Genetics and Genomics Commons^™

Enhanced Bypass Of Pd-L1 Translation Reduces The Therapeutic Response To Mtor Kinase Inhibitors, Yanan Cao, Qing Ye, Murong Ma, Qing-Bai She

Markey Cancer Center Faculty Publications

Increased PD-L1 expression in cancer cells is known to enhance immunosuppression, but the mechanism underlying PD-L1 upregulation is incompletely characterized. We show that PD-L1 expression is upregulated through internal ribosomal entry site (IRES)-mediated translation upon mTORC1 inhibition. We identify an IRES element in the PD-L1 50-UTR that permits cap-independent translation and promotes continuous production of PD-L1 protein despite effective inhibition of mTORC1. eIF4A is found to be a key PD-L1 IRES-binding protein that enhances PD-L1 IRES activity and protein production in tumor cells treated with mTOR kinase inhibitors (mTORkis). Notably, treatment with mTORkis in vivo elevates PD-L1 levels and reduces …

Exploring The Interactions Between Sars-Cov-2 And Host Proteins, Sojan Shrestha

School of Biological Sciences: Dissertations, Theses, and Student Research

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of the current pandemic, Coronavirus Disease 2019 (COVID-19). SARS-CoV-2 is considered to be of zoonotic origin; it originated in non-human animals and was transmitted to humans. Since the early stage of the pandemic, however, the evidence of transmissions from humans to animals (reverse zoonoses) has been found in multiple animal species including mink, white-tailed deer, and pet and zoo animals. Furthermore, secondary zoonotic events of SARS-CoV-2, transmissions from animals to humans, have been also reported. It is suggested that non-human hosts can act as SARS-CoV-2 reservoirs where accumulated …

Mid-Gestation Maternofetal Inflammation Impacts Growth, Skeletal Muscle Glucose Metabolism, And Inflammatory Tone In The Ovine Fetus During Late Gestation, Zena Mariah Hicks

Department of Animal Science: Dissertations, Theses, and Student Research

Our 1^st and 2^nd studies assessed the impact of mid-gestation maternofetal inflammation on growth, skeletal muscle glucose metabolism, and inflammatory tone in the late gestation ovine fetus. The objective was to determine if inducing maternofetal inflammation during peak placental growth would lead to more profound IUGR characteristics in the fetus. MI-IUGR fetuses exhibited reduced body and skeletal muscle weights and hallmark asymmetric growth at late gestations. Fetuses had higher baseline glucose:insulin ratios and reduced glucose-stimulated insulin secretion. Moreover, hindlimb glucose oxidation was impaired independent of glucose uptake. Skeletal muscle specific glucose uptake and oxidation was reduced in MI-IUGR …

The Time-Course Of Cancer Cachexia Onset Reveals Biphasic Transcriptional Disruptions In Female Skeletal Muscle Distinct From Males, Francielly Morena, Seongkyun Lim, Ana Regina Cabrera, Eleanor R. Schrems, Ronald G. Jones, Megan E. Rosa-Caldwell, Tyrone A. Washington, Kevin A. Murach, Nicholas P. Greene

Health, Human Performance and Recreation Faculty Publications and Presentations

Background

Cancer-cachexia (CC) is a debilitating condition affecting up to 80% of cancer patients and contributing to 40% of cancer-related deaths. While evidence suggests biological sex differences in the development of CC, assessments of the female transcriptome in CC are lacking, and direct comparisons between sexes are scarce. This study aimed to define the time course of Lewis lung carcinoma (LLC)-induced CC in females using transcriptomics, while directly comparing biological sex differences.

Results

We found the global gene expression of the gastrocnemius muscle of female mice revealed biphasic transcriptomic alterations, with one at 1 week following tumor allograft and another …

Genome-Wide Association Study Of Thoracic Aortic Aneurysm And Dissection In The Million Veteran Program, Derek Klarin, Poornima Devineni, Anoop K Sendamarai, Anthony R Angueira, Sarah E Graham, Ying H Shen, Michael G Levin, James P Pirruccello, Ida Surakka, Purushotham R Karnam, Tanmoy Roychowdhury, Yanming Li, Minxian Wang, Krishna G Aragam, Kaavya Paruchuri, Verena Zuber, Gabrielle E Shakt, Noah L Tsao, Renae L Judy, Ha My T Vy, Shefali S Verma, Daniel J Rader, Ron Do, Joseph E Bavaria, Girish N Nadkarni, Marylyn D Ritchie, Stephen Burgess, Dong-Chuan Guo, Patrick T Ellinor, Scott A Lemaire, Dianna M Milewicz, Cristen J Willer, Pradeep Natarajan, Philip S Tsao, Saiju Pyarajan, Scott M Damrauer

Faculty, Staff and Student Publications

The current understanding of the genetic determinants of thoracic aortic aneurysms and dissections (TAAD) has largely been informed through studies of rare, Mendelian forms of disease. Here, we conducted a genome-wide association study (GWAS) of TAAD, testing ~25 million DNA sequence variants in 8,626 participants with and 453,043 participants without TAAD in the Million Veteran Program, with replication in an independent sample of 4,459 individuals with and 512,463 without TAAD from six cohorts. We identified 21 TAAD risk loci, 17 of which have not been previously reported. We leverage multiple downstream analytic methods to identify causal TAAD risk genes and …

Pdcl2 Is Essential For Sperm Acrosome Formation And Male Fertility In Mice, Yoshitaka Fujihara, Kiyonori Kobayashi, Ferheen Abbasi, Tsutomu Endo, Zhifeng Yu, Masahito Ikawa, Martin M Matzuk

Faculty, Staff and Students Publications

BACKGROUND: Each year, infertility affects 15% of couples worldwide, with 50% of cases attributed to men. Globozoospermia is an uncommon cause of male factor infertility, characterized by defects in sperm acrosome formation, leading to round-headed spermatozoa.

OBJECTIVE: We generated Pdcl2 knockout mice to investigate the essential roles of PDCL2 in mammalian reproduction.

MATERIALS AND METHODS: We used reverse transcription-polymerase chain reaction to demonstrate that PDCL2 was expressed exclusively in the male reproductive tract in mice and humans. We created Pdcl2 knockout mice using the CRISPR-Cas9 system and analyzed their fertility. Pdcl2 null spermatozoa underwent further evaluation using computer-assisted sperm analysis, …

Remote Neuronal Activity Drives Glioma Progression Through Sema4f, Emmet Huang-Hobbs, Yi-Ting Cheng, Yeunjung Ko, Estefania Luna-Figueroa, Brittney Lozzi, Kathryn R Taylor, Malcolm Mcdonald, Peihao He, Hsiao-Chi Chen, Yuhui Yang, Ehson Maleki, Zhung-Fu Lee, Sanjana Murali, Michael R Williamson, Dongjoo Choi, Rachel Curry, James Bayley, Junsung Woo, Ali Jalali, Michelle Monje, Jeffrey L Noebels, Akdes Serin Harmanci, Ganesh Rao, Benjamin Deneen

Faculty, Staff and Students Publications

The tumor microenvironment (TME) plays an essential role in malignancy and neurons have emerged as a key component of the TME that promotes tumorigenesis across a host of cancers1,2. Recent studies on glioblastoma (GBM) highlight bi-directional signaling between tumors and neurons that propagates a vicious cycle of proliferation, synaptic integration, and brain hyperactivity3-8; however, the identity of neuronal subtypes and tumor subpopulations driving this phenomenon are incompletely understood. Here we show that callosal projection neurons located in the hemisphere contralateral to primary GBM tumors promote progression and widespread infiltration. Using this platform …

Atoh1 Drives The Heterogeneity Of The Pontine Nuclei Neurons And Promotes Their Differentiation, Sih-Rong Wu, Jessica C Butts, Matthew S Caudill, Jean-Pierre Revelli, Ryan S Dhindsa, Mark A Durham, Huda Y Zoghbi

Faculty, Staff and Students Publications

Pontine nuclei (PN) neurons mediate the communication between the cerebral cortex andthe cerebellum to refine skilled motor functions. Prior studies showed that PN neurons fall into two subtypes based on their anatomic location and region-specific connectivity, but the extent of their heterogeneity and its molecular drivers remain unknown. Atoh1 encodes a transcription factor that is expressed in the PN precursors. We previously showed that partial loss of Atoh1 function in mice results in delayed PN development and impaired motor learning. In this study, we performed single-cell RNA sequencing to elucidate the cell state–specific functions of Atoh1 during PN development and …

Immune Cells Localize To Sites Of Corneal Erosions In C57bl/6 Mice., Phuong M. Le, Sonali Pal-Ghosh, A. Menko, Mary Ann Stepp

Computational Medicine Center Faculty Papers

Recurrent epithelial erosions develop in the cornea due to prior injury or genetic predisposition. Studies of recurrent erosions in animal models allow us to gain insight into how erosions form and are resolved. While slowing corneal epithelial cell migration and reducing their proliferation following treatment with mitomycin C reduce erosion formation in mice after sterile debridement injury, additional factors have been identified related to cytokine expression and immune cell activation. The relationship between recruitment of immune cells to the region of the cornea where erosions form and their potential roles in erosion formation and/or erosion repair remains unexplored in the …

Regulation Of The Wnt/Wingless Receptor Lrp6/Arrow By The Deubiquitylating Complex Usp46, Zachary T. Spencer

Dartmouth College Ph.D Dissertations

The evolutionarily conserved Wnt/Wingless signal transduction pathway is critical for the proper development of all animals and implicated in numerous diseases in adulthood. Upon binding of the Wnt/Wingless ligand, a cascade of events culminates in inactivation of the destruction complex, a negative regulator of the pathway, and the subsequent formation of singalosomes which mediate pathway activation. A critical component of signalosome formation is the Wnt/Wingless receptor LRP6/Arrow. Upon canonical pathway activation, LRP6/Arrow undergoes activation via phosphorylation by several kinases and complexes with another Wnt/Wingless receptor Frizzled, along with several cytoplasmic components. While many studies have investigated the regulatory mechanisms of …

The Pros Of Changing Trna Identity, Michael Ibba

Biology, Chemistry, and Environmental Sciences Faculty Articles and Research

The notion that errors in protein synthesis are universally harmful to the cell has been questioned by findings that suggest such mistakes may sometimes be beneficial. However, how often these beneficial mistakes arise from programmed changes in gene expression as opposed to reduced accuracy of the translation machinery is still unclear. A new study published in JBC shows that some bacteria have beneficially evolved the ability to mistranslate specific parts of the genetic code, a trait that allows improved antibiotic resistance.

Novel Genetic Interactions Of The Sgs1 Helicase In The Maintenance Of Genome Integrity, Sonia Vidushi Gupta

USF Tampa Graduate Theses and Dissertations

Mutagenesis and genome instability are characteristics of cancer cells. People afflictedwith Bloom’s syndrome due to mutations in the BLM gene suffer from reduced life expectancy, accelerated aging, sensitivity to sun exposure, immune system abnormalities and increased risk of cancer. The predisposition to cancer is typically due to abnormal DNA repair that results in chromosome breakage and rearrangements. The homologous recombination factor Sgs1, which is a RecQ-like helicase and an ortholog of the human BLM helicase, functions primarily in DNA repair, but has also been implicated in other cellular functions like replication. Several functions of BLM such as its involvement in …

Drugging Evolution Of Antibiotic Resistance At A Regulatory Network Hub, Yin Zhai, John P Pribis, Sean W Dooling, Libertad Garcia-Villada, P J Minnick, Jun Xia, Jingjing Liu, Qian Mei, Devon M Fitzgerald, Christophe Herman, P J Hastings, Mauro Costa-Mattioli, Susan M Rosenberg

Faculty, Staff and Students Publications

Evolution of antibiotic resistance is a world health crisis, fueled by new mutations. Drugs to slow mutagenesis could, as cotherapies, prolong the shelf-life of antibiotics, yet evolution-slowing drugs and drug targets have been underexplored and ineffective. Here, we used a network-based strategy to identify drugs that block hubs of fluoroquinolone antibiotic-induced mutagenesis. We identify a U.S. Food and Drug Administration- and European Medicines Agency-approved drug, dequalinium chloride (DEQ), that inhibits activation of the

Diversity And Dispersal Among Eastern Continental Divide Headwater Stream Fishes In Gwinnett County, Georgia., James E. Russell, Molly M. Botting, Ryan M. Davenport, Emilee J. Story, Mark Patterson

Georgia Journal of Science

The eastern continental divide that bisects Georgia runs through Gwinnett County, separating headwater streams of the western Chattahoochee River watershed from headwater streams of the eastern Ocmulgee and Oconee River watersheds. This landscape feature was used to test hypotheses regarding headwater habitat, fish diversity and gene flow. Headwater habitats are dominant components of river network ecosystems delivering vital ecosystem services and biodiversity. Three headwater streams, one in the Chattahoochee watershed and two in the Oconee watershed, on Gwinnett County Park property, were sampled for differences in physical and chemical properties and fish inter- and intraspecific diversity. Our results suggest the …

Tumor Biology And Immune Infiltration Define Primary Liver Cancer Subsets Linked To Overall Survival After Immunotherapy, Anuradha Budhu, Erica C Pehrsson, Aiwu He, Lipika Goyal, Robin Kate Kelley, Hien Dang, Changqing Xie, Cecilia Monge, Mayank Tandon, Lichun Ma, Mahler Revsine, Laura Kuhlman, Karen Zhang, Islam Baiev, Ryan Lamm, Keyur Patel, David E Kleiner, Stephen M Hewitt, Bao Tran, Jyoti Shetty, Xiaolin Wu, Yongmei Zhao, Tsai-Wei Shen, Sulbha Choudhari, Yuliya Kriga, Kris Ylaya, Andrew C Warner, Elijah F Edmondson, Marshonna Forgues, Tim F Greten, Xin Wei Wang

Kimmel Cancer Center Faculty Papers

Primary liver cancer is a rising cause of cancer deaths in the US. Although immunotherapy with immune checkpoint inhibitors induces a potent response in a subset of patients, response rates vary among individuals. Predicting which patients will respond to immune checkpoint inhibitors is of great interest in the field. In a retrospective arm of the National Cancer Institute Cancers of the Liver: Accelerating Research of Immunotherapy by a Transdisciplinary Network (NCI-CLARITY) study, we use archived formalin-fixed, paraffin-embedded samples to profile the transcriptome and genomic alterations among 86 hepatocellular carcinoma and cholangiocarcinoma patients prior to and following immune checkpoint inhibitor treatment. …

Influence Of Maternal Dietary Protein Precursor On Reproductive Endocrinology Of Neonatal Bovine Offspring, Jennifer F. Thorson, Ligia D. Prezotto

Department of Animal Science: Faculty Publications

Bovine oogenesis and follicular maturation are initiated during in utero development, a process that is stringently orchestrated by the endocrine milieu. Of paramount importance are the three major biologically active estrogens: estron, estradiol, and estriol that are involved in the development and maintenance of germ cells. Previous work using the current model have revealed that maternal urea (protein precursor) supplementation reduces the ovarian follicular reserve without compromising the number of secondary and tertiary follicles. Therefore, we did not anticipate an influence of dietary treatment on biologically active estrogens. However, as the ovarian reserve is positively associated with circulating concentrations of …

Mineral Composition Of Serially Slaughtered Holstein Steers Supplemented With Zilpaterol Hydrochloride, Andrea K. Watson, Trent J. Mcevers, Lee-Anne J. Walter, Nathan D. May, Jacob A. Reed, J. C. Macdonald, Galen E. Erickson, N. Andy Cole, Johnjohn P. Hutcheson, Ty E. Lawrence

Department of Animal Science: Faculty Publications

Calf-fed Holstein steers (n = 115; 449 ± 20 kg) were utilized in a serial harvest experiment. A baseline group of five steers was harvested after 226 d on feed (DOF), which was designated day 0. The remaining cattle were assigned randomly to 11 harvest groups, with slaughter every 28 d. Cattle were either not (CON) or were fed zilpaterol hydrochloride for 20 d followed by a 3 d withdrawal (ZH). There were five steers per treatment in each slaughter group ranging from days 28 to 308. Whole carcasses were divided into lean, …

A Short History Of The Holmes County, Ohio, Amish Directory And Genetics Research, Harold Cross

Journal of Amish and Plain Anabaptist Studies

In this first-hand account, Harold “Hal” Cross, a researcher instrumental in the dawning of Amish genetic/demographic studies, recounts his memories of early projects and the development of the first Amish directories. Interest in Amish genetics emerged in the 1960s, as Cross, then a graduate student at Johns Hopkins University School of Medicine, informed Victor A McKusick, Professor of Medicine, about the potential for studying genetic disease among the Amish. Cross, working under McKusick’s direction, then collaborated with Amishman Ervin Gingerich of Holmes County, OH, in completing the first full-size household-level Amish directory in 1965. The effort was financed in part …

Atomistic Assessment Of Drug-Phospholipid Interactions Consequent To Cancer Treatment: A Study Of Anthracycline Cardiotoxicity, Yara Elsayed Ahmed

Theses and Dissertations

Despite being one of the most effective chemotherapeutic agents developed to date, Anthracyclines are notorious for their cardiotoxicity. Their clinical use is frequently limited both in dosage and in prescription due to the severe cardiac damage they cause. The mechanism of anthracycline-induced cardiotoxicity is not yet fully understood. However, it is hypothesized that interactions with the myocardial membrane play an important role in imparting cardiotoxicity. In this study, we use molecular dynamics simulations and density functional theory calculations to study the anthracycline drug molecules and the interactions that they have with the myocardial membrane. We construct a myocardial membrane model …

Genetic Considerations For The Conservation Of The Red Junglefowl, Courtney Lee Mcpheron

University Honors Theses

The undomesticated wild populations of our domestic species deserve heightened consideration when it comes to their conservation. Not only do they carry significant socio-cultural and economic roles, but they offer an exceptionally unique case study for population genetics. The red junglefowl (Gallus gallus) of southern and south-eastern Asia is considered to be the living ancestor and progenitor of the domestic chicken. This literature review examines how published research has evaluated its genetic relationship with the chicken and implications for its conservation. A special emphasis is given to the threat of genetic introgression with domestic and feral chicken populations …