Biological Phenomena, Cell Phenomena, and Immunity Commons^™

Proteome Analysis For Inflammation Related To Acute And Convalescent Infection, Tara K Sigdel, Swastika Sur, Patrick Boada, Suzanne M Mcdermott, Cecilia S Lindestam Arlehamn, Kristy O Murray, Linda K Bockenstedt, Maggie Kerwin, Elaine F Reed, Eva Harris, Ken Stuart, Bjoern Peters, Ana Sesma, Ruth R Montgomery, Minnie M Sarwal

Faculty, Staff and Students Publications

Infectious diseases are a significant burden in global healthcare. Pathogens engage with different host defense mechanisms. However, it is currently unknown if there are disease-specific immune signatures and/or if different pathogens elicit common immune-associated molecular entities to common therapeutic interventions. We studied patients enrolled through the Human Immunology Project Consortium (HIPC), which focuses on immune responses to various infections. Blood samples were collected and analyzed from patients during infection and follow-up time points at the convalescent stage. The study included samples from patients with Lyme disease (LD), tuberculosis (TB), malaria (MLA), dengue virus (DENV), and West Nile virus (WNV), as …

Expression Of Atoh1, Gfi1, And Pou4f3 In The Mature Cochlea Reprograms Nonsensory Cells Into Hair Cells, Melissa M Mcgovern, Ishwar V Hosamani, Yichi Niu, Ken Y Nguyen, Chenghang Zong, Andrew K Groves

Faculty, Staff and Students Publications

Mechanosensory hair cells of the mature mammalian organ of Corti do not regenerate; consequently, loss of hair cells leads to permanent hearing loss. Although nonmammalian vertebrates can regenerate hair cells from neighboring supporting cells, many humans with severe hearing loss lack both hair cells and supporting cells, with the organ of Corti being replaced by a flat epithelium of nonsensory cells. To determine whether the mature cochlea can produce hair cells in vivo, we reprogrammed nonsensory cells adjacent to the organ of Corti with three hair cell transcription factors: Gfi1, Atoh1, and Pou4f3. We generated numerous hair cell–like …

Systematic Review Of Mortality And Survival Rates For Apds, Jennifer Hanson, Penelope E Bonnen

Faculty, Staff and Students Publications

Activated phosphoinositide 3-kinase delta syndrome (APDS) is a rare genetic disorder that presents clinically as a primary immunodeficiency. Clinical presentation of APDS includes severe, recurrent infections, lymphoproliferation, lymphoma, and other cancers, autoimmunity and enteropathy. Autosomal dominant variants in two independent genes have been demonstrated to cause APDS. Pathogenic variants in PIK3CD and PIK3R1, both of which encode components of the PI3-kinase, have been identified in subjects with APDS. APDS1 is caused by gain of function variants in the PIK3CD gene, while loss of function variants in PIK3R1 have been reported to cause APDS2. We conducted a review of the medical …

Genetics And Pathologic Landscape Of Lineage Switch Of Acute Leukemia During Therapy, Ting Zhou, Choladda V Curry, Mahsa Khanlari, Min Shi, Wei Cui, Deniz Peker, Weina Chen, Endi Wang, Juehua Gao, Qi Shen, Wei Xie, Fatima Z Jelloul, Rebecca L King, Ji Yuan, Xiaoqiong Wang, Chen Zhao, Ifeyinwa E Obiorah, Elizabeth L Courville, Eric Nomura, Sindhu Cherian, Mina L Xu, W Richard Burack, Hong-Xing Liu, Elias J Jabbour, Koichi Takahashi, Wei Wang, Sa A Wang, Joseph D Khoury, L Jeffrey Medeiros, Shimin Hu

Faculty, Staff and Students Publications

No abstract provided.

Virology-The Path Forward, Angela L Rasmussen, Gigi K Gronvall, Anice C Lowen, Felicia Goodrum, James Alwine, Kristian G Andersen, Simon J Anthony, Joel Baines, Arinjay Banerjee, Andrew J Broadbent, Christopher B Brooke, Samuel K Campos, Patrizia Caposio, Arturo Casadevall, Gary C Chan, Anna R Cliffe, Donna Collins-Mcmillen, Nancy Connell, Blossom Damania, Matthew D Daugherty, Kari Debbink, Terence S Dermody, Daniel Dimaio, W Paul Duprex, Michael Emerman, Denise A Galloway, Robert F Garry, Stephen A Goldstein, Alexander L Greninger, Amy L Hartman, Brenda G Hogue, Stacy M Horner, Peter J Hotez, Jae U Jung, Jeremy P Kamil, Stephanie M Karst, Lou Laimins, Seema S Lakdawala, Igor Landais, Michael Letko, Brett Lindenbach, Shan-Lu Liu, Micah Luftig, Grant Mcfadden, Andrew Mehle, Juliet Morrison, Anne Moscona, Elke Mühlberger, Joshua Munger, Karl Münger, Eain Murphy, Christopher J Neufeldt, Janko Z Nikolich, Christine M O'Connor, Andrew Pekosz, Sallie R Permar, Julie K Pfeiffer, Saskia V Popescu, John G Purdy, Vincent R Racaniello, Charles M Rice, Jonathan A Runstadler, Martin J Sapp, Rona S Scott, Gregory A Smith, Erin M Sorrell, Emily Speranza, Daniel Streblow, Scott A Tibbetts, Zsolt Toth, Koenraad Van Doorslaer, Susan R Weiss, Elizabeth A White, Timothy M White, Christiane E Wobus, Michael Worobey, Satoko Yamaoka, Andrew Yurochko

Faculty, Staff and Students Publications

In the United States (US), biosafety and biosecurity oversight of research on viruses is being reappraised. Safety in virology research is paramount and oversight frameworks should be reviewed periodically. Changes should be made with care, however, to avoid impeding science that is essential for rapidly reducing and responding to pandemic threats as well as addressing more common challenges caused by infectious diseases. Decades of research uniquely positioned the US to be able to respond to the COVID-19 crisis with astounding speed, delivering life-saving vaccines within a year of identifying the virus. We should embolden and empower this strength, which is …

Comparison Of Three Rapid Diagnostic Tests For Bloodstream Infections Using Benefit-Risk Evaluation Framework (Bed-Frame), Richard D Smith, Min Zhan, Shanshan Zhang, Surbhi Leekha, Anthony Harris, Yohei Doi, Scott Evans, J Kristie Johnson, Robert K Ernst

Faculty, Staff and Student Publications

Rapid diagnostic tests (RDTs) for bloodstream infections have the potential to reduce time to appropriate antimicrobial therapy and improve patient outcomes. Previously, an in-house, lipid-based, matrix-assisted laser desorption/ionization-time of flight mass spectrometry (MALDI-TOF MS) method, Fast Lipid Analysis Technique (FLAT MS), has shown promise as a rapid pathogen identification method. In this study, FLAT MS for direct from blood culture identification was evaluated and compared to FDA-cleared identification methods using the Benefit-risk Evaluation Framework (BED-FRAME) analysis. FLAT MS was evaluated and compared to Bruker Sepsityper and bioMérieux BioFire FilmArray BCID2 using results from a previous study. For this study, 301 …

Expanded T Lymphocytes In The Cerebrospinal Fluid Of Multiple Sclerosis Patients Are Specific For Epstein-Barr-Virus-Infected B Cells, Assaf Gottlieb, H Phuong T Pham, Jerome G Saltarrelli, J William Lindsey

Faculty, Staff and Student Publications

Epstein-Barr virus (EBV) infection has long been associated with multiple sclerosis (MS), but the role of EBV in the pathogenesis of MS is not clear. Our hypothesis is that a major fraction of the expanded clones of T lymphocytes in the cerebrospinal fluid (CSF) are specific for autologous EBV-infected B cells. We obtained blood and CSF samples from eight relapsing-remitting patients in the process of diagnosis. We stimulated cells from the blood with autologous EBV-infected lymphoblastoid cell lines (LCL), EBV, varicella zoster virus, influenza, and candida and sorted the responding cells with flow cytometry after 6 d. We sequenced the …

Novel Species Of Triatoma (Hemiptera: Reduviidae) Identified In A Case Of Vectorial Transmission Of Chagas Disease In Northern Belize, Sarah M Gunter, Alisa Nelson, Alexander R Kneubehl, Silvia A Justi, Russell Manzanero, Emily Zielinski-Gutierrez, Claudia Herrera, Julie Thompson, Rajendra Mandage, Hans Desale, Adrianna Maliga, Kim Bautista, Shannon E Ronca, Francis Morey, Rafael Chacon Fuentes, Beatriz Lopez, Eric Dumonteil, Gerhaldine H Morazan, Kristy O Murray

Faculty, Staff and Students Publications

Chagas disease is a leading cause of non-ischemic cardiomyopathy in endemic regions of Central and South America. In Belize, Triatoma dimidiata sensu lato has been identified as the predominate taxon but vectorial transmission of Chagas disease is considered to be rare in the country. We recently identified an acute case of vector-borne Chagas disease in the northern region of Belize. Here we present a subsequent investigation of triatomines collected around the case-patient's home. We identified yet undescribed species, closely related to Triatoma huehuetenanguensis vector by molecular systematics methods occurring in the peridomestic environment. The identification of a T. cruzi-positive, novel …

The Pan-Microbiome Profiling System Taxa4meta Identifies Clinical Dysbiotic Features And Classifies Diarrheal Disease, Qinglong Wu, Shyam Badu, Sik Yu So, Todd J Treangen, Tor C Savidge

Faculty, Staff and Students Publications

Targeted metagenomic sequencing is an emerging strategy to survey disease-specific microbiome biomarkers for clinical diagnosis and prognosis. However, this approach often yields inconsistent or conflicting results owing to inadequate study power and sequencing bias. We introduce Taxa4Meta, a bioinformatics pipeline explicitly designed to compensate for technical and demographic bias. We designed and validated Taxa4Meta for accurate taxonomic profiling of 16S rRNA amplicon data acquired from different sequencing strategies. Taxa4Meta offers significant potential in identifying clinical dysbiotic features that can reliably predict human disease, validated comprehensively via reanalysis of individual patient 16S data sets. We leveraged the power of Taxa4Meta's pan-microbiome …

Targeting Innate Immunity In Glioma Therapy, Andrew G Gillard, Dong Ho Shin, Lethan A Hampton, Andres Lopez-Rivas, Akhila Parthasarathy, Juan Fueyo, Candelaria Gomez-Manzano

Faculty, Staff and Student Publications

Currently, there is a lack of effective therapies for the majority of glioblastomas (GBMs), the most common and malignant primary brain tumor. While immunotherapies have shown promise in treating various types of cancers, they have had limited success in improving the overall survival of GBM patients. Therefore, advancing GBM treatment requires a deeper understanding of the molecular and cellular mechanisms that cause resistance to immunotherapy. Further insights into the innate immune response are crucial for developing more potent treatments for brain tumors. Our review provides a brief overview of innate immunity. In addition, we provide a discussion of current therapies …

Aging Fly Cell Atlas Identifies Exhaustive Aging Features At Cellular Resolution, Kenneth A Wilson, Sudipta Bar, Eric B Dammer, Enrique M Carrera, Brian A Hodge, Tyler A U Hilsabeck, Joanna Bons, George W Brownridge, Jennifer N Beck, Jacob Rose, Melia Granath-Panelo, Christopher S Nelson, Grace Qi, Akos A Gerencser, Jianfeng Lan, Alexandra Afenjar, Geetanjali Chawla, Rachel B Brem, Philippe M Campeau, Hugo J Bellen, Birgit Schilling, Nicholas T Seyfried, Lisa M Ellerby, Pankaj Kapahi

Faculty, Staff and Students Publications

Dietary restriction (DR) delays aging, but the mechanism remains unclear. We identified polymorphisms in mtd, the fly homolog of OXR1, which influenced lifespan and mtd expression in response to DR. Knockdown in adulthood inhibited DR-mediated lifespan extension in female flies. We found that mtd/OXR1 expression declines with age and it interacts with the retromer, which regulates trafficking of proteins and lipids. Loss of mtd/OXR1 destabilized the retromer, causing improper protein trafficking and endolysosomal defects. Overexpression of retromer genes or pharmacological restabilization with R55 rescued lifespan and neurodegeneration in mtd-deficient flies and endolysosomal defects in fibroblasts from patients with lethal loss-of-function …

Delineating The Mechanism Of Fragility At Bcl6 Breakpoint Region Associated With Translocations In Diffuse Large B Cell Lymphoma, Vidya Gopalakrishnan, Urbi Roy, Shikha Srivastava, Khyati M Kariya, Shivangi Sharma, Saniya M Javedakar, Bibha Choudhary, Sathees C Raghavan

Faculty, Staff and Student Publications

BCL6 translocation is one of the most common chromosomal translocations in cancer and results in its enhanced expression in germinal center B cells. It involves the fusion of BCL6 with any of its twenty-six Ig and non-Ig translocation partners associated with diffuse large B cell lymphoma (DLBCL). Despite being discovered long back, the mechanism of BCL6 fragility is largely unknown. Analysis of the translocation breakpoints in 5' UTR of BCL6 reveals the clustering of most of the breakpoints around a region termed Cluster II. In silico analysis of the breakpoint cluster sequence identified sequence motifs that could potentially fold into …

Genome-Wide Study Investigating Effector Genes And Polygenic Prediction For Kidney Function In Persons With Ancestry From Africa And The Americas, Odessica Hughes, Amy R Bentley, Charles E Breeze, Francois Aguet, Xiaoguang Xu, Girish Nadkarni, Quan Sun, Bridget M Lin, Thomas Gilliland, Mariah C Meyer, Jiawen Du, Laura M Raffield, Holly Kramer, Robert W Morton, Mateus H Gouveia, Elizabeth G Atkinson, Adan Valladares-Salgado, Niels Wacher-Rodarte, Nicole D Dueker, Xiuqing Guo, Yang Hai, Adebowale Adeyemo, Lyle G Best, Jianwen Cai, Guanjie Chen, Michael Chong, Ayo Doumatey, James Eales, Mark O Goodarzi, Eli Ipp, Marguerite Ryan Irvin, Minzhi Jiang, Alana C Jones, Charles Kooperberg, Jose E Krieger, Ethan M Lange, Matthew B Lanktree, James P Lash, Paulo A Lotufo, Ruth J F Loos, Vy Thi Ha My, Jesús Peralta-Romero, Lihong Qi, Leslie J Raffel, Stephen S Rich, Erik J Rodriquez, Eduardo Tarazona-Santos, Kent D Taylor, Jason G Umans, Jia Wen, Bessie A Young, Zhi Yu, Ying Zhang, Yii-Der Ida Chen, Tanja Rundek, Jerome I Rotter, Miguel Cruz, Myriam Fornage, Maria Fernanda Lima-Costa, Alexandre C Pereira, Guillaume Paré, Pradeep Natarajan, Shelley A Cole, April P Carson, Leslie A Lange, Yun Li, Eliseo J Perez-Stable, Ron Do, Fadi J Charchar, Maciej Tomaszewski, Josyf C Mychaleckyj, Charles Rotimi, Andrew P Morris, Nora Franceschini

Faculty, Staff and Students Publications

Chronic kidney disease is a leading cause of death and disability globally and impacts individuals of African ancestry (AFR) or with ancestry in the Americas (AMS) who are under-represented in genome-wide association studies (GWASs) of kidney function. To address this bias, we conducted a large meta-analysis of GWASs of estimated glomerular filtration rate (eGFR) in 145,732 AFR and AMS individuals. We identified 41 loci at genome-wide significance (p < 5 × 10−8), of which two have not been previously reported in any ancestry group. We integrated fine-mapped loci with epigenomic and transcriptomic resources to highlight potential effector genes relevant to kidney physiology and disease, and reveal key regulatory elements and pathways involved in renal function and development. We demonstrate the varying but increased predictive power offered by a multi-ancestry polygenic score for eGFR and highlight the importance of population diversity in GWASs and multi-omics resources to enhance opportunities for clinical translation for all.

Variants In The Wdr44 Wd40-Repeat Domain Cause A Spectrum Of Ciliopathy By Impairing Ciliogenesis Initiation, Andrea Accogli, Saurabh Shakya, Taewoo Yang, Christine Insinna, Soo Yeon Kim, David Bell, Kirill R Butov, Mariasavina Severino, Marcello Niceta, Marcello Scala, Hyun Sik Lee, Taekyeong Yoo, Jimmy Stauffer, Huijie Zhao, Chiara Fiorillo, Marina Pedemonte, Maria C Diana, Simona Baldassari, Viktoria Zakharova, Anna Shcherbina, Yulia Rodina, Christina Fagerberg, Laura Sønderberg Roos, Jolanta Wierzba, Artur Dobosz, Amanda Gerard, Lorraine Potocki, Jill A Rosenfeld, Seema R Lalani, Tiana M Scott, Daryl Scott, Mahshid S Azamian, Raymond Louie, Hannah W Moore, Neena L Champaigne, Grace Hollingsworth, Annalaura Torella, Vincenzo Nigro, Rafal Ploski, Vincenzo Salpietro, Federico Zara, Simone Pizzi, Giovanni Chillemi, Marzia Ognibene, Erin Cooney, Jenny Do, Anders Linnemann, Martin J Larsen, Suzanne Specht, Kylie J Walters, Hee-Jung Choi, Murim Choi, Marco Tartaglia, Phillippe Youkharibache, Jong-Hee Chae, Valeria Capra, Sung-Gyoo Park, Christopher J Westlake

Faculty, Staff and Students Publications

WDR44 prevents ciliogenesis initiation by regulating RAB11-dependent vesicle trafficking. Here, we describe male patients with missense and nonsense variants within the WD40 repeats (WDR) of WDR44, an X-linked gene product, who display ciliopathy-related developmental phenotypes that we can model in zebrafish. The patient phenotypic spectrum includes developmental delay/intellectual disability, hypotonia, distinct craniofacial features and variable presence of brain, renal, cardiac and musculoskeletal abnormalities. We demonstrate that WDR44 variants associated with more severe disease impair ciliogenesis initiation and ciliary signaling. Because WDR44 negatively regulates ciliogenesis, it was surprising that pathogenic missense variants showed reduced abundance, which we link to misfolding of …

Fusionpdb:: A Knowledgebase Of Human Fusion Proteins, Himansu Kumar, Lin-Ya Tang, Chengyuan Yang, Pora Kim

Faculty, Staff and Student Publications

Tumorigenic functions due to the formation of fusion genes have been targeted for cancer therapeutics (i.e. kinase inhibitors). However, many fusion proteins involved in various cellular processes have not been studied for targeted therapeutics. This is because the lack of complete fusion protein sequences and their whole 3D structures has made it challenging to develop new therapeutic strategies. To fill these critical gaps, we developed a computational pipeline and a resource of human fusion proteins named FusionPDB, available at https://compbio.uth.edu/FusionPDB. FusionPDB is organized into four levels: 43K fusion protein sequences (14.7K in-frame fusion genes, Level 1), over 2300 + 1267 …

Clinicalomicsdb: Exploring Molecular Associations Of Oncology Drug Responses In Clinical Trials, Chang In Moon, John Michael Elizarraras, Jonathan Thomas Lei, Byron Jia, Bing Zhang

Faculty, Staff and Students Publications

Matching patients to optimal treatment is challenging, in part due to the limited availability of real-world clinical datasets for predictive biomarker identification. The growing integration of omics profiling into clinical trials presents a new opportunity to tackle this challenge. Here, we introduce ClinicalOmicsDB, a web application for exploring molecular associations of oncology drug responses in clinical trials. This database includes transcriptomic data from 40 clinical trial studies, with 5913 patients spanning 11 cancer types. These studies include 67 treatment arms with a variety of chemotherapy, targeted therapy and immunotherapy drugs, and their combinations, which we organize based on an established …

A Syndromic Neurodevelopmental Disorder Caused By Rare Variants In Ppfia3, Maimuna S Paul, Sydney L Michener, Hongling Pan, Hiuling Chan, Jessica M Pfliger, Jill A Rosenfeld, Vanesa C Lerma, Alyssa Tran, Megan A Longley, Richard A Lewis, Monika Weisz-Hubshman, Mir Reza Bekheirnia, Nasim Bekheirnia, Lauren Massingham, Michael Zech, Matias Wagner, Hartmut Engels, Kirsten Cremer, Elisabeth Mangold, Sophia Peters, Jessica Trautmann, Jessica L Mester, Maria J Guillen Sacoto, Richard Person, Pamela P Mcdonnell, Stacey R Cohen, Laina Lusk, Ana S A Cohen, Jean-Baptiste Le Pichon, Tomi Pastinen, Dihong Zhou, Kendra Engleman, Caroline Racine, Laurence Faivre, Sébastien Moutton, Anne-Sophie Denommé-Pichon, Hyun Yong Koh, Annapurna Poduri, Jeffrey Bolton, Cordula Knopp, Dong Sun Julia Suh, Andrea Maier, Mehran Beiraghi Toosi, Ehsan Ghayoor Karimiani, Reza Maroofian, Gerald Bradley Schaefer, Vijayalakshmi Ramakumaran, Pradeep Vasudevan, Chitra Prasad, Matthew Osmond, Sarah Schuhmann, Georgia Vasileiou, Sophie Russ-Hall, Ingrid E Scheffer, Gemma L Carvill, Heather Mefford, Undiagnosed Diseases Network, Carlos A Bacino, Brendan H Lee, Hsiao-Tuan Chao

Faculty, Staff and Students Publications

PPFIA3 encodes the protein-tyrosine phosphatase, receptor-type, F-polypeptide-interacting-protein-alpha-3 (PPFIA3), which is a member of the LAR-protein-tyrosine phosphatase-interacting-protein (liprin) family involved in synapse formation and function, synaptic vesicle transport, and presynaptic active zone assembly. The protein structure and function are evolutionarily well conserved, but human diseases related to PPFIA3 dysfunction are not yet reported in OMIM. Here, we report 20 individuals with rare PPFIA3 variants (19 heterozygous and 1 compound heterozygous) presenting with developmental delay, intellectual disability, hypotonia, dysmorphisms, microcephaly or macrocephaly, autistic features, and epilepsy with reduced penetrance. Seventeen unique PPFIA3 variants were detected in 18 families. To determine the pathogenicity …

Preclinical Repurposing Of Sitagliptin As A Drug Candidate For Colorectal Cancer By Targeting Cd24/Ctnnb1/Sox4-Centered Signaling Hub, Jing-Wen Shih, Alexander T H Wu, Ntlotlang Mokgautsi, Po-Li Wei, Yan-Jiun Huang

Faculty, Staff and Student Publications

Despite significant advances in treatment modalities, colorectal cancer (CRC) remains a poorly understood and highly lethal malignancy worldwide. Cancer stem cells (CSCs) and the tumor microenvironment (TME) have been shown to play critical roles in initiating and promoting CRC progression, metastasis, and treatment resistance. Therefore, a better understanding of the underlying mechanisms contributing to the generation and maintenance of CSCs is crucial to developing CSC-specific therapeutics and improving the current standard of care for CRC patients. To this end, we used a bioinformatics approach to identify increased CD24/SOX4 expression in CRC samples associated with poor prognosis. We also …

An Evolutionary Perspective On Complex Neuropsychiatric Disease, Jon M Mcclellan, Anthony W Zoghbi, Joseph D Buxbaum, Carolina Cappi, James J Crowley, Jonathan Flint, Dorothy E Grice, Suleyman Gulsuner, Conrad Iyegbe, Sanjeev Jain, Po-Hsiu Kuo, Maria Claudia Lattig, Maria Rita Passos-Bueno, Meera Purushottam, Dan J Stein, Anna B Sunshine, Ezra S Susser, Christopher A Walsh, Olivia Wootton, Mary-Claire King

Faculty, Staff and Students Publications

The forces of evolution-mutation, selection, migration, and genetic drift-shape the genetic architecture of human traits, including the genetic architecture of complex neuropsychiatric illnesses. Studying these illnesses in populations that are diverse in genetic ancestry, historical demography, and cultural history can reveal how evolutionary forces have guided adaptation over time and place. A fundamental truth of shared human biology is that an allele responsible for a disease in anyone, anywhere, reveals a gene critical to the normal biology underlying that condition in everyone, everywhere. Understanding the genetic causes of neuropsychiatric disease in the widest possible range of human populations thus yields …

Antiviral Effects Of Micafungin Against Pteropine Orthoreovirus, An Emerging Zoonotic Virus Carried By Bats, Eiichi Hondo, Tetsufumi Katta, Ayato Sato, Naoya Kadofusa, Tomoki Ishibashi, Hiroshi Shimoda, Hirokazu Katoh, Atsuo Iida

Faculty, Staff and Student Publications

Bat-borne emerging zoonotic viruses cause major outbreaks, such as the Ebola virus, Nipah virus, and/or beta coronavirus. Pteropine orthoreovirus (PRV), whose spillover event occurred from fruits bats to humans, causes respiratory syndrome in humans widely in South East Asia. Repurposing approved drugs against PRV is an effective tool to confront future PRV pandemics. We screened 2,943 compounds in an FDA-approved drug library and identified eight hit compounds that reduce viral cytopathic effects on cultured Vero cells. Real-time quantitative PCR analysis revealed that six of eight hit compounds significantly inhibited PRV replication. Among them, micafungin used clinically as an antifungal drug, …

Synergistic Effects Of Antimicrobial Components Of The Human-Derived Composite Amnion-Chorion Membrane On Bacterial Growth, Alexandra Su Brummerhop, Chun-Teh Lee, Robin Weltman, Gena D Tribble, Ransome Van Der Hoeven, Yulun Chiu, Jianming Hong, Bing-Yan Wang

Faculty, Staff and Student Publications

Introduction: The human-derived amnion-chorion membrane (ACM) has endogenous antimicrobial properties, which are important for preventing the colonization and survival of oral bacteria on exposed membranes. This project aimed to decipher the underlying mechanism by identifying the components of ACM that confer antibacterial properties. In addition, the antimicrobial efficacy of these identified components on oral bacteria was assessed.

Methods: Four antimicrobial proteins, histone H2A/H2B, cathelicidin LL-37, lactoferrin, and lysozyme, were identified via mass spectrometry in ACM. These proteins were then assessed for their efficacy in killing Streptococcus gordonii Challis. Log-phased bacterial cells were cultured with the commercially available proteins that were …

Measurement Of 8-Hydroxy-2′-Deoxyguanosine In Serum And Cerebrospinal Fluid Of Horses With Neuroaxonal Degeneration And Other Causes Of Proprioceptive Ataxia, Megan Palmisano, Jeaneen Kulp, Susan Bender, Darko Stefanovski, Mary Robinson, Amy Johnson

Faculty, Staff and Student Publications

BACKGROUND: Eight-hydroxy-2'-deoxyguanosine (8-OHdG), a biomarker of oxidative damage evaluated in human neurodegenerative disease, has potential to correlate with postmortem diagnosis of neuroaxonal dystrophy/degenerative myeloencephalopathy (NAD/DM) in horses.

HYPOTHESIS: We hypothesized that 8-OHdG will be higher in CSF and serum from NAD/DM horses compared with horses with other neurologic diseases (CVSM, EPM) and a control group of neurologically normal horses. We also hypothesized that 8-OHdG will be higher in CSF compared with serum from NAD/DM horses.

ANIMALS: Fifty client-owned horses with postmortem diagnoses: 20 NAD/DM, 10 CVSM, 10 EPM, and 10 control horses. Serum and CSF samples were obtained between November …

Persistent Microbial Infections And Idiopathic Pulmonary Fibrosis – An Insight Into Non-Typeable Haemophilus Influenza Pathogenesis, Anthony Shadid, Haydn E Rich, Hunter Devaughn, Aleksey Domozhirov, Marie-Françoise Doursout, Tingting Weng-Mills, Kristin L Eckel-Mahan, Harry Karmouty-Quintana, Marcos I Restrepo, Pooja Shivshankar

Faculty, Staff and Student Publications

Interstitial lung disease (ILD) is characterized by chronic inflammation and scarring of the lungs, of which idiopathic pulmonary fibrosis (IPF) is the most devastating pathologic form. Idiopathic pulmonary fibrosis pathogenesis leads to loss of lung function and eventual death in 50% of patients, making it the leading cause of ILD-associated mortality worldwide. Persistent and subclinical microbial infections are implicated in the acute exacerbation of chronic lung diseases. However, while epidemiological studies have highlighted pollutants, gastric aspirate, and microbial infections as major causes for the progression and exacerbation of IPF, the role of persistent microbial infections in the pathogenesis of IPF …

Multiple Unfolded Protein Response Pathways Cooperate To Link Cytosolic Dsdna Release To Stimulator Of Interferon Gene Activation, Tiancheng Hu, Yiping Liu, Jeremy Fleck, Cason King, Elaine Schalk, Zhenyu Zhang, Andrew Mehle, Judith A Smith

Faculty, Staff and Student Publications

The double-stranded DNA (dsDNA) sensor STING has been increasingly implicated in responses to "sterile" endogenous threats and pathogens without nominal DNA or cyclic di-nucleotide stimuli. Previous work showed an endoplasmic reticulum (ER) stress response, known as the unfolded protein response (UPR), activates STING. Herein, we sought to determine if ER stress generated a STING ligand, and to identify the UPR pathways involved. Induction of IFN-β expression following stimulation with the UPR inducer thapsigargin (TPG) or oxygen glucose deprivation required both STING and the dsDNA-sensing cyclic GMP-AMP synthase (cGAS). Furthermore, TPG increased cytosolic mitochondrial DNA, and immunofluorescence visualized dsDNA punctae in …

Mouse Models Of Chronic Lymphocytic Leukemia And Richter Transformation: What We Have Learnt And What We Are Missing, Maria Teresa Sabrina Bertilaccio, Shih-Shih Chen

Faculty, Staff and Student Publications

Although the chronic lymphocytic leukemia (CLL) treatment landscape has changed dramatically, unmet clinical needs are emerging, as CLL in many patients does not respond, becomes resistant to treatment, relapses during treatment, or transforms into Richter. In the majority of cases, transformation evolves the original leukemia clone into a diffuse large B-cell lymphoma (DLBCL). Richter transformation (RT) represents a dreadful clinical challenge with limited therapeutic opportunities and scarce preclinical tools. CLL cells are well known to highly depend on survival signals provided by the tumor microenvironment (TME). These signals enhance the frequency of immunosuppressive cells with protumor function, including regulatory CD4

Fluoxetine And Sertraline Inhibit Height Growth And Growth Hormone Signaling During Puberty, Chadi Calarge, Chima Amushie, Stephanie Dinh, James A Mills, Sridevi Devaraj, Griselda Barba-Villalobos, Jacqueline Nguyen, Jose M Garcia, Stephanie Sisley, Fida Bacha, Babette Zemel

Faculty, Staff and Students Publications

Purpose: The aim of this study was to examine the effect of fluoxetine and sertraline on height growth and insulin-like growth factor-1 (IGF-1) during puberty.

Methods: In this 6-month cohort study, electronic medical records were used to identify 8- to 15-year-old participants, within 1 month of starting fluoxetine (n = 39) or sertraline (n = 27), and sexual maturation stages 2 to 4 were confirmed. Conditions that interfere with height growth led to exclusion. Participants underwent anthropometric assessments and phlebotomy. Healthy, unmedicated children (n = 36) also provided anthropometric data.

Results: After the baseline height Z-score, sex, Tanner stage, daily …

The Mars Complex: A Critical Mediator Of Immune Regulation And Homeostasis, Sharon Bright Amanya, Damilola Oyewole-Said, Keenan J Ernste, Nalini Bisht, Arnav Murthy, Jonathan Vazquez-Perez, Vanaja Konduri, William K Decker

Faculty, Staff and Students Publications

Over the course of evolution, many proteins have undergone adaptive structural changes to meet the increasing homeostatic regulatory demands of multicellularity. Aminoacyl tRNA synthetases (aaRS), enzymes that catalyze the attachment of each amino acid to its cognate tRNA, are such proteins that have acquired new domains and motifs that enable non-canonical functions. Through these new domains and motifs, aaRS can assemble into large, multi-subunit complexes that enhance the efficiency of many biological functions. Moreover, because the complexity of multi-aminoacyl tRNA synthetase (mARS) complexes increases with the corresponding complexity of higher eukaryotes, a contribution to regulation of homeostatic functions in multicellular …

High-Fat Diets Promote Peritoneal Inflammation And Augment Endometriosis-Associated Abdominal Hyperalgesia, Tristin Herup-Wheeler, Mingxin Shi, Madeleine E Harvey, Chandni Talwar, Ramakrishna Kommagani, James A Maclean, Kanako Hayashi

Faculty, Staff and Students Publications

Immune dysfunction is one of the central components in the development and progression of endometriosis by establishing a chronic inflammatory environment. Western-style high-fat diets (HFD) have been linked to greater systemic inflammation to cause metabolic and chronic inflammatory diseases, and are also considered an environmental risk factor for gynecologic diseases. Here, we aimed to examine how HFD cause an inflammatory environment in endometriosis and discern their contribution to endometriotic-associated hyperalgesia. Our results showed that HFD-induced obesity enhanced abdominal hyperalgesia that was induced by endometriotic lesions. Peritoneal inflammatory macrophages and cytokine levels increased by lesion induction were elevated by chronic exposure …

Genetic Variation Between Small Bowel And Colon-Predominant Crohn's Disease, Halee Patel, R Alan Harris, Justin H Qian, Numan Oezguen, Ashleigh Watson, Reka G Szigeti, Stanley Cho, Wenly Ruan, Savini Britto, Antone Opekun, Geoffrey Preidis, Richard Kellermayer

Faculty, Staff and Students Publications

No abstract provided.

Optimizing Immunogenicity And Product Presentation Of A Sars-Cov-2 Subunit Vaccine Composition: Effects Of Delivery Route, Heterologous Regimens With Self-Amplifying Rna Vaccines, And Lyophilization, William R Lykins, Jeroen Pollet, Jessica A White, Brian Keegan, Leroy Versteeg, Ulrich Strych, Wen-Hsiang Chen, Raodoh Mohamath, Gabi Ramer-Denisoff, Sierra Reed, Christina Renshaw, Samuel Beaver, Alana Gerhardt, Emily A Voigt, Mark A Tomai, Robert Sitrin, Robert K M Choy, Frederick J Cassels, Peter J Hotez, Maria Elena Bottazzi, Christopher B Fox

Faculty, Staff and Students Publications

INTRODUCTION: Dozens of vaccines have been approved or authorized internationally in response to the ongoing SARS-CoV-2 pandemic, covering a range of modalities and routes of delivery. For example, mucosal delivery of vaccines via the intranasal (i.n.) route has been shown to improve protective mucosal responses in comparison to intramuscular (i.m.) delivery. As we gain knowledge of the limitations of existing vaccines, it is of interest to understand if changes in product presentation or combinations of multiple vaccine modalities can further improve immunological outcomes.

METHODS: We investigated a commercial-stage SARS-CoV-2 receptor binding domain (RBD) antigen adjuvanted with a clinical-stage TLR-7/8 agonist …