Medical Genetics Commons^™

Ongoing Study Of The Association Of Apoe Gene Polymorphisms With Cognitive Impairment In The Rio Grande Valley Hispanic Population, Jaime Miguel L. Saveron, Daniela Gamez, Chun Xu

Research Symposium

Background: Alzheimer's disease (AD), a prevalent neurodegenerative disorder, exhibits a significant genetic component. In addition, mild cognitive impairment (MCI) is a key risk factor for AD. While certain demographic factors and genetic variants associated with AD and cognitive impairment have been identified in non-Hispanic populations, limited research exists on this subject within the Hispanic population, particularly in the Rio Grande Valley. This study aims to investigate the relationship between the APOE gene, specifically its ε4 allele, and cognitive impairment in the Hispanic population of the Rio Grande Valley.

Methods: A total of 269 Hispanic subjects, aged 60 and above, with …

Deep Phenotyping Of Post-Infectious Myalgic Encephalomyelitis/Chronic Fatigue Syndrome, Brian Walitt, Komudi Singh, Samuel R. Lamunion, Mark Hallett, Steve Jacobson, Kong Chen, Yoshimi Enose-Akahata, Richard Apps, Jennifer J. Barb, Patrick Bedard, Robert J. Brychta, Ashura Williams Buckley, Peter D. Burbelo, Brice Calco, Brianna Cathay, Li Chen, Snigdha Chigurupati, Jinguo Chen, Foo Cheung, Lisa M.K. Chin, Benjamin W. Coleman, Amber B. Courville, Madeleine S. Deming, Bart Drinkard, Li Rebekah Feng, Luigi Ferrucci, Scott A. Gabel, Angelique Gavin, David S. Goldstein, Shahin Hassanzadeh, Sean C. Horan, Silvina G. Horovitz, Kory R. Johnson, Anita Jones Govan, Kristine M. Knutson, Joy D. Kreskow, Mark Levin, Jonathan J. Lyons, Nicholas Madian, Nasir Malik, Andrew L. Mammen, John A. Mcculloch, Patrick M. Mcgurrin, Joshua D. Milner, Ruin Moaddel, Geoffrey A. Mueller, Amrita Mukherjee, Sandra Muñoz-Braceras, Gina Norato, Katherine Pak, Iago Pinal-Fernandez, Traian Popa, Lauren B. Reoma, Michael N. Sack, Farinaz Safavi, Leorey N. Saligan, Brian A. Sellers, Stephen Sinclair, Bryan Smith, Joseph Snow, Stacey Solin, Barbara J. Stussman, Giorgio Trinchieri, Sara A. Turner, C. Stephenie Vetter, Felipe Vial, Carlotta Vizioli, Ashley Williams, Shanna B. Yang, Avindra Nath

Student Papers, Posters & Projects

Post-infectious myalgic encephalomyelitis/chronic fatigue syndrome (PI-ME/CFS) is a disabling disorder, yet the clinical phenotype is poorly defined, the pathophysiology is unknown, and no disease-modifying treatments are available. We used rigorous criteria to recruit PI-ME/CFS participants with matched controls to conduct deep phenotyping. Among the many physical and cognitive complaints, one defining feature of PI-ME/CFS was an alteration of effort preference, rather than physical or central fatigue, due to dysfunction of integrative brain regions potentially associated with central catechol pathway dysregulation, with consequences on autonomic functioning and physical conditioning. Immune profiling suggested chronic antigenic stimulation with increase in naïve and decrease …

Investigating The Genetic Makeup Of The Major Histocompatibility Complex (Mhc) In The United Arab Emirates Population Through Next-Generation Sequencing, Nour A. D. Marzouka, Halima Alnaqbi, Amira Al-Aamri, Guan Tay, Habiba Alsafar

Research outputs 2022 to 2026

The Human leukocyte antigen (HLA) molecules are central to immune response and have associations with the phenotypes of various diseases and induced drug toxicity. Further, the role of HLA molecules in presenting antigens significantly affects the transplantation outcome. The objective of this study was to examine the extent of the diversity of HLA alleles in the population of the United Arab Emirates (UAE) using Next-Generation Sequencing methodologies and encompassing a larger cohort of individuals. A cohort of 570 unrelated healthy citizens of the UAE volunteered to provide samples for Whole Genome Sequencing and Whole Exome Sequencing. The definition of the …

Assessing Adequacy: A Meta-Analysis Of Rapid Onsite Evaluation Of Thyroid Nodules, Peter P. Issa, Christina Mccarthy, Mohammad Hussein, Aaron L. Albuck, Essam Emad, Mohamed Shama, Krzysztof Moroz, Eman Toraih, Emad Kandil

School of Medicine Faculty Publications

Introduction: Fine-needle aspiration (FNA) is the standard form of preoperative evaluation of thyroid nodule cytological status. A significant number FNAs are classified as inadequate for interpretation, requiring a repeat FNA which is potentially avoidable, costly, and delays treatment. To address these concerns and maximize first-time FNA adequacy, rapid onsite evaluation (ROSE) of FNA specimens was introduced. Our study aims to determine the impact of ROSE on FNA adequacy. Methods: PubMed, Embase, and Web of Science were searched for primary articles assessing the adequacy of ROSE in thyroid nodules. Results: A total of 17 studies were included for a total of …

Modifying Peptide/Lipid-Associated Nucleic Acids (Planas) For Crispr/Cas9 Ribonucleoprotein Delivery, Abdulelah Alhazza, Parvin Mahdipoor, Ryley Hall, Arthur Manda, Sandeep Lohan, Keykavous Parang, Hamidreza Montazeri Aliabadi

Pharmacy Faculty Articles and Research

With the first reports on the possibility of genome editing by Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) and CRISPR-associated protein (Cas)9 surfacing in 2005, the enthusiasm for protein silencing via nucleic acid delivery experienced a resurgence following a period of diminished enthusiasm due to challenges in delivering small interfering RNAs (siRNA), especially in vivo. However, delivering the components necessary for this approach into the nucleus is challenging, maybe even more than the cytoplasmic delivery of siRNA. We previously reported the birth of peptide/lipid-associated nucleic acids (PLANAs) for siRNA delivery. This project was designed to investigate the efficiency of …

Regulation Of Tissue Factor Activity By Interaction With The First Pdz Domain Of Magi1, Mohammad A. Mohammad, Sophie Featherby, Camille Ettelaie

School of Medicine Faculty Publications

Background; Tissue factor (TF) activity is stringently regulated through processes termed encryption. Post-translational modification of TF and its interactions with various protein and lipid moieties allows for a multi-step de-encryption of TF and procoagulant activation. Membrane-associated guanylate kinase-with inverted configuration (MAGI) proteins are known to regulate the localisation and activity of a number of proteins including cell-surface receptors. Methods; The interaction of TF with MAGI1 protein was examined as a means of regulating TF activity. MDA-MB-231 cell line was used which express TF and MAGI1, and respond well to protease activated receptor (PAR)2 activation. Proximity ligation assay (PLA), co-immunoprecipitation and …

Impact Of Genetic And Non-Genetic Factors On Phenotypic Diversity In Nbas-Associated Disease, Nicole Hammann, Dominic Lenz, Ivo Baric, Ellen Crushell, Carlo Dionisi Vici, Felix Distelmaier, Francois Feillet, Peter Freisinger, Maja Hempel, Anna L. Khoreva, Martin W. Laass, Yves Lacassie, Elke Lainka, Catherine Larson-Nath, Zhongdie Li, Patryk Lipiński, Eberhard Lurz, André Mégarbané, Susana Nobre, Giorgia Olivieri, Bianca Peters, Paolo Prontera, Lea D. Schlieben, Christine M. Seroogy, Cristina Sobacchi, Shigeru Suzuki, Christel Tran, Jerry Vockley

School of Medicine Faculty Publications

Biallelic pathogenic variants in neuroblastoma-amplified sequence (NBAS) cause a pleiotropic multisystem disorder. Three clinical subgroups have been defined correlating with the localisation of pathogenic variants in the NBAS gene; variants affecting the C-terminal region of NBAS result in SOPH syndrome (short stature, optic atrophy, Pelger-Huët anomaly), variants affecting the Sec 39 domain are associated with infantile liver failure syndrome type 2 (ILFS2) and variants affecting the ß-propeller domain give rise to a combined phenotype. However, there is still unexplained phenotypic diversity across the three subgroups, challenging the current concept of genotype-phenotype correlations in NBAS-associated disease. Therefore, besides examining the genetic …

Lung Cancer In Ever- And Never-Smokers: Findings From Multi-Population Gwas Studies, Yafang Li, Xiangjun Xiao, Jianrong Li, Younghun Han, Chao Cheng, Gail F. Fernandes, Shannon E. Slewitzke, Susan M. Rosenberg, Meng Zhu, Jinyoung Byun, Yohan Bossé, James D. Mckay, Demetrios Albanes, Stephan Lam, Adonina Tardon, Chu Chen, Stig E. Bojesen, Maria T. Landi, Mattias Johansson, Angela Risch, Heike Bickeböller, H-Erich Wichmann, David C. Christiani, Gad Rennert, Susanne M. Arnold, Gary E. Goodman, John K. Field, Diptasri Mandal, Et Al

School of Graduate Studies Faculty Publications

BACKGROUND: Clinical, molecular, and genetic epidemiology studies displayed remarkable differences between ever- and never-smoking lung cancer. METHODS: We conducted a stratified multi-population (European, East Asian, and African descent) association study on 44,823 ever-smokers and 20,074 never-smokers to identify novel variants that were missed in the non-stratified analysis. Functional analysis including eQTL colocalization and DNA damage assays, and annotation studies were conducted to evaluate the functional roles of the variants. We further evaluated the impact of smoking quantity on lung cancer risk for the variants associated with ever-smoking lung cancer. RESULTS: Five novel independent loci, GABRA4, inter-genic region 12q24.33, LRRC4C, LINC01088, …

Investigation Into Cardiac Myhc-Α 334-352-Specific Tcr Transgenic Mice Reveals A Role For Cytotoxic Cd4 T Cells In The Development Of Cardiac Autoimmunity, Meghna Sur, Mahima T. Rasquinha, Kiruthiga Mone, Chandirasegaran Massilamany, Ninaad Lasrado, Channabasavaiah B. Gurumurthy, Raymond A Sobel, Jay Reddy

Journal Articles: Genetics, Cell Biology & Anatomy

Myocarditis is one of the major causes of heart failure in children and young adults and can lead to dilated cardiomyopathy. Lymphocytic myocarditis could result from autoreactive CD4⁺ and CD8⁺ T cells, but defining antigen specificity in disease pathogenesis is challenging. To address this issue, we generated T cell receptor (TCR) transgenic (Tg) C57BL/6J mice specific to cardiac myosin heavy chain (Myhc)-α 334-352 and found that Myhc-α-specific TCRs were expressed in both CD4⁺ and CD8⁺ T cells. To investigate if the phenotype is more pronounced in a myocarditis-susceptible genetic background, we backcrossed with A/J mice. At …

An Ewas Of Dementia Biomarkers And Their Associations With Age, African Ancestry, And Ptsd, Mark W. Miller, Erika J. Wolf, Xiang Zhao, Mark W. Logue, Sage E. Hawn

Psychology Faculty Publications

Background

Large-scale cohort and epidemiological studies suggest that PTSD confers risk for dementia in later life but the biological mechanisms underlying this association remain unknown. This study examined this question by assessing the influences of PTSD, APOE ε4 genotypes, DNA methylation, and other variables on the age- and dementia-associated biomarkers Aβ40, Aβ42, GFAP, NfL, and pTau-181 measured in plasma. Our primary hypothesis was that PTSD would be associated with elevated levels of these markers.

Methods

Analyses were based on data from a PTSD-enriched cohort of 849 individuals. We began by performing factor analyses of the biomarkers, the results of which …

Actin Depolymerization Of Tenocytes Promotes A Tendinosis-Like Gene Expression, Kameron Inguito, Ba, Valerie West, Karl Matthew Ebron, Justin Parreno, Phd

Alpha Omega Alpha Research Symposium Posters

Optimal cellular mechanotransduction is essential for tendon matrix homeostasis. We recently developed an in vivo rat model of tendinosis, where the plantaris tendon are overloaded through ablation of the synergistic Achilles tendon. Using this model we determined that tissue overload disrupts matrix-cell interactions, which results in under-stimulation of tendon cells (tenocytes) (Fig.1)

Using an ex vivo model of tendon stress deprivation by maintaining tail tendon fascicles in floating culture we showed that tenocyte under-stimulation results in destabilization of filamentous (F-)actin (Fig.2). F-actin destabilization coincides with tendinosis-like gene expression: downregulation of tenogenic genes (Col1, Tnc, asma, Scx), upregulation of chondrogenic (Acan, …

Maternal Western Diet Programs Cardiometabolic Dysfunction And Hypothalamic Inflammation Via Epigenetic Mechanisms Predominantly In The Male Offspring, Mona Elgazzaz, Clara Berdasco, Jone Garai, Melody Baddoo, Shiping Lu, Hisham Daoud, Jovanny Zabaleta, Franck Mauvais-Jarvis, Eric Lazartigues

School of Medicine Faculty Publications

Objective; Maternal exposure during pregnancy is a strong determinant of offspring health outcomes. Such exposure induces changes in the offspring epigenome resulting in gene expression and functional changes. In this study, we investigated the effect of maternal Western hypercaloric diet (HCD) programming during the perinatal period on neuronal plasticity and cardiometabolic health in adult offspring. Methods; C57BL/6J dams were fed HCD for 1 month prior to mating with regular diet (RD) sires and kept on the same diet throughout pregnancy and lactation. At weaning, offspring were maintained on either HCD or RD for 3 months resulting in 4 treatment groups …

Safety And Efficacy Of Ixoberogene Soroparvovec In Neovascular Age-Related Macular Degeneration In The United States (Optic): A Prospective, Two-Year, Multicentre Phase 1 Study, Arshad M. Khanani, David S. Boyer, Charles C. Wykoff, Carl D. Regillo, Brandon G. Busbee, Dante Pieramici, Carl J. Danzig, Brian C. Joondeph, James C. Major, Adam Turpcu, Szilárd Kiss

Wills Eye Hospital Papers

Background

Gene therapy, successfully used in rare, monogenetic disorders, may prove to be a durable management approach for common, polygenetic conditions, including neovascular age-related macular degeneration (nAMD). Repeated injections, oftentimes monthly, and possibly for decades, of vascular endothelial growth factor antagonists (anti-VEGF), is the standard for nAMD. We hypothesised that an in-office, intravitreal administration of ixoberogene soroparvovec (ixo-vec, formerly ADVM-022), a single-dose gene therapy encoding for the proven anti-VEGF protein, aflibercept, would transform retinal cells to continually produce aflibercept to minimise treatment burden in nAMD.

Methods

In this two-year, open-label, prospective, multicentre phase 1 study, patients with nAMD responding to …

Myod-Skp2 Axis Boosts Tumorigenesis In Fusion Negative Rhabdomyosarcoma By Preventing Differentiation Through P57kip2 Targeting, Silvia Pomella, Matteo Cassandri, Lucrezia D’Archivio, Antonella Porrazzo, Cristina Cossetti, Doris Phelps, Clara Perrone, Michele Pezzella, Antonella Cardinale, Marco Wachtel, Sara Aloisi, David Milewski, Marta Colletti, Prethish Sreenivas, Zoë S. Walters, Giovanni Barillari, Angela Di Giannatale, Giuseppe Maria Milano, Cristiano De Stefanis, Rita Alaggio, Sonia Rodriguez-Rodriguez, Nadia Carlesso, Christopher R. Vakoc, Enrico Velardi, Beat W. Schafer, Ernesto Guccione, Susanne A. Gatz, Lucio Miele

School of Medicine Faculty Publications

Rhabdomyosarcomas (RMS) are pediatric mesenchymal-derived malignancies encompassing PAX3/7-FOXO1 Fusion Positive (FP)-RMS, and Fusion Negative (FN)-RMS with frequent RAS pathway mutations. RMS express the master myogenic transcription factor MYOD that, whilst essential for survival, cannot support differentiation. Here we discover SKP2, an oncogenic E3-ubiquitin ligase, as a critical pro-tumorigenic driver in FN-RMS. We show that SKP2 is overexpressed in RMS through the binding of MYOD to an intronic enhancer. SKP2 in FN-RMS promotes cell cycle progression and prevents differentiation by directly targeting p27Kip1 and p57Kip2, respectively. SKP2 depletion unlocks a partly MYOD-dependent myogenic transcriptional program and strongly affects stemness and tumorigenic …

A Phenotypically Robust Model Of Spinal And Bulbar Muscular Atrophy In Drosophila, Kristin Richardson, Medha Sengupta, Alyson Sujkowski, Kozeta Libohova, Autumn C. Harris, Robert Wessells, Diane E. Merry, Sokol V. Todi

Department of Biochemistry and Molecular Biology Faculty Papers

Spinal and bulbar muscular atrophy (SBMA) is an X-linked disorder that affects males who inherit the androgen receptor (AR) gene with an abnormal CAG triplet repeat expansion. The resulting protein contains an elongated polyglutamine (polyQ) tract and causes motor neuron degeneration in an androgen-dependent manner. The precise molecular sequelae of SBMA are unclear. To assist with its investigation and the identification of therapeutic options, we report here a new model of SBMA in Drosophila melanogaster. We generated transgenic flies that express the full-length, human AR with a wild-type or pathogenic polyQ repeat. Each transgene is inserted into the same safe …

Investigation Of Heterocyclic Amines And N-Acetyltransferase 2 Genetic Polymorphism In The Dysregulation Of Hepatic Energy Homeostasis: A Gene-Environment Approach., Kennedy M Walls

Electronic Theses and Dissertations

Heterocyclic amines (HCAs) are mutagens generated when cooking meat for prolonged periods of time or until well-done. Recent epidemiological studies reported significant associations between dietary HCA exposure and insulin resistance and type II diabetes. However, no previous studies have examined if HCAs, independent of meat consumption, contributes to pathogenesis of insulin resistance or metabolic disease. It is well known that HCAs require hepatic bioactivation by cytochrome P450 1A2 (CYP1A2) and N-acetyltransferase 2 (NAT2). NAT2 expresses a well-defined genetic polymorphism in humans that, depending on the combination of NAT2 alleles, correlate to rapid, intermediate, or slow acetylator phenotypes that exhibit differential …

Caregiver Perspectives On The Daily Function Of People Living With Hnrnph2-Related Neurodevelopmental Disorder: Developing A Conceptual Model, Rachel Salazar

Seton Hall University Dissertations and Theses (ETDs)

Introduction: Neurodevelopmental disorders are a group of conditions that start in childhood and lead to impairments in functioning. HNRNPH2-related neurodevelopmental disorder is an ultra-rare disorder in which individuals present with cognitive, behavioral, language and motor function impairments that often leads to reliance on their caregivers. Existing conceptual models of neurodevelopment are not specific to this ultra rare disorder and do not highlight the caregiver impact of living with HNRNPH2-related neurodevelopmental disorder.

Purpose: The purpose of this study is to understand the caregiver perspective on the everyday functioning of people living with HNRNPH2-related neurodevelopmental disorder to generate a …

Tolfenamic Acid Derivatives: A New Class Of Transcriptional Modulators With Potential Therapeutic Applications For Alzheimer’S Disease And Related Disorders, Juanetta Hill, Karim E. Shalaby, Syed W. Bihaqi, Bothaina H. Alansi, Benjamin Barlock, Keykavous Parang, Richard Thompson, Khalid Ourarhni, Nasser H. Zawia

Pharmacy Faculty Articles and Research

The field of Alzheimer’s disease (AD) has witnessed recent breakthroughs in the development of disease-modifying biologics and diagnostic markers. While immunotherapeutic interventions have provided much-awaited solutions, nucleic acid-based tools represent other avenues of intervention; however, these approaches are costly and invasive, and they have serious side effects. Previously, we have shown in AD animal models that tolfenamic acid (TA) can lower the expression of AD-related genes and their products and subsequently reduce pathological burden and improve cognition. Using TA as a scaffold and the zinc finger domain of SP1 as a pharmacophore, we developed safer and more potent brain-penetrating analogs …

Functional Characterization Of The Ipsc Generated Hepatocytes Using Genome-Wide Transcriptomic Analysis, Ashley Ikwuezunma, Erica De Leon, Ana C. Leandro, Joanne E. Curran, John Blangero, Satish Kumar

Research Colloquium

Advances in iPSC technologies now allow us to consider non-invasive large-scale in-vitro disease modeling experiments on disease appropriate cell types in human subjects to better understand human disease pathophysiology, disease genetics and to develop better diagnostic and therapeutic technologies. We performed differential gene expression and functional annotation analysis using genome wide mRNA sequencing data to evaluate the functional and disease modeling potential of iPSC generated hepatocytes. Following the criteria moderated t statistics FDR corrected p-value ≤ 0.05 and fold change-absolute ≥ 2.0, 7,246 genes/transcripts were significantly differentially expressed iPSCs and hepatocytes. The 3,791 of these DE genes/transcripts were significantly …

Gene By Environment Interaction And Metabolic-Associated Fatty Liver Disease In Mexican American Patients With Depression, Khalid Sheikh, Vincent P. Diego, Sandra L. Laston, Eron G. Manusov, Sarah Williams-Blangero, John Blangero

Research Colloquium

Knowledge of genetic and environmental (G x E) interaction effects on metabolic-associated fatty liver disease (MAFLD) is limited. The purpose of this study was to examine the impact of G x E interaction effects on MAFLD in Mexican Americans in the Rio Grande Valley (RGV). The environment examined was depression as measured by the Beck Depression Inventory-II (BDI-II). We examined potential G x E interaction in the phenotypic expression of MAFLD, including hepatic steatosis and hepatic fibrosis, using variance component models and likelihood-based statistical inference. Significant G x E interactions were identified for hepatic fibrosis x BDI-II. These findings provide …