Biological Phenomena, Cell Phenomena, and Immunity Commons^™

Beneficial Impacts Of Nod-Like Receptor X1(Nlrx1) Agonism In Lipopolysaccharide-Induced Inflammation, Mena Mansy

Graduate Theses, Dissertations, and Problem Reports (ETD)

Introduction: The regulation of inflammation at the cellular and molecular level is a crucial aspect of homeostasis that is often overlooked, and most treatment options are limited to antibiotics and symptom management drugs. The development of novel molecular-targeted therapy options downstream of pathogen recognition receptors will fulfill the unmet need for therapy to effectively regulate excessive inflammation. NLRX1 is a unique NOD-like receptor that is anti-inflammatory in nature; it has been shown to negatively regulate the NF-kB pathway and has been involved in the pathology of a plethora of inflammatory disorders. This makes NLRX1 an emerging therapeutic molecular target for …

Il-27 Negatively Impacts Immunity Developed Following Bcg Administration, Shelby D. Bradford

Graduate Theses, Dissertations, and Problem Reports (ETD)

Mycobacterium tuberculosis (Mtb) is the causative agent of tuberculosis (TB), a predominantly respiratory pathogen responsible for over ten million infections and one million deaths last year. Despite it being a primary objective of the World Health Organization (WHO) for several decades to irradicate TB, progress toward this objective has fallen short of the 2020 target to end TB by 2035. Meeting this goal will require advancements in diagnostic tools, education, healthcare access, and treatments and preventatives. Regarding prevention, the primary tool for this strategy is through vaccination. Currently, the only licensed vaccine for protection against TB is the century old …

Deciphering The Role Of Qpctl In Glioma Progression And Cancer Immunotherapy, Yu'e Liu, Shaojuan Lu, Yihong Sun, Fei Wang, Shibo Yu, Xi Chen, Lei-Lei Wu, Hui Yang, Yufeng Shi, Kaijun Zhao

Faculty, Staff and Students Publications

BACKGROUND: Glioma is the most lethal and most aggressive brain cancer, and currently there is no effective treatment. Cancer immunotherapy is an advanced therapy by manipulating immune cells to attack cancer cells and it has been studied a lot in glioma treatment. Targeting the immune checkpoint CD47 or blocking the CD47-SIRPα axis can effectively eliminate glioma cancer cells but also brings side effects such as anemia. Glutaminyl-peptide cyclotransferase-like protein (QPCTL) catalyzes the pyroglutamylation of CD47 and is crucial for the binding between CD47 and SIRPα. Further study found that loss of intracellular QPCTL limits chemokine function and reshapes myeloid infiltration …

Integrative Metabolomics And Transcriptomics Analysis Reveals Novel Therapeutic Vulnerabilities In Lung Cancer, Jose Thaiparambil, Jianrong Dong, Sandra L Grimm, Dimuthu Perera, Chandra Shekar R Ambati, Vasanta Putluri, Matthew J Robertson, Tajhal D Patel, Brandon Mistretta, Preethi H Gunaratne, Min P Kim, Jason T Yustein, Nagireddy Putluri, Cristian Coarfa, Randa El-Zein

Faculty, Staff and Students Publications

BACKGROUND: Non-small cell lung cancer (NSCLC) comprises the majority (~85%) of all lung tumors, with lung adenocarcinoma (LUAD) and squamous cell carcinoma (LUSC) being the most frequently diagnosed histological subtypes. Multi-modal omics profiling has been carried out in NSCLC, but no studies have yet reported a unique metabolite-related gene signature and altered metabolic pathways associated with LUAD and LUSC.

METHODS: We integrated transcriptomics and metabolomics to analyze 30 human lung tumors and adjacent noncancerous tissues. Differential co-expression was used to identify modules of metabolites that were altered between normal and tumor.

RESULTS: We identified unique metabolite-related gene signatures specific for …

The Nr2f2-Hand2 Signaling Axis Regulates Progesterone Actions In The Uterus At Early Pregnancy, Yeongseok Oh, Elvis Quiroz, Tianyuan Wang, Yassmin Medina-Laver, Skylar Montague Redecke, Francisco Dominguez, John P Lydon, Francesco J Demayo, San-Pin Wu

Faculty, Staff and Students Publications

Endometrial function is dependent on a tight crosstalk between the epithelial and stromal cells of the endometrium. This communication is critical to ensure a fertile uterus and relies on progesterone and estrogen signaling to prepare a receptive uterus for embryo implantation in early pregnancy. One of the key mediators of this crosstalk is the orphan nuclear receptor NR2F2, which regulates uterine epithelial receptivity and stromal cell differentiation. In order to determine the molecular mechanism regulated by NR2F2, RNAseq analysis was conducted on the uterus of

Global Regulatory Reforms To Promote Equitable Vaccine Access In The Next Pandemic, Richard Mahoney, Peter J Hotez, Maria Elena Bottazzi

Faculty, Staff and Students Publications

There is broad consensus that the global response to the Covid-19 pandemic was inadequate, leading to unacceptable levels of avoidable morbidity and mortality. Three strategic missteps led to the lack of equitable vaccine access: The heavy reliance on commercial vaccine manufacturers in high-income countries (HICs) versus low- and middle-income countries (LMICs); the emergence of vaccine nationalism restricting and delaying the supply of vaccines to LMICs; and an inadequate support or recognition for LMIC national regulatory authorities. To avoid these inequities in a future pandemic, we focus on three successful vaccine development and technology transfer case studies-the Hepatitis B vaccine produced …

Vaccine-Linked Chemotherapy Improves Cardiac Structure And Function In A Mouse Model Of Chronic Chagas Disease, Kathryn M Jones, Elise N Mangin, Corey L Reynolds, Liliana E Villanueva, Julio Vladimir Cruz, Leroy Versteeg, Brian Keegan, April Kendricks, Jeroen Pollet, Fabian Gusovsky, Maria Elena Bottazzi, Peter J Hotez

Faculty, Staff and Students Publications

INTRODUCTION: Chagas disease, caused by chronic infection with the protozoan parasite Trypanosoma cruzi, affects 6-7 million people worldwide. The major clinical manifestation of Chagas disease is chronic Chagasic cardiomyopathy (CCC), which encompasses a spectrum of symptoms including arrhythmias, hypertrophy, dilated cardiomyopathy, heart failure, and sudden death. Current treatment is limited to two antiparasitic drugs, benznidazole (BNZ) and nifurtimox, but both have limited efficacy to halt the progression of CCC. We developed a vaccine-linked chemotherapy strategy using our vaccine consisting of recombinant Tc24-C4 protein and a TLR-4 agonist adjuvant in a stable squalene emulsion, in combination with low dose benznidazole treatment. …

Prevalence Of Trypanosoma Cruzi, The Etiologic Agent Of Chagas Disease, Infection In Texas Skunks (Mammalia: Mephitidae), Bonnie E Gulas-Wroblewski, Rodion Gorchakov, Rebecca B Kairis, Robert C Dowler, Kristy O Murray

Faculty, Staff and Students Publications

Background:

Chagas disease is one of the world's most neglected tropical diseases, infecting over six million people across the Americas. The hemoparasite Trypanosoma cruzi is the etiological agent for the disease, circulating in domestic, peridomestic, and sylvatic transmission cycles that are maintained by triatomine vectors and a diversity of wild and synanthropic hosts. Public health and wildlife management interventions targeting the interruption of T. cruzi transmission rely on an understanding of the dynamics driving the ecology of this zoonotic pathogen. One wildlife host that purportedly plays a role in the transmission of Chagas disease within the southern United States is …

The Neurobiology Of Duration Of Untreated Psychosis: A Comprehensive Review, Anthony W Zoghbi, Jeffrey A Lieberman, Ragy R Girgis

Faculty, Staff and Students Publications

Duration of untreated psychosis (DUP) is defined as the time from the onset of psychotic symptoms until the first treatment. Studies have shown that longer DUP is associated with poorer response rates to antipsychotic medications and impaired cognition, yet the neurobiologic correlates of DUP are poorly understood. Moreover, it has been hypothesized that untreated psychosis may be neurotoxic. Here, we conducted a comprehensive review of studies that have examined the neurobiology of DUP. Specifically, we included studies that evaluated DUP using a range of neurobiologic and imaging techniques and identified 83 articles that met inclusion and exclusion criteria. Overall, 27 …

A Population-Based Assessment Of Metastatic Hepatoblastoma In Texas Reveals Ethnic Disparities, Andres F Espinoza, Michael E Scheurer, Tiffany M Chambers, Sanjeev A Vasudevan, Philip J Lupo

Faculty, Staff and Students Publications

BACKGROUND: Hepatoblastoma (HB) is the most common primary liver cancer in children with emerging evidence that incidence is increasing globally. While overall survival for low risk hepatoblastoma is >90%, children with metastatic disease have worse survival. As identifying factors associated with high-risk disease is critical for improving outcomes for these children, a need for a further understanding of the epidemiology of hepatoblastoma is warranted. Therefore, we conducted a population-based epidemiologic study of hepatoblastoma in Texas, a large state characterized by ethnic and geographic diversity.

METHODS: Information on children diagnosed with hepatoblastoma at 0-19 years of age for the period of …

Evaluating The Proportion Of Isolated Cases Among A Spectrum Of Birth Defects In A Population-Based Registry, Peter H Langlois, Lisa Marengo, Philip J Lupo, Margaret Drummond-Borg, A J Agopian, Wendy N Nembhard, Mark A Canfield

Faculty, Staff and Students Publications

INTRODUCTION: Because the etiology and outcomes of birth defects may differ by the presence vs. absence of co-occurring anomalies, epidemiologic studies often attempt to classify cases into isolated versus non-isolated groupings. This report describes a computer algorithm for such classification and presents results using data from the Texas Birth Defects Registry (TBDR).

METHODS: Each of the 1,041 birth defects coded by the TBDR was classified as chromosomal, syndromic, minor, or "needs review" by a group of three clinical geneticists. A SAS program applied those classifications to each birth defect in a case (child/fetus), and then hierarchically combined them to obtain …

Factors Associated With Nonsyndromic Anotia And Microtia, Texas, 1999–2014, Jeremy M Schraw, J P Woodhouse, Renata H Benjamin, Charles J Shumate, Joanne Nguyen, Mark A Canfield, A J Agopian, Philip J Lupo

Faculty, Staff and Students Publications

BACKGROUND: Few risk factors have been identified for nonsyndromic anotia/microtia (A/M).

METHODS: We obtained data on cases and a reference population of all livebirths in Texas for 1999-2014 from the Texas Birth Defects Registry (TBDR) and Texas vital records. We estimated prevalence ratios (PRs) and 95% confidence intervals (CIs) for A/M (any, isolated, nonisolated, unilateral, and bilateral) using Poisson regression. We evaluated trends in prevalence rates using Joinpoint regression.

RESULTS: We identified 1,322 cases, of whom 982 (74.3%) had isolated and 1,175 (88.9%) had unilateral A/M. Prevalence was increased among males (PR: 1.3, 95% CI: 1.2-1.4), offspring of women with …

Disease Modeling Of Adamts9-Related Nephropathy Using Kidney Organoids Reveals Its Roles In Tubular Cells And Podocytes, Seyoung Yu, Yo Jun Choi, John Hoon Rim, Hye-Youn Kim, Nasim Bekheirnia, Sarah Jane Swartz, Hongzheng Dai, Shen Linda Gu, Soyeon Lee, Ryuichi Nishinakamura, Friedhelm Hildebrandt, Mir Reza Bekheirnia, Heon Yung Gee

Faculty, Staff and Students Publications

INTRODUCTION: Mutations in ADAMTS9 cause nephronophthisis-related ciliopathies (NPHP-RC), which are characterized by multiple developmental defects and kidney diseases. Patients with NPHP-RC usually have normal glomeruli and negligible or no proteinuria. Herein, we identified novel compound-heterozygous ADAMTS9 variants in two siblings with NPHP-RC who had glomerular manifestations, including proteinuria.

METHODS: To investigate whether ADAMTS9 dysfunction causes NPHP and glomerulopathy, we differentiated ADAMTS9 knockout human induced pluripotent stem cells (hiPSCs) into kidney organoids. Single-cell RNA sequencing was utilized to elucidate the gene expression profiles from the ADAMTS9 knockout kidney organoids.

RESULTS:ADAMTS9 knockout had no effect on nephron differentiation; however, it reduced …

Cumulative Comorbid Conditions Influence Mortality Risk After Staged Palliation For Hypoplastic Left Heart Syndrome And Variants, Emily R Backes, Natasha S Afonso, Danielle Guffey, James S Tweddell, Sarah Tabbutt, Nancy A Rudd, Ginny O'Harrow, Silvana Molossi, George M Hoffman, Garick Hill, Jeffrey S Heinle, Priya Bhat, Jeffrey B Anderson, Nancy S Ghanayem

Faculty, Staff and Students Publications

Objective: Prematurity, low birth weight, genetic syndromes, extracardiac conditions, and secondary cardiac lesions are considered high-risk conditions associated with mortality after stage 1 palliation. We report the impact of these conditions on outcomes from a prospective multicenter improvement collaborative.

Methods: The National Pediatric Cardiology Quality Improvement Collaborative Phase II registry was queried. Comorbid conditions were categorized and quantified to determine the cumulative burden of high-risk diagnoses on survival to the first birthday. Logistic regression was applied to evaluate factors associated with mortality.

Results: Of the 1421 participants, 40% (575) had at least 1 high-risk condition. The aggregate high-risk group had …

Resveratrol Attenuates Staphylococcal Enterotoxin B-Activated Immune Cell Metabolism, Hasan Alghetaa, Amira Mohammed, Narendra Singh, Kiesha Wilson, Goushuai Cai, Nagireddy Putluri, Mitzi Nagarkatti, Prakash Nagarkatti

Faculty, Staff and Students Publications

Acute Respiratory Distress Syndrome (ARDS) is triggered by a variety of insults, such as bacterial and viral infections, including SARS-CoV-2, leading to high mortality. In the murine model of ARDS induced by Staphylococcal enterotoxin-B (SEB), our previous studies showed that while SEB triggered 100% mortality, treatment with Resveratrol (RES) completely prevented such mortality by attenuating inflammation in the lungs. In the current study, we investigated the metabolic profile of SEB-activated immune cells in the lungs following treatment with RES. RES-treated mice had higher expression of miR-100 in the lung mononuclear cells (MNCs), which targeted mTOR, leading to its decreased expression. …

From Concept To Delivery: A Yeast-Expressed Recombinant Protein-Based Covid-19 Vaccine Technology Suitable For Global Access, Peter J Hotez, Rakesh Adhikari, Wen-Hsiang Chen, Yi-Lin Chen, Portia Gillespie, Nelufa Y Islam, Brian Keegan, Rakhi Tyagi Kundu, Jungsoon Lee, Zhuyun Liu, Jason T Kimata, Numan Oezguen, Jeroen Pollet, Cristina Poveda, Kay Razavi, Shannon E Ronca, Ulrich Strych, Syamala R Thimmiraju, Leroy Versteeg, Maria Jose Villar-Mondragon, Junfei Wei, Bin Zhan, Maria Elena Bottazzi

Faculty, Staff and Students Publications

Introduction: The development of a yeast-expressed recombinant protein-based vaccine technology co-developed with LMIC vaccine producers and suitable as a COVID-19 vaccine for global access is described. The proof-of-concept for developing a SARS-CoV-2 spike protein receptor-binding domain (RBD) antigen as a yeast-derived recombinant protein vaccine technology is described.

Areas covered: Genetic Engineering: The strategy is presented for the design and genetic modification used during cloning and expression in the yeast system. Process and Assay Development: A summary is presented of how a scalable, reproducible, and robust production process for the recombinant protein COVID-19 vaccine antigen was developed. Formulation and Pre-clinical Strategy: …

Atrial Standstill In The Pediatric Population: A Multi-Institution Collaboration, Taylor S Howard, David Y Chiang, Scott R Ceresnak, Virginie Beausejour Ladouceur, Robert D Whitehill, Richard J Czosek, Timothy K Knilans, Agnethe M Ahnfeldt, Malene Lando Borresen, Edgar Jaeggi, Sharmila Udupa, Robert Gow, Jeremy P Moore, Roberto G Galloti, Doug Y Mah, Jeffrey J Kim, Santiago O Valdes, Dianna M Milewicz, Christina Y Miyake

Faculty, Staff and Students Publications

Background: Atrial standstill (AS) is a rare condition characterized by absence of electrical activity within the atria. Studies to date have been limited.

Objectives: The authors sought to describe the clinical characteristics, genetics, and outcomes of patients with AS.

Methods: This was a retrospective multicenter study of patients < 18 years at AS diagnosis, defined as absence of atrial activity documented during an electrophysiology study, device placement, or noninvasive rhythm tracings and confirmed by echocardiogram. Patients with acquired disorders were excluded. Clinical details and genetic variants were recorded and analyzed.

Results: Twenty patients were diagnosed at a median age of 6.6 years (IQR: 2.9-10.8 years). Arrhythmias included 16 (80%) with atrial/supraventricular arrhythmias and 8 (40%) with ventricular tachycardia, including 4 with cardiac arrests. A type 1 Brugada pattern was documented in 4. Pacemakers were implanted in 18 (90%). Although atrial leads were …

Oocyte-Specific Wee1-Like Protein Kinase 2 Is Dispensable For Fertility In Mice, Kaori Nozawa, Zian Liao, Yuhkoh Satouh, Ting Geng, Masahito Ikawa, Diana Monsivais, Martin M Matzuk

Faculty, Staff and Students Publications

Wee1-like protein kinase 2 (WEE2) is an oocyte-specific protein tyrosine kinase involved in the regulation of oocyte meiotic arrest in humans. As such, it has been proposed as a candidate for non-hormonal female contraception although pre-clinical models have not been reported. Therefore, we developed two novel knockout mouse models using CRISPR/Cas9 to test loss-of-function of Wee2 on female fertility. A frameshift mutation at the Wee2 translation start codon in exon 2 had no effect on litter size, litter production, or the ability of oocytes to maintain prophase I arrest. Because of the lack of a reproductive phenotype, we additionally generated …

The Coordinated Management Of Ribosome And Translation During Injury And Regeneration, Thanh Nguyen, Jason C Mills, Charles J Cho

Faculty, Staff and Students Publications

Diverse acute and chronic injuries induce damage responses in the gastrointestinal (GI) system, and numerous cell types in the gastrointestinal tract demonstrate remarkable resilience, adaptability, and regenerative capacity in response to stress. Metaplasias, such as columnar and secretory cell metaplasia, are well-known adaptations that these cells make, the majority of which are epidemiologically associated with an elevated cancer risk. On a number of fronts, it is now being investigated how cells respond to injury at the tissue level, where diverse cell types that differ in proliferation capacity and differentiation state cooperate and compete with one another to participate in regeneration. …

Ultrahigh Resolution Lipid Mass Spectrometry Imaging Of High-Grade Serous Ovarian Cancer Mouse Models, Xin Ma, Andro Botros, Sylvia R Yun, Eun Young Park, Olga Kim, Soojin Park, Thu-Huyen Pham, Ruihong Chen, Murugesan Palaniappan, Martin M Matzuk, Jaeyeon Kim, Facundo M Fernández

Faculty, Staff and Students Publications

No effective screening tools for ovarian cancer (OC) exist, making it one of the deadliest cancers among women. Considering that little is known about the detailed progression and metastasis mechanism of OC at a molecular level, it is crucial to gain more insights into how metabolic and signaling alterations accompany its development. Herein, we present a comprehensive study using ultra-high-resolution Fourier transform ion cyclotron resonance matrix-assisted laser desorption/ionization (MALDI) mass spectrometry imaging (MSI) to investigate the spatial distribution and alterations of lipids in ovarian tissues collected from double knockout (n = 4) and triple mutant mouse models (n …