at E17.5 and P6, followed by smaller capillaries and fewer intermediate blood vessels at P14. Vascular …

Hook3 Mutations And Their Contributions To Different Types Of Cancers, Brittny Mikhaiel, Van Vo Ph.D.

Undergraduate Research Symposium Posters

Hook3 (Hook Microtubule Tethering Protein 3) is a gene that encodes a protein that is localized in the Golgi complex and is linked to cellular trafficking of cargos and the binding of microtubules to organelles. Although there is some literature discussing the known functions of the gene, the phenotypes in mice or humans have not been thoroughly researched and literature on these phenotypes is limited. The literature that is available suggests Hook3 is implicated in diverse phenotypes ranging from bone development to neural development in mice. Since Hook3 is associated with prostate cancer, it is likely that it is involved …

Genetic Mechanisms Of Transcriptional Regulation In Childhood Acute Lymphoblastic Leukemia, Xujie Zhao

Theses and Dissertations (ETD)

Introduction. Advances in genomic profiling and sequencing studies have identified germline and somatic variations that are associated with childhood ALL, improving our understanding of the genetic basis of childhood acute lymphoblastic leukemia (ALL). Recent genome-wide association studies (GWAS) have identified germline genetic variations of ARID5B and, more recently, IGF2BP1 that are associated with susceptibility to ALL. Genome-wide sequencing studies also discovered a new ALL subtype characterized of ZNF384-mediated chromosomal translocations, providing new insights into genetic heterogeneity in childhood ALL. However, the underlying mechanism by which these genetic variants contribute to the transcriptional regulatory circuitries of ALL is still poorly understood. …

Language Interpreters’ Perspective Of The Interpreter-Genetic Counselor Working Alliance, Dacia Lipkea

Theses and Dissertations

Interpreters are an asset to the genetic counseling process as they help to bridge both cultural and linguistic gaps. For various reasons, their ability to accurately render the often-complex information discussed in genetic counseling sessions is likely dependent on their ability to establish a working alliance and collaborate with genetic counselors to overcome any challenges. Studies in other healthcare fields document the elements crucial to forming a working alliance between interpreter and healthcare provider, but little research has been done specifically investigating how to form a working alliance in the context of the specialized nature of genetic counseling. The goal …

Primary Care Providers’ Comfort With Utilization Of Genetics In Practice, Taylor Mackenzie Kupneski

Theses and Dissertations

Primary care providers (PCPs) are often the first opportunity for individuals at risk for a genetic condition to be identified and they must care for patients with known genetic conditions. However, PCPs lag behind other providers in incorporating genetics into their practice. This study aimed to understand which genetics related concepts/topics PCPs (1) find relevant to practice, (2) are currently comfortable utilizing in practice, and (3) desire further education on. A mixed methods survey was sent to internists, family medicine providers, OBGYNs, pediatricians and geriatrics providers in South Carolina via email to assess this information. This included physicians, nurse practitioners, …

A Timeline Of Down Syndrome, Christian Guese, Kristina Mcinnes, Kimberly Miranda

Undergraduate Research Symposium Posters

The purpose of this research timeline is to synthesize the natural history of Down Syndrome (DS) to discover absence of knowledge, discuss the bioethics in prenatal screening and develop a public health message. Our method of research was literature-based. DS is one of the most common aneuploidy disorders in the United States. There are three genetic variations of DS, Trisomy 21, a third copy of chromosome 21, accounts for 95% of cases. DS causes intellectual disability, developmental delays, facial dysmorphia, and low muscle tone. DS also leads to an increased risk for congenital heart defects and Alzheimer’s disease later in …

Discovering Rett Syndrome (Rts) And Understanding Its Enigmatic Development, Fiorella Ramirez-Guasp, Chanel Chan, Sukyeong Kim

Undergraduate Research Symposium Posters

The purpose of this research project is to compose a comprehensive timeline on the rare disease Rett Syndrome (RTS) in order to better understand its enigmatic development as well as furthering the public’s understanding on this degenerative disease. RTS is a panethnic progressive neurodevelopmental disorder that occurs nearly exclusively in girls. This syndrome is characterized by normal prenatal and neonatal development, followed by an onset of neurological symptoms with a mental stagnation anywhere around 6-18 months of age that involves a rapid loss in speech and acquired motor skills. There is limited knowledge about the molecular cause of Rett Syndrome, …

Essential Informational Needs Of Parents Receiving A Turner Syndrome Diagnosis: Parent And Genetic Counselor Perspectives, Jewel Lynne Wasson

Theses and Dissertations

Turner syndrome affects approximately one in 2,500 live female births, and etiology includes the partial or complete loss of the second X-chromosome. Prognosis varies depending on whether a diagnosis is made prenatally or postnatally. Current recommendations state that counselors should be involved in the diagnosis; however, guidelines for what information to include during an initial diagnosis do not exist. The aim of this study was to identify which informational items related to Turner syndrome are considered most essential by parents and genetic counselors.

A survey including 100 informational items related to Turner syndrome was sent to genetic counselors and parents …

The Transcriptional Trajectories Of Pluripotency And Differentiation Comprise Genes With Antithetical Architecture And Repetitive-Element Content., Aristeidis G. Telonis, Isidore Rigoutsos

Computational Medicine Center Faculty Papers

BACKGROUND: Extensive molecular differences exist between proliferative and differentiated cells. Here, we conduct a meta-analysis of publicly available transcriptomic datasets from preimplantation and differentiation stages examining the architectural properties and content of genes whose abundance changes significantly across developmental time points.

RESULTS: Analysis of preimplantation embryos from human and mouse showed that short genes whose introns are enriched in Alu (human) and B (mouse) elements, respectively, have higher abundance in the blastocyst compared to the zygote. These highly expressed genes encode ribosomal proteins or metabolic enzymes. On the other hand, long genes whose introns are depleted in repetitive elements have …

Myd88 L265p Elicits Mutation-Specific Ubiquitination To Drive Nf-Κb Activation And Lymphomagenesis, Xinfang Yu, Wei Li, Qipan Deng, Haidan Liu, Xu Wang, Hui Hu, Ya Cao, Zijun Y Xu-Monette, Ling Li, Mingzhi Zhang, Zhongxin Lu, Ken H Young, Yong Li

Faculty, Staff and Students Publications

Myeloid differentiation primary response protein 88 (MYD88) is a critical universal adapter that transduces signaling from Toll-like and interleukin receptors to downstream nuclear factor-κB (NF-κB). MYD88L265P (leucine changed to proline at position 265) is a gain-of-function mutation that occurs frequently in B-cell malignancies such as Waldenstrom macroglobulinemia. In this study, E3 ligase RING finger protein family 138 (RNF138) catalyzed K63-linked nonproteolytic polyubiquitination of MYD88L265P, resulting in enhanced recruitment of interleukin-1 receptor-associated kinases and elevated NF-κB activation. However, RNF138 had little effect on wild-type MYD88 (MYD88WT). With either RNF138 knockdown or mutation on MYD88 ubiquitination sites, MYD88L265P did not constitutively activate …

Robust, Flexible, And Scalable Tests For Hardy-Weinberg Equilibrium Across Diverse Ancestries, Alan M. Kwong, Thomas W. Blackwell, Jonathon Lefaive, Mariza De Andrade, John Barnard, Kathleen C. Barnes, John Blangero

School of Medicine Publications

Traditional Hardy-Weinberg equilibrium (HWE) tests (the χ2 test and the exact test) have long been used as a metric for evaluating genotype quality, as technical artifacts leading to incorrect genotype calls often can be identified as deviations from HWE. However, in datasets comprised of individuals from diverse ancestries, HWE can be violated even without genotyping error, complicating the use of HWE testing to assess genotype data quality. In this manuscript, we present the Robust Unified Test for HWE (RUTH) to test for HWE while accounting for population structure and genotype uncertainty, and evaluate the impact of population heterogeneity and genotype …

Synthesis, Structure-Activity Relationships, And Antiviral Activity Of Allosteric Inhibitors Of Flavivirus Ns2b-Ns3 Protease, Shenyou Nie, Yuan Yao, Fangrui Wu, Xiaowei Wu, Jidong Zhao, Yuanda Hua, Jingyu Wu, Tong Huo, Yi-Lun Lin, Alexander R Kneubehl, Megan B Vogt, Josephine Ferreon, Rebecca Rico-Hesse, Yongcheng Song

Faculty, Staff and Students Publications

Flaviviruses, including Zika, dengue and West Nile virus, are important human pathogens. The highly conserved NS2B-NS3 protease of Flavivirus is essential for viral replication and therefore a promising drug target. Through compound screen followed by medicinal chemistry studies, a novel series of 2,5,6-trisubstituted pyrazine compounds are found to be potent, allosteric inhibitors of Zika virus protease (ZVpro) with IC50 values as low as 130 nM. Their structure-activity relationships are discussed. The ZVpro inhibitors also inhibit homologous proteases of dengue and West Nile virus and their inhibitory activities are correlated. The most potent compounds 47 and 103 potently inhibited Zika virus …

Genome-Wide Association Meta-Analysis Identifies Pleiotropic Risk Loci For Aerodigestive Squamous Cell Cancers, Corina Lesseur, Aida Ferreiro-Iglesias, James D. Mckay, Yohan Bossé, Mattias Johansson, Valerie Gaborieau, Maria Teresa Landi, David C. Christiani, Neil C. Caporaso, Stig E. Bojesen, Christopher I. Amos, Sanjay Shete, Geoffrey Liu, Gadi Rennert, Demetrius Albanes, Melinda C. Aldrich, Adonina Tardon, Chu Chen, Liloglou Triantafillos, John K. Field, Susanne Arnold

Markey Cancer Center Faculty Publications

Squamous cell carcinomas (SqCC) of the aerodigestive tract have similar etiological risk factors. Although genetic risk variants for individual cancers have been identified, an agnostic, genome-wide search for shared genetic susceptibility has not been performed. To identify novel and pleotropic SqCC risk variants, we performed a meta-analysis of GWAS data on lung SqCC (LuSqCC), oro/pharyngeal SqCC (OSqCC), laryngeal SqCC (LaSqCC) and esophageal SqCC (ESqCC) cancers, totaling 13,887 cases and 61,961 controls of European ancestry. We identified one novel genome-wide significant (P_meta< 5x10^-8) aerodigestive SqCC susceptibility loci in the 2q33.1 region (rs56321285, TMEM273). Additionally, three previously unknown …

Discovery And Characterization Of Bromodomain 2-Specific Inhibitors Of Brdt, Zhifeng Yu, Angela F Ku, Justin L Anglin, Rajesh Sharma, Melek Nihan Ucisik, John C Faver, Feng Li, Pranavanand Nyshadham, Nicholas Simmons, Kiran L Sharma, Sureshbabu Nagarajan, Kevin Riehle, Gundeep Kaur, Banumathi Sankaran, Marta Storl-Desmond, Stephen S Palmer, Damian W Young, Choel Kim, Martin M Matzuk

Faculty, Staff and Students Publications

Bromodomain testis (BRDT), a member of the bromodomain and extraterminal (BET) subfamily that includes the cancer targets BRD2, BRD3, and BRD4, is a validated contraceptive target. All BET subfamily members have two tandem bromodomains (BD1 and BD2). Knockout mice lacking BRDT-BD1 or both bromodomains are infertile. Treatment of mice with JQ1, a BET BD1/BD2 nonselective inhibitor with the highest affinity for BRD4, disrupts spermatogenesis and reduces sperm number and motility. To assess the contribution of each BRDT bromodomain, we screened our collection of DNA-encoded chemical libraries for BRDT-BD1 and BRDT-BD2 binders. High-enrichment hits were identified and resynthesized off-DNA and examined …