Genetics and Genomics Commons^™

With Love, ; An Interdisciplinary And Intersectional Look At Why Creativity Is Essential, Theo Starr Gardner

Whittier Scholars Program

My Whittier Scholars Program self-designed major, Teaching Creativity, is a mixture of Art, Literature, and Education classes. My research and praxis classes have been focused on the ‘how?’s and 'why?’s of creativity, so it felt only right that my project should be a constructivist, generative project. The project I have been working on throughout my time at Whittier, and that has just fully come to fruition on April 11th, 2024, was a solo art gallery/open mic event entitled ‘With Love,’. With Love, was conceptually inspired by the research I’ve conducted on creativity and creative arts education over the past few …

Integrated Transcriptomics And Histopathology Approach Identifies A Subset Of Rejected Donor Livers With Potential Suitability For Transplantation, Ankita Srivastava, Alexandra Manchel, John Waters, Manju Ambelil, Benjamin K. Barnhart, Jan B. Hoek, Ashesh P. Shah, Rajanikanth Vadigepalli

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

BACKGROUND: Liver transplantation is an effective treatment for liver failure. There is a large unmet demand, even as not all donated livers are transplanted. The clinical selection criteria for donor livers based on histopathological evaluation and liver function tests are variable. We integrated transcriptomics and histopathology to characterize donor liver biopsies obtained at the time of organ recovery. We performed RNA sequencing as well as manual and artificial intelligence-based histopathology (10 accepted and 21 rejected for transplantation).

RESULTS: We identified two transcriptomically distinct rejected subsets (termed rejected-1 and rejected-2), where rejected-2 exhibited a near-complete transcriptomic overlap with the accepted livers, …

The Effects Of Temperature And Mito-Nuclear Interaction On Male Fertility In Drosophila., Violetta Bakunina

Honors Theses

The (simw⁵⁰¹);Ore genotype is a strain of Drosophila melanogaster that has impaired mitochondrial function as a result of a disrupted interaction between a mitochondrially-encoded tRNA^Tyr and the nuclear-encoded synthetase that aminoacylates mt-tRNATyr. We hypothesized that disruption of mitochondrial protein synthesis and oxidative phosphorylation (OXPHOS) in this genotype decreases mitochondrial translation and results in the sterility of (simw⁵⁰¹);OreR males at 28^oC. The results of Mitotracker staining showcased the reduced Mean Fluorescence Intensity (MFI), which confirms that sterility has an energetic basis, yet also that mature sperm function is compromised. Cytological dissection of male gonads …

When Problems Become Solutions: Harnessing The Osteogenic Capacity Of Disease-Causing Stem Cells To Repair Bone Fractures, Mehreen Pasha

University Scholar Projects

While we often perceive disease as negative, there is potential to engineer seemingly negative biological phenomena into therapeutics to treat a variety of human illnesses. Fibrodysplasia ossificans progressiva (FOP) is a genetic disorder involving uncontrolled, widespread, extraskeletal bone growth, or heterotopic ossification (HO). In FOP patients, stem cells called fibro/adipogenic progenitors (FAPs) follow an abnormal, osteogenic pathway. In the present study, we investigate whether we can adapt these Acvr1 mutant FAPs, which are exceptional at producing bone, to repair bone fractures in otherwise normal patients. The primary aims of this study are (1) to devise and optimize a novel method …

Using Machine Learning To Recognize Chronic Rhinosinusitis, Irene Liu '23

Student Publications & Research

Chronic Rhinosinusitis (CRS) is a nasal disease characterized by the inflammation of the mucosa and paranasal sinuses with a duration of at least 12 consecutive weeks. So, to diagnose CRS, one needs to keep a record of their symptoms for ~12 weeks before they are recommended to get a tomography which will allow physicians to classify them as a patient with CRS or without. This is a timely and costly process; thus, machine learning should be used to speed the process up. Since patients with CRS have more obstructed noses, the sound produced should be different than an individual without …

Robust Meta-Analysis For Large-Scale Genomic Experiments Based On An Empirical Approach, Sinjini Sikdar

Mathematics & Statistics Faculty Publications

BACKGROUND: Recent high-throughput technologies have opened avenues for simultaneous analyses of thousands of genes. With the availability of a multitude of public databases, one can easily access multiple genomic study results where each study comprises of significance testing results of thousands of genes. Researchers currently tend to combine this genomic information from these multiple studies in the form of a meta-analysis. As the number of genes involved is very large, the classical meta-analysis approaches need to be updated to acknowledge this large-scale aspect of the data.

METHODS: In this article, we discuss how application of standard theoretical null distributional assumptions …

Estimating Partial Body Ionizing Radiation Exposure By Automated Cytogenetic Biodosimetry, Ben Shirley, Peter Rogan

Biochemistry Publications

Purpose: Inhomogeneous exposures to ionizing radiation can be detected and quantified with the dicentric chromosome assay (DCA) of metaphase cells. Complete automation of interpretation of the DCA for whole-body irradiation has significantly improved throughput without compromising accuracy, however, low levels of residual false positive dicentric chromosomes (DCs) have confounded its application for partial-body exposure determination.

Materials and methods: We describe a method of estimating and correcting for false positive DCs in digitally processed images of metaphase cells. Nearly all DCs detected in unirradiated calibration samples are introduced by digital image processing. DC frequencies of irradiated calibration samples and those exposed …

Estimating Partial Body Ionizing Radiation Exposure By Automated Cytogenetic Biodosimetry, Peter Rogan

Biochemistry Publications

Purpose: Inhomogeneous exposures to ionizing radiation can be detected and quantified with the Dicentric Chromosome Assay (DCA) of metaphase cells. Complete automation of interpretation of the DCA for whole body irradiation has significantly improved throughput without compromising accuracy, however low levels of residual false positive dicentric chromosomes (DCs) have confounded its application for partial body exposure determination.

Materials and Methods: We describe a method of estimating and correcting for false positive DCs in digitally processed images of metaphase cells. Nearly all DCs detected in unirradiated calibration samples are introduced by digital image processing. DC frequencies of irradiated calibration …

Machine Learning Approaches For Fracture Risk Assessment: A Comparative Analysis Of Genomic And Phenotypic Data In 5130 Older Men, Qing Wu, Fatma Nasoz, Jongyun Jung, Bibek Bhattarai, Mira V. Han

Public Health Faculty Publications

The study aims were to develop fracture prediction models by using machine learning approaches and genomic data, as well as to identify the best modeling approach for fracture prediction. The genomic data of Osteoporotic Fractures in Men, cohort Study (n = 5130), were analyzed. After a comprehensive genotype imputation, genetic risk score (GRS) was calculated from 1103 associated Single Nucleotide Polymorphisms for each participant. Data were normalized and split into a training set (80%) and a validation set (20%) for analysis. Random forest, gradient boosting, neural network, and logistic regression were used to develop prediction models for major osteoporotic fractures …

An Epistatic Interaction Between Pre-Natal Smoke Exposure And Socioeconomic Status Has A Significant Impact On Bronchodilator Drug Response In African American Youth With Asthma., J Magaña, M G Contreras, K L Keys, O Risse-Adams, P C Goddard, A M Zeiger, A C Y Mak, J R Elhawary, L A Samedy-Bates, E Lee, N Thakur, D Hu, C Eng, S Salazar, S Huntsman, T Hu, E G Burchard, M J White

Department of Medicine Faculty Papers

Background: Asthma is one of the leading chronic illnesses among children in the United States. Asthma prevalence is higher among African Americans (11.2%) compared to European Americans (7.7%). Bronchodilator medications are part of the first-line therapy, and the rescue medication, for acute asthma symptoms. Bronchodilator drug response (BDR) varies substantially among different racial/ethnic groups. Asthma prevalence in African Americans is only 3.5% higher than that of European Americans, however, asthma mortality among African Americans is four times that of European Americans; variation in BDR may play an important role in explaining this health disparity. To improve our understanding of disparate …

Acute Promyelocytic Leukemia: A Case Study Correlating Cytogenetic Abnormality With Prognosis, Alyssa Lamond, Theresa Tellier-Castellone

Senior Honors Projects

Advancements in medical technology today have positively impacted the diagnosis, treatment, and prognosis of cancers. Particularly acute promyelocytic leukemia (APL) has completely improved from having the poorest prognosis to one of the best. Acute promyelocytic leukemia is a malignant disease of hematopoietic tissue classified by WHO as leukemia with >20% blasts from the myeloid lineage, specifically promyelocytes. Determined in 1976, FAB classified AML subtypes M1-M7, with APL being M3. Specific characteristics classify the subtype of AML, with each resulting from a different genetic abnormality. The focus of APL diagnosis, treatment, and prognosis occurs around the known PML-RARα fusion gene. Flow …

Large-Scale Genome-Wide Meta-Analysis Of Polycystic Ovary Syndrome Suggests Shared Genetic Architecture For Different Diagnosis Criteria, Felix Day, Tugce Karaderi, Michelle R. Jones, Cindy Meun, Chunyan He, Alex Drong, Peter Kraft, Nan Lin, Hongyan Huang, Linda Broer, Reedik Magi, Richa Saxena, Triin Laisk, Margrit Urbanek, M. Geoffrey Hayes, Gudmar Thorleifsson, Juan Fernandez-Tajes, Anubha Mahajan, Benjamin H. Mullin, Bronwyn G. A. Stuckey, Timothy D. Spector, Scott G. Wilson, Mark O. Goodarzi, Lea Davis, Barbara Obermayer-Pietsch, André G. Uitterlinden, Verneri Anttila, Benjamin M. Neale, Marjo-Riitta Jarvelin, Bart Fauser

Internal Medicine Faculty Publications

Polycystic ovary syndrome (PCOS) is a disorder characterized by hyperandrogenism, ovulatory dysfunction and polycystic ovarian morphology. Affected women frequently have metabolic disturbances including insulin resistance and dysregulation of glucose homeostasis. PCOS is diagnosed with two different sets of diagnostic criteria, resulting in a phenotypic spectrum of PCOS cases. The genetic similarities between cases diagnosed based on the two criteria have been largely unknown. Previous studies in Chinese and European subjects have identified 16 loci associated with risk of PCOS. We report a fixed-effect, inverse-weighted-variance meta-analysis from 10,074 PCOS cases and 103,164 controls of European ancestry and characterisation of PCOS related …

Modeling And Analyzing An Optogenetic System For Photoactivatable Protein Dissociation, Anvin Thomas, James Schaff

Honors Scholar Theses

Computational modeling of cell-cell interactions can grant clues and can answer questions about an experiment, especially for observations about binding interactions and kinetics. This approach was used to investigate an interaction between a light-oxygen-voltage (LOV) domain and an engineered protein called Zdark (Zdk). The LOV domain is membrane-bound while Zdk is cytosolic. The LOV domain and Zdk bind strongly in dark (K_d 26.2 nM), and weakly upon exposure to blue light (K_d > 4 μM). Total internal reflection fluorescence (TIRF) images are acquired of Zdk, the fluorescent species bound to a mCherry tag, and the loss of fluorescence is …

Genetic Variants In Hsd17b3, Smad3, And Ipo11 Impact Circulating Lipids In Response To Fenofibrate In Individuals With Type 2 Diabetes, Daniel M. Rotroff, Sonja S. Pijut, Skylar W. Marvel, John R. Jack, Tammy M. Havener, Aurora Pujol, Agatha Schluter, Gregory A. Graf, Henry N. Ginsberg, Hetal S. Shah, He Gao, Mario-Luca Morieri, Alessandro Doria, Josyf C. Mychaleckyi, Howard L. Mcleod, John B. Buse, Michael J. Wagner, Alison A. Motsinger-Reif, Accord/Accordion Investigators

Pharmaceutical Sciences Faculty Publications

Individuals with type 2 diabetes (T2D) and dyslipidemia are at an increased risk of cardiovascular disease. Fibrates are a class of drugs prescribed to treat dyslipidemia, but variation in response has been observed. To evaluate common and rare genetic variants that impact lipid responses to fenofibrate in statin‐treated patients with T2D, we examined lipid changes in response to fenofibrate therapy using a genomewide association study (GWAS). Associations were followed‐up using gene expression studies in mice. Common variants in SMAD3 and IPO11 were marginally associated with lipid changes in black subjects (P < 5 × 10^‐6). Rare variant and gene expression changes …

In Silico Study Of Newly Synthesized Opioid Analgesics Bound To Three Opioid Receptors, Abdullah Allaoa, Mai Zahran

Publications and Research

Opioids are the most widely used drugs for the treatment of moderate to severe, chronic pain. They achieve antinociception by activation of mu (MOR-1), kappa (KOR-1), and delta (DOR-1) opioid receptors. Natural products found in kratom plant, Mitragyna speciosa, represent diverse chemical groups with opioid activity, providing opportunities to better understand opioid pharmacology. Pharmacology studies show that Mitragynine pseudoindoxyl is a mu agonist/delta antagonist opioid with a signaling bias for G-protein-mediated signaling pathways in vitro and which produced potent antinociception in vivo. Respiratory depression assays along with other behavioral testing also showed that some of the major problems …

The Genomic Cds Sandbox: An Assessment Among Domain Experts., Ayesha Aziz, Kensaku Kawamoto, Karen Eilbeck, Marc S Williams, Robert R Freimuth, Mark A Hoffman, Luke V Rasmussen, Casey L Overby, Brian H Shirts, James M Hoffman, Brandon M Welch

Manuscripts, Articles, Book Chapters and Other Papers

Genomics is a promising tool that is becoming more widely available to improve the care and treatment of individuals. While there is much assertion, genomics will most certainly require the use of clinical decision support (CDS) to be fully realized in the routine clinical setting. The National Human Genome Research Institute (NHGRI) of the National Institutes of Health recently convened an in-person, multi-day meeting on this topic. It was widely recognized that there is a need to promote the innovation and development of resources for genomic CDS such as a CDS sandbox. The purpose of this study was to evaluate …

Optimization Algorithms For Functional Deimmunization Of Therapeutic Proteins, Andrew S. Parker, Wei Zheng, Karl E. Griswold, Chris Bailey-Kellogg

Dartmouth Scholarship

To develop protein therapeutics from exogenous sources, it is necessary to mitigate the risks of eliciting an anti-biotherapeutic immune response. A key aspect of the response is the recognition and surface display by antigen-presenting cells of epitopes, short peptide fragments derived from the foreign protein. Thus, developing minimal-epitope variants represents a powerful approach to deimmunizing protein therapeutics. Critically, mutations selected to reduce immunogenicity must not interfere with the protein's therapeutic activity.

Desulfovibrio Desulfuricans G20 Tetraheme Cytochrome Structure At 1.5 A˚ And Cytochrome Interaction With Metal Complexes, Mrunalini Pattarkine, J J. Tanner, C A. Bottoms, Y H. Lee, Judy D. Wall

Faculty Works

The structure of the type I tetraheme cytochrome c3 from Desulfovibrio desulfuricans G20 was determined to 1.5 A˚ by X-ray crystallography. In addition to the oxidized form, the structure of the molybdate-bound form of the protein was determined from oxidized crystals soaked in sodium molybdate. Only small structural shifts were obtained with metal binding, consistent with the remarkable structural stability of this protein. In vitro experiments with pure cytochrome showed that molybdate could oxidize the reduced cytochrome, although not as rapidly as U(VI) present as uranyl acetate. Alterations in the overall conformation and thermostability of the metal-oxidized protein were investigated …

Studies On The Formation Of Dna-Cationic Lipid Composite Films And Dna Hybridization In The Composites, Murali Sastry, Vidya Ramakrishnan, Mrunalini Pattarkine, Krishna N. Ganesh

Faculty Works

The formation of composite films of double-stranded DNA and cationic lipid molecules (octadecylamine, ODA) and the hybridization of complementary single-stranded DNA molecules in such composite films are demonstrated. The immobilization of DNA is accomplished by simple immersion of a thermally evaporated ODA film in the DNA solution at close to physiological pH. The entrapment of the DNA molecules in the cationic lipid film is dominated by attractive electrostatic interaction between the negatively charged phosphate backbone of the DNA molecules and the protonated amine molecules in the thermally evaporated film and has been quantified using quartz crystal microgravimetry (QCM). Fluorescence studies …

Cationic Surfactant Mediated Hybridization And Hydrophobization Of Dna Molecules At The Liquid/Liquid Interface And Their Phase Transfer, Murali Sastry, Ashavani Kumar, Mrunalini Pattarkine, Vidya Ramakrishnan, Krishna N. Ganesh

Faculty Works

Hybridization of complementary oligonucleotides mediated by a cationic surfactant at the water/hexane interface leads to hydrophobic, double-helical DNA which may be readily phase transferred to the organic phase and cast into thin films on solid substrates.

Hybridization Of Dna By Sequential Immobilization Of Oligonucleotides At The Air-Water Interface, Murali Sastry, Vidya Ramakrishnan, Mrunalini Pattarkine, Anand Gole, K. N. Ganesh

Faculty Works

The hybridization of DNA by sequential electrostatic and hydrogen-bonding immobilization of single-stranded complementary oligonucleotides at the air-water interface with cationic Langmuir monolayers is demonstrated. The complexation of the single-stranded DNA molecules with octadecylamine (ODA) Langmuir monolayers was followed in time by monitoring the pressure-area isotherms. A large (and slow) expansion of the ODA monolayer was observed during each stage of complexation in the following sequence: primary single-stranded DNA followed by complementary single-stranded DNA followed by the intercalator, ethidium bromide. Langmuir-Blodgett (LB) films of the ODA-DNA complex were formed on different substrates and characterized using quartz-crystal microgravimetry (QCM), Fourier transform infrared …

A Simple Method For Generating Full Length Cdna From Low Abundance Partial Genomic Clones, Yongxin Wang, Joseph M. Fugaro, Fauzia Siddiq, Chandra Mouli V. Goparaju, Fulvio Lonardo, Anil Wali, John F. Lechner, Harvey I. Pass

Wayne State University Associated BioMed Central Scholarship

Abstract

Background

PCR amplification of target molecules involves sequence specific primers that flank the region to be amplified. While this technique is generally routine, its applicability may not be sufficient to generate a desired target molecule from two separate regions involving intron /exon boundaries. For these situations, the generation of full-length complementary DNAs from two partial genomic clones becomes necessary for the family of low abundance genes.

Results

The first approach we used for the isolation of full-length cDNA from two known genomic clones of Hox genes was based on fusion PCR. Here we describe a simple and efficient method …

Anion Induced Blue To Purple Transition In Bacteriorhodopsin, Mrunalini Pattarkine, Anil K. Singh

Faculty Works

Purple membrane (PM, λ" role="presentation">λmax" role="presentation">max 570 nm) of H. halobium on treatment with sulphuric acid changes its colour to blue (λ" role="presentation">λmax" role="presentation">max 608 nm). The purple chromophore can be regenerated from the blue chromophore by exogeneous addition of anions such as CI−" role="presentation">− and HPO42−" role="presentation">2−4. Chloride ion is found to be more effective than the dibasic phosphate ion in regenerating the purple chromophore. Nevertheless, one thing common to the anion regeneration is that both CI−" role="presentation">− and HPO42−" role="presentation">2−4 show marked pH effect. At pH 1.0 the efficiency of …