Digital Commons Network^™

Clonal Hematopoiesis Analyses In Clinical, Epidemiologic, And Genetic Aging Studies To Unravel Underlying Mechanisms Of Age-Related Dysfunction In Humans, Kenneth Walsh, Nalini Raghavachari, Candace Kerr, Alexander G Bick, Steven R Cummings, Todd Druley, Cynthia E Dunbar, Giulio Genovese, Margaret A Goodell, Siddhartha Jaiswal, Jaroslaw Maciejewski, Pradeep Natarajan, Anastasia V Shindyapina, Alan R Shuldiner, Erik B Van Den Akker, Jan Vijg

Faculty, Staff and Students Publications

Aging is characterized by increased mortality, functional decline, and exponential increases in the incidence of diseases such as cancer, stroke, cardiovascular disease, neurological disease, respiratory disease, etc. Though the role of aging in these diseases is widely accepted and considered to be a common denominator, the underlying mechanisms are largely unknown. A significant age-related feature observed in many population cohorts is somatic mosaicism, the detectable accumulation of somatic mutations in multiple cell types and tissues, particularly those with high rates of cell turnover (e.g., skin, liver, and hematopoietic cells). Somatic mosaicism can lead to the development of cellular clones that …

Targeting The Pro-Survival Protein Bcl-2 To Prevent Breast Cancer, Adelaide Young, Wen Bu, Weiyu Jiang, Amy Ku, Jyoti Kapali, Sagar Dhamne, Lan Qin, Susan G Hilsenbeck, Yi-Chieh Nancy Du, Yi Li

Faculty, Staff and Students Publications

Current chemopreventive strategies require 3-5 years of continuous treatment and have the concerns of significant side effects; therefore, new chemopreventive agents that require shorter and safer treatments are urgently needed. In this study, we developed a new murine model of breast cancer that mimics human breast cancer initiation and is ideal for testing the efficacy of chemopreventive therapeutics. In this model, introduction of lentivirus carrying a PIK3CA gene mutant commonly found in breast cancers infects a small number of the mammary cells, leading to atypia first and then to ductal carcinomas that are positive for both estrogen receptor and progesterone …

Nuclear Progesterone Receptor Expressed By The Cortical Thymic Epithelial Cells Dictates Thymus Involution In Murine Pregnancy, Soo Hyun Ahn, Sean L Nguyen, Tae Hoon Kim, Jae-Wook Jeong, Ripla Arora, John P Lydon, Margaret G Petroff

Faculty, Staff and Students Publications

Progesterone is a gonadal pro-gestational hormone that is absolutely necessary for the success of pregnancy. Most notable actions of progesterone are observed in the female reproductive organs, the uterus and the ovary. Acting through the nuclear progesterone receptor (PGR), progesterone prepares the endometrium for implantation of the embryo. Interestingly, the maternal thymus also is a known expressor of Pgr; its absence is associated with murine pregnancy complications. However, the localization of its expression and its functional importance were not known. Here, we used a transgenic dual fluorescent reporter mouse model and genetic deletion of Pgr in Foxn1+ thymic epithelial …

Rotavirus-Induced Lipid Droplet Biogenesis Is Critical For Virus Replication, Jeanette M Criglar, Mary K Estes, Sue E Crawford

Faculty, Staff and Students Publications

A variety of pathogens, including viruses, bacteria and parasites, target cellular lipid droplets for their replication. Rotaviruses (RVs) infect the villous epithelium of the small intestine and are a major cause of acute gastroenteritis in infants and young children worldwide. RVs induce and require lipid droplets for the formation of viroplasms, sites of virus genome replication, and nascent particle assembly. Here we review the role of lipid droplets in RV replication. Inhibitors of fatty acid synthesis or chemicals that interfere with lipid droplet homeostasis decrease the number and size of viroplasms and the yield of infectious virus. We used a …

Development Of Phage Cocktails To Treate Coli Catheter-Associated Urinary Tract Infection And Associated Biofilms, Belkys C Sanchez, Emmaline R Heckmann, Sabrina I Green, Justin R Clark, Heidi B Kaplan, Robert F Ramig, Casey Hines-Munson, Felicia Skelton, Barbara W Trautner, Anthony W Maresso

Faculty, Staff and Students Publications

High rates of antimicrobial resistance and formation of biofilms makes treatment of Escherichia coli catheter-associated urinary tract infections (CAUTI) particularly challenging. CAUTI affect 1 million patients per year in the United States and are associated with morbidity and mortality, particularly as an etiology for sepsis. Phage have been proposed as a potential therapeutic option. Here, we report the development of phage cocktails that lyse contemporary E. coli strains isolated from the urine of patients with spinal cord injury (SCI) and display strong biofilm-forming properties. We characterized E. coli phage against biofilms in two in vitro CAUTI models. Biofilm viability was …

Modified Vaccinia Ankara Expressing Eehv1a Glycoprotein B Elicits Humoral And Cell-Mediated Immune Responses In Mice, Taylor Pursell, Jennifer L Spencer Clinton, Jie Tan, Rongsheng Peng, Paul D Ling

Faculty, Staff and Students Publications

Elephant endotheliotropic herpesvirus (EEHV) can cause lethal hemorrhagic disease (EEHV-HD) in Asian elephants and is the largest cause of death in captive juvenile Asian elephants in North America and Europe. EEHV-HD also has been documented in captive and wild elephants in their natural range countries. A safe and effective vaccine to prevent lethal EEHV infection would significantly improve conservation efforts for this endangered species. Recent studies from our laboratory suggest that EEHV morbidity and mortality are often associated with primary infection. Therefore, we aim to generate a vaccine, particularly for EEHV1 naïve animals, with the goal of preventing lethal EEHV-HD. …

Meta-Analysis Comparing Outcomes Of High-Power Short-Duration And Low-Power Long-Duration Radiofrequency Ablation For Atrial Fibrillation, Dibbendhu Khanra, Abdul Hamid, Saurabh Deshpande, Anindya Mukherjee, Sanjiv Petkar, Mohammad Saeed, Indranill Basu-Ray

Faculty, Staff and Students Publications

OBJECTIVE: High power short duration (HPSD) ablation strategy is proposed to be more effective than low power long duration (LPLD) for radiofrequency ablation of atrial fibrillation. Although small trials abound, data from a large cohort are lacking. This meta-analysis compares all the existing studies comparing these two approaches to evaluate perceived advantages of one over the other.

METHODS: A systematic search of PubMed, EMBASE, and Cochrane databases identified studies comparing HPSD to LPLD ablation. All the analyses used the random-effects model.

RESULTS: Ablation settings varied widely across 20 studies comprising 2,136 patients who underwent HPSD and 1,753 patients who underwent …

Exercise-Induced Myokines Downregulates The Ace2 Level In Bronchial Epithelial Cells: Implications For Sars-Cov-2 Prevention, Vaishali Bhardwaj, Mart Dela Cruz, Deepika Subramanyam, Rohit Kumar, Sandeep Markan, Beth Parker, Hemant K Roy

Faculty, Staff and Students Publications

BACKGROUND: The Covid-19 pandemic has emerged as the leading public health challenge of our time (20th century). While vaccinations have finally blunted the death rate, concern has remained about more virulent forms highlighting the need for alternative approaches. Epidemiological studies indicate that physical activity has been shown to decrease the risk of infection of some respiratory viruses. Part of the salutary effects of exercise is believed to be through the elaboration of cytokines by contracting skeletal muscles (termed myokines). The objective of this study was to investigate whether exercise-induced myokines would mitigate the SARS-CoV-2 infectivity of the bronchial epithelium through …

Pcsk9 Inhibitors In The Management Of Cardiovascular Risk: A Practical Guidance, Xiaoming Jia, Mahmoud Al Rifai, Anum Saeed, Christie M Ballantyne, Salim S Virani

Faculty, Staff and Students Publications

Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors are potent medications in the toolkit for treatment of atherosclerotic cardiovascular disease. These agents have been well studied in clinical trials supporting their efficacy in dramatically reducing low-density lipoprotein cholesterol (LDL-C) and impact on cardiovascular outcomes. Since the approval of commercial use for PCSK9 inhibitors in 2015, we have also gained significant experience in the use of these therapeutics in the real-world setting. In this article, we review current guideline recommendations, clinical trial evidence on efficacy and safety as well as data on cost-effectiveness, prescription and adherence. We focus primarily on the monoclonal …

In Silico Integrative Analysis Of Multi-Omics Reveals Regulatory Layers For Diurnal Gene Expression In Mouse Liver, Chunjie Jiang, Panpan Liu, Cam Mong La, Dongyin Guan

Faculty, Staff and Students Publications

Diurnal oscillation persists throughout the body and plays an essential role in maintaining physiological homeostasis. Disruption of diurnal rhythm contributes to many diseases including type 2 diabetes. The regulatory mechanism of the transcription-translation feedback loop (TTFL) of core clock genes is well-established, while a systematic study across all regulatory layers of gene expression, including gene transcription, RNA translation, and DNA binding protein (DBP) activities, is still lacking. We comprehensively bioinformatics analyzed the rhythmicity of gene transcription, mature RNA abundance, protein abundance and DBP activity using publicly available omic-datasets from mouse livers. We found that the core clock genes,

Defining The Transcriptional Control Of Pediatric Aml Highlights Rara As A Superenhancer-Regulated Druggable Dependency, Monika W Perez, Oscar Sias-Garcia, Alfred Daramola, Helen Wei, Maci Terrell, Raushan Rashid, Woojun D Park, Kevin Duong, Terzah M Horton, Feng Li, Nikitha Cherayil, Jost Vrabic Koren, Vincent U Gant, Jacob J Junco, Choladda V Curry, Alexandra M Stevens, Charles Y Lin, Joanna S Yi

Faculty, Staff and Students Publications

Somatic mutations are rare in pediatric acute myeloid leukemia (pAML), indicating that alternate strategies are needed to identify targetable dependencies. We performed the first enhancer mapping of pAML in 22 patient samples. Generally, pAML samples were distinct from adult AML samples, and MLL (KMT2A)-rearranged samples were also distinct from non-KMT2A-rearranged samples. Focusing specifically on superenhancers (SEs), we identified SEs associated with many known leukemia regulators. The retinoic acid receptor alpha (RARA) gene was differentially regulated in our cohort, and a RARA-associated SE was detected in 64% of the study cohort across all cytogenetic and molecular subtypes tested. RARA SE+ pAML …

Intra-Tumoral Nerve-Tracing In A Novel Syngeneic Model Of High-Grade Serous Ovarian Carcinoma, Jeffrey L Barr, Allison Kruse, Anthony C Restaino, Natalia Tulina, Sarah Stuckelberger, Samuel J Vermeer, Caitlin S Williamson, Daniel W Vermeer, Marianna Madeo, Jillian Stamp, Maria Bell, Mark Morgan, Ju-Yoon Yoon, Marilyn A Mitchell, Anna Budina, Dalia K Omran, Lauren E Schwartz, Ronny Drapkin, Paola D Vermeer

Faculty, Staff and Student Publications

Dense tumor innervation is associated with enhanced cancer progression and poor prognosis. We observed innervation in breast, prostate, pancreatic, lung, liver, ovarian, and colon cancers. Defining innervation in high-grade serous ovarian carcinoma (HGSOC) was a focus since sensory innervation was observed whereas the normal tissue contains predominantly sympathetic input. The origin, specific nerve type, and the mechanisms promoting innervation and driving nerve-cancer cell communications in ovarian cancer remain largely unknown. The technique of neuro-tracing enhances the study of tumor innervation by offering a means for identification and mapping of nerve sources that may directly and indirectly affect the tumor microenvironment. …

Epigenome-Wide Association Study Of Serum Urate Reveals Insights Into Urate Co-Regulation And The Slc2a9 Locus, Adrienne Tin, Pascal Schlosser, Pamela R Matias-Garcia, Chris H L Thio, Roby Joehanes, Hongbo Liu, Zhi Yu, Antoine Weihs, Anselm Hoppmann, Franziska Grundner-Culemann, Josine L Min, Victoria L Halperin Kuhns, Adebowale A Adeyemo, Charles Agyemang, Johan Ärnlöv, Nasir A Aziz, Andrea Baccarelli, Murielle Bochud, Hermann Brenner, Jan Bressler, Monique M B Breteler, Cristian Carmeli, Layal Chaker, Josef Coresh, Tanguy Corre, Adolfo Correa, Simon R Cox, Graciela E Delgado, Kai-Uwe Eckardt, Arif B Ekici, Karlhans Endlich, James S Floyd, Eliza Fraszczyk, Xu Gao, Xīn Gào, Allan C Gelber, Mohsen Ghanbari, Sahar Ghasemi, Christian Gieger, Philip Greenland, Megan L Grove, Sarah E Harris, Gibran Hemani, Peter Henneman, Christian Herder, Steve Horvath, Lifang Hou, Mikko A Hurme, Shih-Jen Hwang, Sharon L R Kardia, Silva Kasela, Marcus E Kleber, Wolfgang Koenig, Jaspal S Kooner, Florian Kronenberg, Brigitte Kühnel, Christine Ladd-Acosta, Terho Lehtimäki, Lars Lind, Dan Liu, Donald M Lloyd-Jones, Stefan Lorkowski, Ake T Lu, Riccardo E Marioni, Winfried März, Daniel L Mccartney, Karlijn A C Meeks, Lili Milani, Pashupati P Mishra, Matthias Nauck, Christoph Nowak, Annette Peters, Holger Prokisch, Bruce M Psaty, Olli T Raitakari, Scott M Ratliff, Alex P Reiner, Ben Schöttker, Joel Schwartz, Sanaz Sedaghat, Jennifer A Smith, Nona Sotoodehnia, Hannah R Stocker, Silvia Stringhini, Johan Sundström, Brenton R Swenson, Joyce B J Van Meurs, Jana V Van Vliet-Ostaptchouk, Andrea Venema, Uwe Völker, Juliane Winkelmann, Bruce H R Wolffenbuttel, Wei Zhao, Yinan Zheng, Marie Loh, Harold Snieder, Melanie Waldenberger, Daniel Levy, Shreeram Akilesh, Owen M Woodward, Katalin Susztak, Alexander Teumer, Anna Köttgen

Faculty, Staff and Student Publications

Elevated serum urate levels, a complex trait and major risk factor for incident gout, are correlated with cardiometabolic traits via incompletely understood mechanisms. DNA methylation in whole blood captures genetic and environmental influences and is assessed in transethnic meta-analysis of epigenome-wide association studies (EWAS) of serum urate (discovery, n = 12,474, replication, n = 5522). The 100 replicated, epigenome-wide significant (p < 1.1E-7) CpGs explain 11.6% of the serum urate variance. At SLC2A9, the serum urate locus with the largest effect in genome-wide association studies (GWAS), five CpGs are associated with SLC2A9 gene expression. Four CpGs at SLC2A9 have significant causal effects on serum urate levels and/or gout, and two of these partly mediate the effects of urate-associated GWAS variants. In other genes, including SLC7A11 and PHGDH, 17 urate-associated CpGs are associated with conditions defining metabolic syndrome, suggesting that these CpGs may represent a blood DNA methylation signature of cardiometabolic risk factors. This study demonstrates that EWAS can provide new insights into GWAS loci and the correlation of serum urate with other complex traits.

Practical Considerations Of Dissolved Oxygen Levels For Platelet Function Under Hypoxia, Branden Kusanto, Andrew Gordon, Leigh Naylor-Adamson, Lloyd Atkinson, Charlie Coupland, Zoe Booth, Yusra Ahmed, Isabel M Pires, Graeme J Stasiuk, Roger Sturmey, Simon D J Calaminus, Mònica Arman

Faculty, Staff and Student Publications

Investigating human platelet function in low-oxygen environments is important in multiple settings, including hypobaric hypoxia (e.g., high altitude), sea level hypoxia-related disease, and thrombus stability. These studies often involve drawing blood from which platelets are isolated and analysed at atmospheric conditions or re-exposed to low oxygen levels in hypoxia chambers before testing. However, it remains unknown how the in vitro handling of the samples itself changes their dissolved oxygen concentration, which might affect platelet function and experimental results. Here, we prepared healthy donor platelet-rich plasma and washed platelet (WP) suspensions and exposed them to 2% oxygen. We found that the …

Hypothalamic Steroid Receptor Coactivator-2 Regulates Adaptations To Fasting And Overnutrition, Yongjie Yang, Yanlin He, Hailan Liu, Wenjun Zhou, Chunmei Wang, Pingwen Xu, Xing Cai, Hesong Liu, Kaifan Yu, Zhou Pei, Ilirjana Hyseni, Makoto Fukuda, Qingchun Tong, Jianming Xu, Zheng Sun, Bert W O'Malley, Yong Xu

Faculty, Staff and Students Publications

The neuroendocrine system coordinates metabolic and behavioral adaptations to fasting, including reducing energy expenditure, promoting counterregulation, and suppressing satiation and anxiety to engage refeeding. Here, we show that steroid receptor coactivator-2 (SRC-2) in pro-opiomelanocortin (POMC) neurons is a key regulator of all these responses to fasting. POMC-specific deletion of SRC-2 enhances the basal excitability of POMC neurons; mutant mice fail to efficiently suppress energy expenditure during food deprivation. SRC-2 deficiency blunts electric responses of POMC neurons to glucose fluctuations, causing impaired counterregulation. When food becomes available, these mutant mice show insufficient refeeding associated with enhanced satiation and discoordination of anxiety …

Synthesis, Structure-Activity Relationship And Antiviral Activity Of Indole-Containing Inhibitors Of Flavivirus Ns2b-Ns3 Protease, Shenyou Nie, Jidong Zhao, Xiaowei Wu, Yuan Yao, Fangrui Wu, Yi-Lun Lin, Xin Li, Alexander R Kneubehl, Megan B Vogt, Rebecca Rico-Hesse, Yongcheng Song

Faculty, Staff and Students Publications

Zika virus belongs to the Flavivirus family of RNA viruses, which include other important human pathogens such as dengue and West Nile virus. There are no approved antiviral drugs for these viruses. The highly conserved NS2B-NS3 protease of Flavivirus is essential for the replication of these viruses and it is therefore a drug target. Compound screen followed by medicinal chemistry optimization yielded a novel series of 2,6-disubstituted indole compounds that are potent inhibitors of Zika virus protease (ZVpro) with IC50 values as low as 320 nM. The structure-activity relationships of these and related compounds are discussed. Enzyme kinetics studies show …

Bi-Allelic Variants In Ogdhl Cause A Neurodevelopmental Spectrum Disease Featuring Epilepsy, Hearing Loss, Visual Impairment, And Ataxia, Zheng Yie Yap, Stephanie Efthymiou, Simone Seiffert, Karen Vargas Parra, Sukyeong Lee, Alessia Nasca, Reza Maroofian, Isabelle Schrauwen, Manuela Pendziwiat, Sunhee Jung, Elizabeth Bhoj, Pasquale Striano, Kshitij Mankad, Barbara Vona, Sanmati Cuddapah, Anja Wagner, Javeria Raza Alvi, Elham Davoudi-Dehaghani, Mohammad-Sadegh Fallah, Srinitya Gannavarapu, Costanza Lamperti, Andrea Legati, Bibi Nazia Murtaza, Muhammad Shahid Nadeem, Mujaddad Ur Rehman, Kolsoum Saeidi, Vincenzo Salpietro, Sarah Von Spiczak, Abigail Sandoval, Sirous Zeinali, Massimo Zeviani, Adi Reich, Synaps Study Group, University Of Washington Center For Mendelian Genomics, Cholsoon Jang, Ingo Helbig, Tahsin Stefan Barakat, Daniele Ghezzi, Suzanne M Leal, Yvonne Weber, Henry Houlden, Wan Hee Yoon

Faculty, Staff and Students Publications

The 2-oxoglutarate dehydrogenase-like (OGDHL) protein is a rate-limiting enzyme in the Krebs cycle that plays a pivotal role in mitochondrial metabolism. OGDHL expression is restricted mainly to the brain in humans. Here, we report nine individuals from eight unrelated families carrying bi-allelic variants in OGDHL with a range of neurological and neurodevelopmental phenotypes including epilepsy, hearing loss, visual impairment, gait ataxia, microcephaly, and hypoplastic corpus callosum. The variants include three homozygous missense variants (p.Pro852Ala, p.Arg244Trp, and p.Arg299Gly), three compound heterozygous single-nucleotide variants (p.Arg673Gln/p.Val488Val, p.Phe734Ser/p.Ala327Val, and p.Trp220Cys/p.Asp491Val), one homozygous frameshift variant (p.Cys553Leufs∗16), and one homozygous stop-gain variant (p.Arg440Ter). To support the …

Dietary Supplementation Of Bacillus-Based Probiotics On The Growth Performance, Gut Morphology, Intestinal Microbiota And Immune Response In Low Biosecurity Broiler Chickens, Mohammad Arif, Md Akteruzzaman, Tuhin-Al-Ferdous, Sk Shaheenur Islam, Bidhan Chandra Das, Mahbubul Pratik Siddique, S M Lutful Kabir

Faculty, Staff and Student Publications

A feeding trial was conducted to evaluate the effects of Bacillus-based probiotics on growth performance, intestinal histo-morphology, gut microbial population and immune response in broilers. A total of 2000 Hubbard Classic day-old chicks were randomly enrolled in four experimental groups and 4 replicates of 500 birds in each group, and reared for 35 days under a low- level of biosecurity measures. The trial groups were assigned treatment-1 (T1): basal diet(control), treatment-2 (T2): basal diet plus Bacillus licheniformis (DSM17236), treatment-3 (T3): basal diet plus Bacillus subtilis (PB6), and treatment-4 (T4) basal diet plus 4% Flavomycin. All four groups were fed …

Tavr In Older Adults: Moving Toward A Comprehensive Geriatric Assessment And Away From Chronological Age: Jacc Family Series, Joy M Schmitz, Scott D Lane, Michael F Weaver, Ponnada A Narayana, Khader M Hasan, Delisa D Russell, Robert Suchting, Charles E Green

Faculty, Staff and Student Publications

Cocaine use continues to be a significant public health problem with limited treatment options and no approved pharmacotherapies. Cognitive-behavioral therapy (CBT) remains the mainstay treatment for preventing relapse, however, people with chronic cocaine use display cognitive impairments that are associated with poor response to CBT. Emerging evidence in animal and human studies suggests that the peroxisome proliferator-activated receptor-gamma (PPAR- γ) agonist, pioglitazone, improves white matter integrity that is essential for cognitive function. This project will determine whether adjunctive use of pioglitazone enhances the effect of CBT in preventing relapse during the early phase of recovery from cocaine use disorder. This …

4d Ex Vivo Crispr/Cas9 Whole-Genome Screen To Identify Genes Regulating Lung Cancer Metastasis, Alexandria Plumer

Dissertations and Theses (Open Access)

Metastatic lung cancer has a 5-year survival rate of 5%. Lung cancers tend to be asymptomatic until late stages, and almost 90% are not diagnosed until they are advanced. Metastases are very rare events, often initiated by a single cell from a primary tumor into a new niche at a distant location. Investigation of the early metastatic process is of urgent need for the development of early diagnostics and targeted therapeutics. We performed a proof-of-concept CRISPR/Cas9 whole genome knockout screen in the A549 lung adenocarcinoma cell line and utilized a novel ex vivo 4D lung metastasis model to find gene …

Lgr5 Regulation Of Stat3 Signaling And Drug Resistance In Colorectal Cancer, Tressie Posey, Tressie Alexandra Posey

Dissertations and Theses (Open Access)

LGR5 Regulation of STAT3 Signaling and Drug Resistance in Colorectal Cancer

Tressie Alexandra Capri Posey B.S.

Advisory Professor: Kendra Carmon, Ph.D.

The greatest difficulty in treating colorectal cancer (CRC) is the development of drug resistance which leads to relapse after treatment and progression to metastasis. Cancer stem cells (CSCs) are believed to drive relapse because of their capacity to self-renew, acquire resistance mechanisms, and differentiate promoting tumor growth and heterogeneity. Leucine-rich repeat-containing G protein-coupled receptor 5 (LGR5), is a bona-fide marker of CSCs and has been considered a viable target for CSC specific therapeutic development. While we showed targeting LGR5 …

Transient Ascaris Suum Larval Migration Induces Intractable Chronic Pulmonary Disease And Anemia In Mice, Yifan Wu, Evan Li, Morgan Knight, Grace Adeniyi-Ipadeola, Li-Zhen Song, Alan R Burns, Ana Clara Gazzinelli-Guimaraes, Ricardo Fujiwara, Maria Elena Bottazzi, Jill E Weatherhead

Faculty, Staff and Students Publications

Ascariasis is one of the most common infections in the world and associated with significant global morbidity. Ascaris larval migration through the host's lungs is essential for larval development but leads to an exaggerated type-2 host immune response manifesting clinically as acute allergic airway disease. However, whether Ascaris larval migration can subsequently lead to chronic lung diseases remains unknown. Here, we demonstrate that a single episode of Ascaris larval migration through the host lungs induces a chronic pulmonary syndrome of type-2 inflammatory pathology and emphysema accompanied by pulmonary hemorrhage and chronic anemia in a mouse model. Our results reveal that …

5-Ht Recruits Distinct Neurocircuits To Inhibit Hunger-Driven And Non-Hunger-Driven Feeding, Yanlin He, Xing Cai, Hailan Liu, Krisitine M Conde, Pingwen Xu, Yongxiang Li, Chunmei Wang, Meng Yu, Yang He, Hesong Liu, Chen Liang, Tingting Yang, Yongjie Yang, Kaifan Yu, Julia Wang, Rong Zheng, Feng Liu, Zheng Sun, Lora Heisler, Qi Wu, Qingchun Tong, Canjun Zhu, Gang Shu, Yong Xu

Children’s Nutrition Research Center Staff Publications

Obesity is primarily a consequence of consuming calories beyond energetic requirements, but underpinning drivers have not been fully defined. 5-Hydroxytryptamine (5-HT) neurons in the dorsal Raphe nucleus (5-HTDRN) regulate different types of feeding behavior, such as eating to cope with hunger or for pleasure. Here, we observed that activation of 5-HTDRN to hypothalamic arcuate nucleus (5-HTDRN → ARH) projections inhibits food intake driven by hunger via actions at ARH 5-HT2C and 5-HT1B receptors, whereas activation of 5-HTDRN to ventral tegmental area (5-HTDRN → VTA) projections inhibits non-hunger-driven feeding via actions at 5-HT2C receptors. Further, hunger-driven feeding gradually activates ARH-projecting 5-HTDRN …

Intermittent Bolus Feeding Does Not Enhance Protein Synthesis, Myonuclear Accretion, Or Lean Growth More Than Continuous Feeding In A Premature Piglet Model, Marko Rudar, Jane K Naberhuis, Agus Suryawan, Hanh V Nguyen, Barbara Stoll, Candace C Style, Mariatu A Verla, Oluyinka O Olutoye, Douglas G Burrin, Marta L Fiorotto, Teresa A Davis

Children’s Nutrition Research Center Staff Publications

Optimizing enteral nutrition for premature infants may help mitigate extrauterine growth restriction and adverse chronic health outcomes. Previously, we showed in neonatal pigs born at term that lean growth is enhanced by intermittent bolus compared with continuous feeding. The objective was to determine if prematurity impacts how body composition, muscle protein synthesis, and myonuclear accretion respond to feeding modality. Following preterm delivery, pigs were fed equivalent amounts of formula delivered either as intermittent boluses (INT; n = 30) or continuously (CONT; n = 14) for 21 days. Body composition was measured by dual-energy X-ray absorptiometry (DXA) and muscle growth was …

Stat3 Inhibits Type I Interferon Signaling In Type I Conventional Dendritic Cells, Taylor Chrisikos

Dissertations and Theses (Open Access)

Conventional dendritic cells (cDCs) are an essential immune population, responsible for controlling adaptive immunity and tolerance. Recently, type I cDCs (cDC1s) have been delineated as a distinct cDC subset, uniquely responsible for coordinating T cell-mediated immunity against pathogens and tumors. Although the importance of cDC1s is now well established, the mechanisms that regulate cDC1 function remain largely unknown. Signal Transducer and Activator of Transcription 3 (STAT3) mediates the intracellular signaling of interleukin 10 (IL-10), an immunosuppressive cytokine. Therefore, we hypothesized that STAT3 and IL-10 inhibit cDC1 function and induction of T cell-mediated immunity. Herein, we show that IL-10 inhibits polyinosinic:polycytidylic …

Cross-Seeding Potential Of Misfolded Amyloid-Beta Strains On Tau Protein: Examining The Puzzle Pieces Of Alzheimer's Disease, Sara Kelley

Dissertations and Theses (Open Access)

Alzheimer’s disease (AD) is a neurodegenerative disorder that will progressively impair cognitive function. AD is the leading source of dementia, and affects one third of the senior citizens in the United States. Aging is the primary risk factor for AD and due to the expected rise in human lifespan worldwide, the occurrence rate of AD diagnosis is projected to increase. This observation is increasingly alarming when considering there is no treatment for reversal or prevention of AD yet.

AD is characterized by gross pathological hallmarks in the brain. These include the extracellular accumulation of misfolded amyloid-beta (Aβ) and the intraneuronal …

Deciphering The Role Of Hsp110 Chaperones In Diseases Of Protein Misfolding, Unekwu M. Yakubu

Dissertations and Theses (Open Access)

Molecular chaperones maintain protein homeostasis (proteostasis) by ensuring the proper folding of polypeptides. Loss of proteostasis has been linked to the onset of numerous neurodegenerative disorders including Alzheimer’s, Parkinson’s, and Huntington’s disease. Hsp110 is a member of the Hsp70 class of molecular chaperones and acts as a nucleotide exchange factor (NEF) for Hsp70, the preeminent Hsp70-family protein folding chaperone. Hsp110 promotes rapid cycling of ADP for ATP, allowing Hsp70 to properly fold nascent or unfolded polypeptides in iterative cycles. In addition to its NEF activity, Hsp110 possesses an Hsp70-like substrate binding domain (SBD) whose biological roles are undefined. Previous work …

Pre-Exposure Prophylaxis With Various Doses Of Hydroxychloroquine Among Healthcare Personnel With High-Risk Exposure To Covid-19: A Randomized Controlled Trial, Fibhaa Syed, Muhammad Hassan, Mohammad Ali Arif, Sadia Batool, Rauf Niazi, Ume E Laila, Sadia Ashraf, Junaid Arshad

Faculty, Staff and Student Publications

Objective This trial aimed to evaluate the safety and efficacy of pre-exposure prophylaxis (PrEP) with various hydroxychloroquine (HCQ) doses against a placebo among healthcare personnel (HCP) with high-risk exposure to coronavirus disease 2019 (COVID 19). Methods A phase II, randomized, placebo-controlled trial was conducted including 200 subjects with no active or past severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (antibody testing and reverse transcription-polymerase chain reaction (RT-PCR) were taken at the time of enrollment). Subjects of experimental groups one to three received HCQ in various doses and the control group received a placebo. The study outcomes in terms of …

Interaction Between Alcohol Consumption And Pnpla3 Variant In The Prevalence Of Hepatic Steatosis In The Us Population, Mariana Lazo, Usama Bilal, Mack C Mitchell, James Potter, Ruben Hernaez, Jeanne M Clark

Faculty, Staff and Students Publications

BACKGROUND & AIMS: To our knowledge, the interaction between alcohol consumption and PNPLA3 genotype on hepatic steatosis has not been explored in a representative sample. To examine the interaction between alcohol consumption and PNPLA3 genotype on hepatic steatosis in the US adult population.

METHODS: Cross-sectional study of 4,674 adult participants of the Third National Health and Nutrition Examination Survey, Phase 2 (1991-1994) with data on PNPLA3 genotype, self-reported alcohol consumption, ultrasound-defined hepatic steatosis and socio-demographic characteristics.

RESULTS: In 1991-1994 in the U.S. population, the weighted allele frequency of the G (risk) allele of the rs738409 at PNPLA3 was 25.4%. We …

The Cross-Sectional Association Of Cognition With Diabetic Peripheral And Autonomic Neuropathy–The Grade Study, Joshua I Barzilay, Alokananda Ghosh, Rodica Pop Busui, Andrew Ahmann, Ashok Balasubramanyam, Mary Ann Banerji, Robert M Cohen, Jennifer Green, Faramarz Ismail-Beigi, Catherine L Martin, Elizabeth Seaquist, José A Luchsinger, Grade Research Group

Faculty, Staff and Students Publications

BACKGROUND: Studies examining whether measures of cognition are related to the presence of diabetic peripheral neuropathy (DPN) and/or cardiovascular autonomic neuropathy (CAN) are lacking, as are data regarding factors potentially explaining such associations.

METHODS: Participants were from the Glycemia Reduction Approaches in Diabetes Study (GRADE) that examined 5047 middle-aged people with type 2 diabetes of(memory) were assessed with the Spanish English Verbal Learning Test; frontal executive function and processing speed with the Digit Symbol Substitution Test; and ability to concentrate and organize data with word and animal fluency tests. DPN was assessed with the Michigan Neuropathy Screening Instrument and CAN …