Medicine and Health Sciences Commons^™

Penalized Mixed-Effects Ordinal Response Models For High-Dimensional Genomic Data In Twins And Families, Amanda E. Gentry

Theses and Dissertations

The Brisbane Longitudinal Twin Study (BLTS) was being conducted in Australia and was funded by the US National Institute on Drug Abuse (NIDA). Adolescent twins were sampled as a part of this study and surveyed about their substance use as part of the Pathways to Cannabis Use, Abuse and Dependence project. The methods developed in this dissertation were designed for the purpose of analyzing a subset of the Pathways data that includes demographics, cannabis use metrics, personality measures, and imputed genotypes (SNPs) for 493 complete twin pairs (986 subjects.) The primary goal was to determine what combination of SNPs and …

Parental Experience With Whole Exome Sequencing Reanalysis And Its Impact On The Diagnostic Odyssey, Nicole D. Lucas

Theses and Dissertations

Advances in genomic technology and an increase in the number of gene-disease associations have helped reduce the number of individuals living without a diagnosis. Whole exome sequencing (WES) analyzes the entire human exome in an attempt to determine if there is a molecular etiology for individuals who remain undiagnosed after other clinical or molecular investigations. Still, WES leaves most individuals undiagnosed, resulting in feelings of disappointment and uncertainty. Individuals who remain undiagnosed after WES can subsequently undergo WES reanalysis later due to improvements in bioinformatics, software updates, and an increase in known genedisease associations. This is the first study, to …

Metatranscriptome Of Human Faecal Microbial Communities In A Cohort Of Adult Men, Galeb S. Abu-Ali, Raaj S. Mehta, Jason Lloyd-Price, Himel Mallick, Tobyn Branck, Kerry L. Ivey, David A. Drew, Casey Dulong, Eric Rimm, Jacques Izard, Andrew T. Chan, Curtis Huttenhower

Department of Food Science and Technology: Faculty Publications

The gut microbiome is intimately related to human health, but it is not yet known which functional activities are driven by specific microorganisms' ecological configurations or transcription. We report a large-scale investigation of 372 human fecal metatranscriptomes and 929 metagenomes from a subset of 308 men in the Health Professionals Follow-Up Study. We identified a metatranscriptomic 'core' universally transcribed over time and across participants, often by different microorganisms. In contrast to the housekeeping functions enriched in this core, a 'variable' metatranscriptome included specialized pathways that were differentially expressed both across participants and among microorganisms. Finally, longitudinal metagenomic profiles allowed ecological …

Role Of Mycobacterium Avium Paratuberculosis (Map) And Tnfsf15 Snps On Tl1a In Cd, Sayf Al-Deen Hassouneh

Electronic Theses and Dissertations

Tumor Necrosis Factor-Like Ligand 1a (TL1A) is a cytokine encoded by Tumor Necrosis Factor Super Family 15 gene (TNFSF15) gene mostly in endothelial cells which binds to T-cells and foments the production of pro-inflammatory cytokines including TNF-α, IL-6, IL-1b, IFN- γ and IL-13. TL1A level is elevated in inflammatory diseases including Crohn's Disease (CD). Although Single Nucleotide Polymorphisms (SNPs) in TNFSF15 have been reported in CD, no studies have investigated the effect of these SNPs on TL1A, inflammation, and susceptibility to Mycobacterium avium subspecies paratuberculosis (MAP) infection. MAP is a strong candidate in CD pathogenesis. This study is designed to …

Mechanotransduction Signaling In Podocytes From Fluid Flow Shear Stress., Tarak Srivastava, Hongying Dai, Daniel P. Heruth, Uri S. Alon, Robert E. Garola, Jianping Zhou, R Scott Duncan, Ashraf El-Meanawy, Ellen T. Mccarthy, Ram Sharma, Mark L. Johnson, Virginia J. Savin, Mukut Sharma

Manuscripts, Articles, Book Chapters and Other Papers

Recently, we and others have found that hyperfiltration-associated increase in biomechanical forces, namely, tensile stress and fluid flow shear stress (FFSS), can directly and distinctly alter podocyte structure and function. The ultrafiltrate flow over the major processes and cell body generates FFSS to podocytes. Our previous work suggests that the cyclooxygenase-2 (COX-2)-PGE2-PGE2 receptor 2 (EP2) axis plays an important role in mechanoperception of FFSS in podocytes. To address mechanotransduction of the perceived stimulus through EP2, cultured podocytes were exposed to FFSS (2 dyn/cm2) for 2 h. Total RNA from cells at the end of FFSS treatment, 2-h post-FFSS, and 24-h …

Assessing The Barriers To Cardiac Care In Carriers Of Duchenne And Becker Muscular Dystrophy, Lauren Renae Eekhoff

Theses and Dissertations

Duchenne and Becker muscular dystrophy (DBMD) are X-linked conditions due to mutations within the dystrophin gene that cause progressive muscle weakness, respiratory insufficiency, and cardiomyopathy in affected males. Approximately twothirds of women who have a son with DBMD are carriers of the condition. Carriers typically do not manifest muscular symptoms but are at risk for cardiac abnormalities such as dilated cardiomyopathies. The American Academy of Pediatrics (AAP) recommends that carriers of DBMD receive a complete cardiac evaluation by a cardiologist that includes an echocardiogram and electrocardiogram (EKG) with reevaluation every five years. According to a recent study33, as many as …

The Impact Of Communication Deficits On Puberty And Sexual Development In Adolescents On The Autism Spectrum, Ashton Wolfe

Theses and Dissertations

Transitioning into a sexually mature adult is a challenging time for both an adolescent with autism spectrum disorder (ASD) and his or her family. Sexual development begets challenges due to the demands it places on the social and communication skills needed to explore developmental changes that are occurring physically, emotionally and hormonally. A diagnosis of ASD is largely established by quantifying impediments in social and communication skills through observation. With deficits in these skills, one can assume that social and communication difficulties can create obstacles in the sexual development of affected individuals. Our study used quantitative and qualitative measures to …

Is Current Fragile X Syndrome Counseling Enough? Expanding The Clinical Phenotype Of Fragile X In Premutation And Intermediate Allele Carriers, Zahra Saadat Girnary

Theses and Dissertations

Fragile X syndrome (FXS) is caused by a triplet repeat expansion on the FMR1 gene. Individuals with >200 repeats have FXS, while individuals between 45-54 and 55- 200 repeats have the FMR1 intermediate allele and premutation, respectively. FXS is characterized by autism and intellectual disability while the premutation is associated with fragile X-associated tremor/ataxia syndrome (FXTAS) and fragile X-associated primary ovarian insufficiency (FXPOI). However, recent research shows that the premutation may be associated with psychiatric manifestations. Currently, there are no established clinical features associated with the intermediate allele. This study sought to 1) study knowledge regarding FXTAS, FXPOI, as well …

Discussing History Of Mental Illness During Prenatal Genetic Counseling: Patient Interest And Comfort, Sarah Nimrichter

Theses and Dissertations

Purpose: This study aimed to explore patient interest in and comfort with discussing a personal and/or family history of mental illness with a genetic counselor during a prenatal genetic counseling session. Methods: Participants included pregnant women who met with a genetic counselor for routine prenatal screening/testing counseling at Palmetto Health USC Medical Group Department of OB/GYN. Following their appointment, they were given a copy of the invitation to participate, questionnaire, and mental health resource page by the genetic counselor who performed their genetic counseling. Results: Forty participants completed questionnaires. 70% of participants indicated some level of interest in discussing mental …

Increased Risk For Obesity And Diabetes With Neurodegeneration In Developing Countries, I. J. Martins

Research outputs 2014 to 2021

The incidence of global obesity and Type 2 diabetes has increased and is predicted to rise to 30% of the global population. Diet and lifestyle factors are incapable to resolve the increased incidence for obesity and diabetes in various populations of the world. Developing countries have come to the forefront because of the higher diabetic epidemic. The urbanization may possibly provide an explanation for the global diabetic epidemic. In Western countries the metabolic syndrome and non alcoholic fatty liver disease (NAFLD) have reached 30 % of the population and now at present NAFLD afflicts 20% of developing populations. Western diets …

Analysis Of Diagnostic, Preventive, And Disease-Modifying Therapeutic Measures Of Alzheimer’S Disease, Ghazal Habib Havoutis

HCNSO Student Capstones

Alzheimer’s disease (AD) is the most common late-onset neurodegenerative disorder and cause of dementia, characterized by the formation of neurofibrillary tangles and senile plaque deposits. The heterogeneous nature of the disease (both genetically and environmentally) makes it difficult to prevent or cure. Without prevention, the prevalence of AD is expected to triple by 2050. However, because the diagnosis of AD is usually preceded by years of cognitive impairment, early detection may aid in reducing prevalence. Thus, there is a need for validated diagnostic measures for early and improved diagnosis and prevention. In this review, current and ongoing classifiers of early …

Development Of The Personal Genomics Industry, Jorge L. Contreras, Vikrant Deshmukh

Utah Law Faculty Scholarship

Today, numerous commercial services offer genetic testing, genotyping and genome sequencing services both to medical providers and directly to the public. Twenty-five years ago, such offerings would have been unthinkable, both in terms of cost and medical practice. This chapter describes the development of the personal genomics industry and its evolving business models and goals.

Revealing A Non-Canonical Role Of Anti-Apoptotic Mcl-1 In Early Embryonic Development, Xue Yang

Theses and Dissertations (ETD)

MCL-1, a well-known pro-survival BCL-2 family member, is indispensable for the survival of various cellular lineages and is also among the most frequently amplified genes in a variety of human malignancies. Gene ablation studies previously revealed that Mcl-1 deficiency leads to embryonic lethality around E3.5 during peri-implantation stage. Strikingly, the study did not detect any increase in apoptotic cells of the blastocyst, indicating a function of MCL-1 beyond regulating apoptosis. Our previous studies revealed an unrecognized role of MCL-1 in promoting mitochondrial physiology, which is independent of its classical anti-apoptotic function and requires being imported into the mitochondrial matrix. In …

Combinational Sirna Delivery Using Hyaluronic Acid Modified Amphiphilic Polyplexes Against Cell Cycle And Phosphatase Proteins To Inhibit Growth And Migration Of Triple-Negative Breast Cancer Cells, Manoj B. Parmar, Daniel Nisakar Meenakshi Sundaram, Remant Bahadur Kc, Robert Maranchuk, Hamidreza Montazeri Aliabadi, Judith C. Hugh, Raimar Löbenberg, Hasan Uludağ

Pharmacy Faculty Articles and Research

Triple-negative breast cancer is an aggressive form of breast cancer with few therapeutic options if it recurs after adjuvant chemotherapy. RNA interference could be an alternative therapy for metastatic breast cancer, where small interfering RNA (siRNA) can silence the expression of aberrant genes critical for growth and migration of malignant cells. Here, we formulated a siRNA delivery system using lipid-substituted polyethylenimine (PEI) and hyaluronic acid (HA), and characterized the size, ζ-potential and cellular uptake of the nanoparticulate delivery system. Higher cellular uptake of siRNA by the tailored PEI/HA formulation suggested better interaction of complexes with breast cancer cells due to …

Small Rna Teg49 Is Derived From A Sara Transcript And Regulates Virulence Genes Independent Of Sara In Staphylococcus Aureus, Adhar Manna, Samin Kim, Liviu Cengher, Anna Corvaglia, Stefano Leo, Patrice Francois, Ambrose L. Cheung

Dartmouth Scholarship

Expression of virulence factors in Staphylococcus aureus is regulated by a wide range of transcriptional regulators, including proteins and small RNAs (sRNAs), at the level of transcription and/or translation. The sarA locus consists of three overlapping transcripts generated from three distinct promoters, all containing the sarA open reading frame (ORF). The 5= untranslated regions (UTRs) of these transcripts contain three separate regions 711, 409, and 146 nucleotides (nt) upstream of the sarA translation start, the functions of which remain unknown. Re- cent transcriptome-sequencing (RNA-Seq) analysis and subsequent characterization indicated that two sRNAs, teg49 and teg48, are processed and likely produced …

Hypotonia And Intellectual Disability Without Dysmorphic Features In A Patient With Pign-Related Disease., Isabelle Thiffault, Britton Zuccarelli, Holly Welsh, Xuan Yuan, Emily Farrow, Lee Zellmer, Neil Miller, Sarah Soden, Ahmed Abdelmoity, Robert A Brodsky, Carol Saunders

Manuscripts, Articles, Book Chapters and Other Papers

BACKGROUND: Defects in the human glycosylphosphatidylinositol anchor biosynthetic pathway are associated with inherited glycosylphosphatidylinositol (GPI)-deficiencies characterized by a broad range of clinical phenotypes including multiple congenital anomalies, dysmorphic faces, developmental delay, hypotonia, and epilepsy. Biallelic variants in PIGN, encoding phosphatidylinositol-glycan biosynthesis class N have been recently associated with multiple congenital anomalies hypotonia seizure syndrome.

CASE PRESENTATION: Our patient is a 2 year old male with hypotonia, global developmental delay, and focal epilepsy. Trio whole-exome sequencing revealed heterozygous variants in PIGN, c.181G > T (p.Glu61*) and c.284G > A (p.Arg95Gln). Analysis of FLAER and anti-CD59 by flow-cytometry demonstrated a shift in this patient's …

Difatty Acyl-Conjugated Linear And Cyclic Peptides For Sirna Delivery, Hung Do, Meenakshi Sharma, Naglaa Salem El-Sayed, Parvin Mahdipoor, Emira Bousoik, Keykavous Parang, Hamidreza Montazeri Aliabadi

Pharmacy Faculty Articles and Research

A number of amphiphilic difatty acyl linear and cyclic R5K2 peptide conjugates were synthesized by solid-phase peptide methods to enhance the interaction with the hydrophobic cellular phospholipid bilayer and to improve siRNA delivery and silencing. Binding to siRNA molecules was significantly less for the cyclic peptide conjugates. A gradual decrease was observed in the particle size of the complexes with increasing peptide/siRNA ratio for most of the synthesized peptides, suggesting the complex formation. Most of the complexes showed a particle size of less than 200 nm, which is considered an appropriate size for in vitro siRNA delivery. A number of …

The Influence Of A Kdt501, A Novel Isohumulone, On Adipocyte Function In Humans, Brian S. Finlin, Beibei Zhu, Bernard P. Kok, Cristina Godio, Philip M. Westgate, Neile Grayson, Robert Sims, Jeffrey S. Bland, Enrique Saez, Philip A. Kern

Internal Medicine Faculty Publications

Objective: In a phase II clinical trial in nine obese, insulin-resistant humans, we observed that treatment with KDT501, a novel isohumulone drug, increased total and high-molecular weight (HMW) adiponectin in plasma. The objective was to determine whether KDT501 increased adiponectin secretion from subcutaneous white adipose tissue (SC WAT) and the underlying mechanism(s).

Methods: Nine obese participants with either prediabetes or with normal glucose tolerance plus three features of metabolic syndrome were part of the study. SC WAT biopsies were performed before and after 28 days of KDT501 treatment in a clinical research setting. In addition, a cold stimulus was used …

Benchmarking Relatedness Inference Methods With Genome-Wide Data From Thousands Of Relatives, Monica D. Ramstetter, Thomas D. Dyer, Donna M. Lehman, Joanne E. Curran, Ravindranath Duggirala, John Blangero, Jason G. Mezey, Amy L. Williams

School of Medicine Publications

Inferring relatedness from genomic data is an essential component of genetic association studies, population genetics, forensics, and genealogy. While numerous methods exist for inferring relatedness, thorough evaluation of these approaches in real data has been lacking. Here, we report an assessment of 12 state-of-the-art pairwise relatedness inference methods using a data set with 2485 individuals contained in several large pedigrees that span up to six generations. We find that all methods have high accuracy (92–99%) when detecting first- and second-degree relationships, but their accuracy dwindles to76% of relative pairs. Overall, the most accurate methods are Estimation of Recent Shared Ancestry …

A Population-Specific Reference Panel Empowers Genetic Studies Of Anabaptist Populations., Liping Hou, Rachel L Kember, Jared C Roach, Jeffrey R O'Connell, David W Craig, Maja Bucan, William K Scott, Margaret Pericak-Vance, Jonathan L Haines, Michael H Crawford, Alan R Shuldiner, Francis J Mcmahon

Articles, Abstracts, and Reports

Genotype imputation is a powerful strategy for achieving the large sample sizes required for identification of variants underlying complex phenotypes, but imputation of rare variants remains problematic. Genetically isolated populations offer one solution, however population-specific reference panels are needed to assure optimal imputation accuracy and allele frequency estimation. Here we report the Anabaptist Genome Reference Panel (AGRP), the first whole-genome catalogue of variants and phased haplotypes in people of Amish and Mennonite ancestry. Based on high-depth whole-genome sequence (WGS) from 265 individuals, the AGRP contains >12 M high-confidence single nucleotide variants and short indels, of which ~12.5% are novel. These …

Examining The Influence And Role Of Pharmacogenetics Among Children With Autism Spectrum Disorder, Nuha Shaker

Masters Theses & Specialist Projects

Pharmacogenetics is the study of genomic-guided individualized drug prescription that plays an important role in preventing the severe adverse effects of drugs, decreasing the time and cost of therapeutic choices, and directing healthcare professionals to choose medications that are effective and safe. It is noteworthy that this approach becomes highly beneficial in patients suffering from chronic diseases or disorders, since these conditions may require multiple and long term pharmacological therapies, as in children with autism spectrum disorder (ASD). However, public acceptance is a major challenge when implementation of pharmacogenetics merges into clinical practice. The purpose of this study is a) …