Digital Commons Network^™

Probiotic Limosilactobacillus Reuteri Dsm 17938 Changes Foxp3 Deficiency-Induced Dyslipidemia And Chronic Hepatitis In Mice, Erini Nessim Kostandy, Ji Ho Suh, Xiangjun Tian, Beanna Okeugo, Erin Rubin, Sara Shirai, Meng Luo, Christopher M Taylor, Kang Ho Kim, J Marc Rhoads, Yuying Liu

Faculty, Staff and Student Publications

The probiotic Limosilactobacillus reuteri DSM 17938 produces anti-inflammatory effects in scurfy (SF) mice, a model characterized by immune dysregulation, polyendocrinopathy, enteropathy, and X-linked inheritance (called IPEX syndrome in humans), caused by regulatory T cell (Treg) deficiency and is due to a Foxp3 gene mutation. Considering the pivotal role of lipids in autoimmune inflammatory processes, we investigated alterations in the relative abundance of lipid profiles in SF mice (± treatment with DSM 17938) compared to normal WT mice. We also examined the correlation between plasma lipids and gut microbiota and circulating inflammatory markers. We noted a significant upregulation of plasma lipids …

Thsd1 Suppresses Autophagy-Mediated Focal Adhesion Turnover By Modulating The Fak-Beclin 1 Pathway, Zhen Xu, Jiayi Lu, Song Gao, Yan-Ning Rui

Faculty, Staff and Student Publications

Focal adhesions (FAs) play a crucial role in cell spreading and adhesion, and their autophagic degradation is an emerging area of interest. This study investigates the role of Thrombospondin Type 1 Domain-Containing Protein 1 (THSD1) in regulating autophagy and FA stability in brain endothelial cells, shedding light on its potential implications for cerebrovascular diseases. Our research reveals a physical interaction between THSD1 and FAs. Depletion of THSD1 significantly reduces FA numbers, impairing cell spreading and adhesion. The loss of THSD1 also induces autophagy independently of changes in mTOR and AMPK activation, implying that THSD1 primarily governs FA dynamics rather than …

Functional Epas1/ Hif2a Missense Variant Is Associated With Hematocrit In Andean Highlanders, Elijah S Lawrence, Wanjun Gu, Ryan J Bohlender, Cecilia Anza-Ramirez, Amy M Cole, James J Yu, Hao Hu, Erica C Heinrich, Katie A O'Brien, Carlos A Vasquez, Quinn T Cowan, Patrick T Bruck, Kysha Mercader, Mona Alotaibi, Tao Long, James E Hall, Esteban A Moya, Marco A Bauk, Jennifer J Reeves, Mitchell C Kong, Rany M Salem, Gustavo Vizcardo-Galindo, Jose-Luis Macarlupu, Rómulo Figueroa-Mujíca, Daniela Bermudez, Noemi Corante, Eduardo Gaio, Keolu P Fox, Veikko Salomaa, Aki S Havulinna, Andrew J Murray, Atul Malhotra, Frank L Powel, Mohit Jain, Alexis C Komor, Gianpiero L Cavalleri, Chad D Huff, Francisco C Villafuerte, Tatum S Simonson

Faculty, Staff and Student Publications

Hypoxia-inducible factor pathway genes are linked to adaptation in both human and nonhuman highland species. EPAS1, a notable target of hypoxia adaptation, is associated with relatively lower hemoglobin concentration in Tibetans. We provide evidence for an association between an adaptive EPAS1 variant (rs570553380) and the same phenotype of relatively low hematocrit in Andean highlanders. This Andean-specific missense variant is present at a modest frequency in Andeans and absent in other human populations and vertebrate species except the coelacanth. CRISPR-base-edited human cells with this variant exhibit shifts in hypoxia-regulated gene expression, while metabolomic analyses reveal both genotype and phenotype associations …

Srf-Deficient Astrocytes Provide Neuroprotection In Mouse Models Of Excitotoxicity And Neurodegeneration, Surya Chandra Rao Thumu, Monika Jain, Sumitha Soman, Soumen Das, Vijaya Verma, Arnab Nandi, David H Gutmann, Balaji Jayaprakash, Deepak Nair, James P Clement, Swananda Marathe, Narendrakumar Ramanan

2020-Current year OA Pubs

Reactive astrogliosis is a common pathological hallmark of CNS injury, infection, and neurodegeneration, where reactive astrocytes can be protective or detrimental to normal brain functions. Currently, the mechanisms regulating neuroprotective astrocytes and the extent of neuroprotection are poorly understood. Here, we report that conditional deletion of serum response factor (SRF) in adult astrocytes causes reactive-like hypertrophic astrocytes throughout the mouse brain. These

Prex1 Improves Homeostatic Proliferation To Maintain A Naive Cd4+ T Cell Compartment In Older Age, Huimin Zhang, Hirohisa Okuyama, Abhinav Jain, Rohit R Jadhav, Bowen Wu, Ines Sturmlechner, Jose Morales, Shozo Ohtsuki, Cornelia M Weyand, Jӧrg J Goronzy

Faculty, Staff and Student Publications

The human adult immune system maintains normal T cell counts and compensates for T cell loss throughout life, mainly through peripheral homeostatic proliferation after the ability of the thymus to generate new T cells has rapidly declined at adolescence. This process is mainly driven by STAT5-activating cytokines, most importantly IL-7, and is very effective in maintaining a large naive CD4+ T cell compartment into older age. Here, we describe that naive CD4+ T cells undergo adaptations to optimize IL-7 responses by upregulating the guanine-nucleotide exchange factor PREX1 in older age. PREX1 promotes nuclear translocation of phosphorylated STAT5, thereby supporting homeostatic …

Impact Of An Integrated Health, Nutrition, And Early Child Stimulation And Responsive Care Intervention Package Delivered To Preterm Or Term Small For Gestational Age Babies During Infancy On Growth And Neurodevelopment: Study Protocol Of An Individually Randomized Controlled Trial In India (Small Babies Trial), Ranadip Chowdhury, Rukman Manapurath, Ingvild Fossgard Sandøy, Ravi Prakash Upadhyay, Neeta Dhabhai, Saijuddin Shaikh, Harish Chellani, Tarun Shankar Choudhary, Abhinav Jain, Jose Martines, Nita Bhandari, Tor A Strand, Sunita Taneja

Faculty, Staff and Student Publications

BACKGROUND: Preterm and term small for gestational age (SGA) babies are at high risk of experiencing malnutrition and impaired neurodevelopment. Standalone interventions have modest and sometimes inconsistent effects on growth and neurodevelopment in these babies. For greater impact, intervention may be needed in multiple domains-health, nutrition, and psychosocial care and support. Therefore, the combined effects of an integrated intervention package for preterm and term SGA on growth and neurodevelopment are worth investigating.

METHODS: An individually randomized controlled trial is being conducted in urban and peri-urban low to middle-socioeconomic neighborhoods in South Delhi, India. Infants are randomized (1:1) into two strata …

Targeting Dna2 Overcomes Metabolic Reprogramming In Multiple Myeloma, Natthakan Thongon, Feiyang Ma, Natalia Baran, Pamela Lockyer, Jintan Liu, Christopher Jackson, Ashley Rose, Ken Furudate, Bethany Wildeman, Matteo Marchesini, Valentina Marchica, Paola Storti, Giannalisa Todaro, Irene Ganan-Gomez, Vera Adema, Juan Jose Rodriguez-Sevilla, Yun Qing, Min Jin Ha, Rodrigo Fonseca, Caleb Stein, Caleb Class, Lin Tan, Sergio Attanasio, Guillermo Garcia-Manero, Nicola Giuliani, David Berrios Nolasco, Andrea Santoni, Claudio Cerchione, Carlos Bueso-Ramos, Marina Konopleva, Philip Lorenzi, Koichi Takahashi, Elisabet Manasanch, Gabriella Sammarelli, Rashmi Kanagal-Shamanna, Andrea Viale, Marta Chesi, Simona Colla

Faculty, Staff and Student Publications

DNA damage resistance is a major barrier to effective DNA-damaging therapy in multiple myeloma (MM). To discover mechanisms through which MM cells overcome DNA damage, we investigate how MM cells become resistant to antisense oligonucleotide (ASO) therapy targeting Interleukin enhancer binding factor 2 (ILF2), a DNA damage regulator that is overexpressed in 70% of MM patients whose disease has progressed after standard therapies have failed. Here, we show that MM cells undergo adaptive metabolic rewiring to restore energy balance and promote survival in response to DNA damage activation. Using a CRISPR/Cas9 screening strategy, we identify the mitochondrial DNA repair protein …

Discovery And Clinical Proof-Of-Concept Of Rly-2608, A First-In-Class Mutant-Selective Allosteric Pi3kα Inhibitor That Decouples Antitumor Activity From Hyperinsulinemia, Andreas Varkaris, Ermira Pazolli, Hakan Gunaydin, Qi Wang, Levi Pierce, Alessandro A Boezio, Artemisa Bulku, Lucian Dipietro, Cary Fridrich, Adam Frost, Fabrizio Giordanetto, Erika P Hamilton, Katherine Harris, Michael Holliday, Tamieka L Hunter, Amanda Iskandar, Yongli Ji, Alexandre Larivée, Jonathan R Larochelle, André Lescarbeau, Fabien Llambi, Brenda Lormil, Mary M Mader, Brenton G Mar, Iain Martin, Thomas H Mclean, Klaus Michelsen, Yakov Pechersky, Erika Puente-Poushnejad, Kevin Raynor, Dipali Rogala, Ramin Samadani, Alison M Schram, Kelley Shortsleeves, Sweta Swaminathan, Shahein Tajmir, Gege Tan, Yong Tang, Roberto Valverde, Bryan Wehrenberg, Jeremy Wilbur, Bret R Williams, Hongtao Zeng, Hanmo Zhang, W Patrick Walters, Beni B Wolf, David E Shaw, Donald A Bergstrom, James Watters, James S Fraser, Pascal D Fortin, D Randal Kipp

Faculty, Staff and Student Publications

PIK3CA (PI3Kα) is a lipid kinase commonly mutated in cancer, including ∼40% of hormone receptor–positive breast cancer. The most frequently observed mutants occur in the kinase and helical domains. Orthosteric PI3Kα inhibitors suffer from poor selectivity leading to undesirable side effects, most prominently hyperglycemia due to inhibition of wild-type (WT) PI3Kα. Here, we used molecular dynamics simulations and cryo-electron microscopy to identify an allosteric network that provides an explanation for how mutations favor PI3Kα activation. A DNA-encoded library screen leveraging electron microscopy-optimized constructs, differential enrichment, and an orthosteric-blocking compound led to the identification of RLY-2608, a first-in-class allosteric mutant-selective inhibitor …

Scaffold Protein Sh3bp2 Signalosome Is Pivotal For Immune Activation In Nephrotic Syndrome., Tarak Srivastava, Robert E. Garola, Jianping Zhou, Varun C. Boinpelly, Mohammad Rezaiekhaligh, Trupti Joshi, Yuexu Jiang, Diba Ebadi, Siddarth Sharma, Christine Sethna, Vincent S. Staggs, Ram Sharma, Debbie S. Gipson, Wei Hao, Yujie Wang, Laura H. Mariani, Jeffrey B. Hodgin, Robert Rottapel, Teruhito Yoshitaka, Yasuyoshi Ueki, Mukut Sharma

Manuscripts, Articles, Book Chapters and Other Papers

Despite clinical use of immunosuppressive agents, the immunopathogenesis of minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS) remains unclear. Src homology 3-binding protein 2 (SH3BP2), a scaffold protein, forms an immune signaling complex (signalosome) with 17 other proteins, including phospholipase Cγ2 (PLCγ2) and Rho-guanine nucleotide exchange factor VAV2 (VAV2). Bioinformatic analysis of human glomerular transcriptome (Nephrotic Syndrome Study Network cohort) revealed upregulated SH3BP2 in MCD and FSGS. The SH3BP2 signalosome score and downstream MyD88, TRIF, and NFATc1 were significantly upregulated in MCD and FSGS. Immune pathway activation scores for Toll-like receptors, cytokine-cytokine receptor, and NOD-like receptors were increased in …

Immunoglobulin Replacement Products Protect Against Sars-Cov-2 Infection In Vivo Despite Poor Neutralizing Activity, Ofer Zimmerman, Alexa Michelle Altman Doss, Baoling Ying, Chieh-Yu Liang, Samantha R. Mackin, Hannah G. Davis-Adams, Lucas J. Adams, Laura A. Vanblargan, Rita E. Chen, Suzanne M. Scheaffer, Pritesh Desai, Saravanan Raju, Tarisa L. Mantia, Caitlin C. O'Shaughnessy, Jennifer Marie Monroy, H. James Wedner, Christopher J. Rigell, Andrew L. Kau, Tiffany Biason Dy, Zhen Ren, Jackson S. Turner, Jane A. O'Halloran, Rachel M. Presti, Peggy L. Kendall, Daved H. Fremont, Ali H. Ellebedy, Michael S Diamond

2020-Current year OA Pubs

Immunoglobulin (IG) replacement products are used routinely in patients with immune deficiency and other immune dysregulation disorders who have poor responses to vaccination and require passive immunity conferred by commercial antibody products. The binding, neutralizing, and protective activity of intravenously administered IG against SARS-CoV-2 emerging variants remains unknown. Here, we tested 198 different IG products manufactured from December 2019 to August 2022. We show that prepandemic IG had no appreciable cross-reactivity or neutralizing activity against SARS-CoV-2. Anti-spike antibody titers and neutralizing activity against SARS-CoV-2 WA1/2020 D614G increased gradually after the pandemic started and reached levels comparable to vaccinated healthy donors …

Genomemuster Mouse Genetic Variation Service Enables Multitrait, Multipopulation Data Integration And Analysis., Robyn L Ball, Molly A. Bogue, Hongping Liang, Anuj Srivastava, David G Ashbrook, Anna Lamoureux, Matthew Gerring, Alexander S Hatoum, Matthew J Kim, Hao He, Jake Emerson, Alexander Berger, David O Walton, Keith Sheppard, Baha El Kassaby, Francisco Castellanos, Govindarajan Kunde-Ramamoorthy, Lu Lu, John Bluis, Sejal Desai, Beth A. Sundberg, Gary Peltz, Zhuoqing Fang, Gary Churchill, Robert W Williams, Arpana Agrawal, Carol J Bult, Vivek M. Philip, Elissa J Chesler

Faculty Research 2024

Hundreds of inbred mouse strains and intercross populations have been used to characterize the function of genetic variants that contribute to disease. Thousands of disease-relevant traits have been characterized in mice and made publicly available. New strains and populations including consomics, the collaborative cross, expanded BXD, and inbred wild-derived strains add to existing complex disease mouse models, mapping populations, and sensitized backgrounds for engineered mutations. The genome sequences of inbred strains, along with dense genotypes from others, enable integrated analysis of trait-variant associations across populations, but these analyses are hampered by the sparsity of genotypes available. Moreover, the data are …

[Summary: International Consensus Statement On Nomenclature And Classification Of The Congenital Bicuspid Aortic Valve And Its Aortopathy, For Clinical, Surgical, Interventional And Research Purposes], Hector I Michelena, Alessandro Della Corte, Arturo Evangelista, Joseph J Maleszewski, William D Edwards, Mary J Roman, Richard B Devereux, Borja Fernández, Federico M Asch, Alex J Barker, Lilia M Sierra, Laurent De Kerchove, Susan M Fernandes, Paul W M Fedak, Evaldas Girdauskas, Victoria Delgado, Suhny Abbara, Emmanuel Lansac, Siddharth K Prakash, Malenka M Bissell, Bogdan A Popescu, Michael D Hope, Marta Sitges, Vinod H Thourani, Phillippe Pibarot, Krishnaswamy Chandrasekaran, Patrizio Lancellotti, Michael A Borger, John K Forrest, John Webb, Dianna M Milewicz, Raj Makkar, Martin B Leon, Stephen P Sanders, Michael Markl, Victor A Ferrari, William C Roberts, Jae-Kwan Song, Philipp Blanke, Charles S White, Samuel Siu, Lars G Svensson, Alan C Braverman, Joseph Bavaria, Thoralf M Sundt, Gebrine El Khoury, Ruggero De Paulis, Maurice Enriquez-Sarano, Jeroen J Bax, Catherine M Otto, Hans-Joachim Schäfers

Faculty, Staff and Student Publications

This consensus of nomenclature and classification for congenital bicuspid aortic valve and its aortopathy is evidence-based and intended for universal use by physicians (both pediatricians and adults), echocardiographers, advanced cardiovascular imaging specialists, interventional cardiologists, cardiovascular surgeons, pathologists, geneticists, and researchers spanning these areas of clinical and basic research. In addition, as long as new key and reference research is available, this international consensus may be subject to change based on evidence-based data1.

Examining Associations Between School-Level Determinants And The Implementation Of Physical Activity Opportunities, Derek W Craig, Timothy J Walker, Shreela V Sharma, Paula Cuccaro, Natalia I Heredia, Andjelka Pavlovic, Laura F Defina, Harold W Kohl, Maria E Fernandez

Faculty, Staff and Student Publications

School-based physical activity (PA) opportunities can help students engage in greater amounts of daily PA, meet PA guidelines, and lead to improved health and educational outcomes. However, we do not completely understand the organizational challenges to implementing these opportunities successfully. This exploratory study examined associations between school-level determinants and the implementation of school-based PA opportunities. We analyzed cross-sectional survey data from schools (n = 46) participating in the Healthy Zone School Program (HZSP) (Dallas, Texas, USA) during 2019-2020. Respondents completed an electronic survey that included measures of school-level determinants (e.g. culture, leadership, priority) and the implementation of school-based PA opportunities. …

Aspscr1-Tfe3 Reprograms Transcription By Organizing Enhancer Loops Around Hexameric Vcp/P97, Amir Pozner, Li Li, Shiv Prakash Verma, Shuxin Wang, Jared J Barrott, Mary L Nelson, Jamie S E Yu, Gian Luca Negri, Shane Colborne, Christopher S Hughes, Ju-Fen Zhu, Sydney L Lambert, Lara S Carroll, Kyllie Smith-Fry, Michael G Stewart, Sarmishta Kannan, Bodrie Jensen, Cini M John, Saif Sikdar, Hongrui Liu, Ngoc Ha Dang, Jennifer Bourdage, Jinxiu Li, Jeffery M Vahrenkamp, Katelyn L Mortenson, John S Groundland, Rosanna Wustrack, Donna L Senger, Franz J Zemp, Douglas J Mahoney, Jason Gertz, Xiaoyang Zhang, Alexander J Lazar, Martin Hirst, Gregg B Morin, Torsten O Nielsen, Peter S Shen, Kevin B Jones

Faculty, Staff and Student Publications

The t(X,17) chromosomal translocation, generating the ASPSCR1::TFE3 fusion oncoprotein, is the singular genetic driver of alveolar soft part sarcoma (ASPS) and some Xp11-rearranged renal cell carcinomas (RCCs), frustrating efforts to identify therapeutic targets for these rare cancers. Here, proteomic analysis identifies VCP/p97, an AAA+ ATPase with known segregase function, as strongly enriched in co-immunoprecipitated nuclear complexes with ASPSCR1::TFE3. We demonstrate that VCP is a likely obligate co-factor of ASPSCR1::TFE3, one of the only such fusion oncoprotein co-factors identified in cancer biology. Specifically, VCP co-distributes with ASPSCR1::TFE3 across chromatin in association with enhancers genome-wide. VCP presence, its hexameric assembly, and its …

How Does Covid-19 Vaccination Affect Long-Covid Symptoms?, Ali Akbar Asadi-Pooya, Meshkat Nemati, Mina Shahisavandi, Hamid Nemati, Afrooz Karimi, Anahita Jafari, Sara Nasiri, Seyyed Saeed Mohammadi, Zahra Rahimian, Hossein Bayat, Ali Akbari, Amir Emami, Owrang Eilami

Department of Neurology Faculty Papers

OBJECTIVE: The current study aimed to identify the association between COVID-19 vaccination and prolonged post-COVID symptoms (long-COVID) in adults who reported suffering from this condition.

METHODS: This was a retrospective follow-up study of adults with long-COVID syndrome. The data were collected during a phone call to the participants in January-February 2022. We inquired about their current health status and also their vaccination status if they agreed to participate.

RESULTS: In total, 1236 people were studied; 543 individuals reported suffering from long long- COVID (43.9%). Chi square test showed that 15 out of 51 people (29.4%) with no vaccination and 528 …

Longitudinal Single-Cell Transcriptional Dynamics Throughout Neurodegeneration In Sca1, Leon Tejwani, Neal G Ravindra, Changwoo Lee, Yubao Cheng, Billy Nguyen, Kimberly Luttik, Luhan Ni, Shupei Zhang, Logan M Morrison, John Gionco, Yangfei Xiang, Jennifer Yoon, Hannah Ro, Fatema Haidery, Rosalie M Grijalva, Eunwoo Bae, Kristen Kim, Regina T Martuscello, Harry T Orr, Huda Y Zoghbi, Hayley S Mcloughlin, Laura P W Ranum, Vikram G Shakkottai, Phyllis L Faust, Siyuan Wang, David Van Dijk, Janghoo Lim

Duncan NRI Faculty and Staff Publications

Neurodegeneration is a protracted process involving progressive changes in myriad cell types that ultimately results in the death of vulnerable neuronal populations. To dissect how individual cell types within a heterogeneous tissue contribute to the pathogenesis and progression of a neurodegenerative disorder, we performed longitudinal single-nucleus RNA sequencing of mouse and human spinocerebellar ataxia type 1 (SCA1) cerebellar tissue, establishing continuous dynamic trajectories of each cell population. Importantly, we defined the precise transcriptional changes that precede loss of Purkinje cells and, for the first time, identified robust early transcriptional dysregulation in unipolar brush cells and oligodendroglia. Finally, we applied a …

Genomemuster Mouse Genetic Variation Service Enables Multitrait, Multipopulation Data Integration And Analysis, Robyn L Ball, Alexander S Hatoum, Arpana Agrawal, Et Al.

2020-Current year OA Pubs

Hundreds of inbred mouse strains and intercross populations have been used to characterize the function of genetic variants that contribute to disease. Thousands of disease-relevant traits have been characterized in mice and made publicly available. New strains and populations including consomics, the collaborative cross, expanded BXD, and inbred wild-derived strains add to existing complex disease mouse models, mapping populations, and sensitized backgrounds for engineered mutations. The genome sequences of inbred strains, along with dense genotypes from others, enable integrated analysis of trait-variant associations across populations, but these analyses are hampered by the sparsity of genotypes available. Moreover, the data are …

Unraveling The Genetic Architecture Of Congenital Vertebral Malformation With Reference To The Developing Spine, Sen Zhao, Hengqiang Zhao, Lina Zhao, Xi Cheng, Zhifa Zheng, Mengfan Wu, Wen Wen, Shengru Wang, Zixiang Zhou, Haibo Xie, Dengfeng Ruan, Qing Li, Xinquan Liu, Chengzhu Ou, Guozhuang Li, Zhengye Zhao, Guilin Chen, Yuchen Niu, Xiangjie Yin, Yuhong Hu, Xiaochen Zhang, Deciphering Disorders Involving Scoliosis And Comorbidities (Disco) Study, Pengfei Liu, Guixing Qiu, Wanlu Liu, Chengtian Zhao, Zhihong Wu, Jianguo Zhang, Nan Wu

Faculty, Staff and Students Publications

Congenital vertebral malformation, affecting 0.13-0.50 per 1000 live births, has an immense locus heterogeneity and complex genetic architecture. In this study, we analyze exome/genome sequencing data from 873 probands with congenital vertebral malformation and 3794 control individuals. Clinical interpretation identifies Mendelian etiologies in 12.0% of the probands and reveals a muscle-related disease mechanism. Gene-based burden test of ultra-rare variants identifies risk genes with large effect sizes (ITPR2, TBX6, TPO, H6PD, and SEC24B). To further investigate the biological relevance of the genetic association signals, we perform single-nucleus RNAseq on human embryonic spines. The burden test signals are enriched in the notochord …

Universal Risk Prediction For Individuals With And Without Atherosclerotic Cardiovascular Disease, Yejin Mok, Zeina Dardari, Yingying Sang, Xiao Hu, Michael P Bancks, Lena Mathews, Ron C Hoogeveen, Silvia Koton, Michael J Blaha, Wendy S Post, Christie M Ballantyne, Josef Coresh, Wayne Rosamond, Kunihiro Matsushita

Faculty, Staff and Students Publications

Background: American College of Cardiology/American Heart Association guidelines recommend distinct risk classification systems for primary and secondary cardiovascular disease prevention. However, both systems rely on similar predictors (eg, age and diabetes), indicating the possibility of a universal risk prediction approach for major adverse cardiovascular events (MACEs).

Objectives: The authors examined the performance of predictors in persons with and without atherosclerotic cardiovascular disease (ASCVD) and developed and validated a universal risk prediction model.

Methods: Among 9,138 ARIC (Atherosclerosis Risk In Communities) participants with (n = 609) and without (n = 8,529) ASCVD at baseline (1996-1998), we examined established predictors in the …

Metabolic Model Predictions Enable Targeted Microbiome Manipulation Through Precision Prebiotics, Georgios Marinos, Inga K Hamerich, Reena Debray, Nancy Obeng, Carola Petersen, Jan Taubenheim, Johannes Zimmermann, Dana Blackburn, Buck S Samuel, Katja Dierking, Andre Franke, Matthias Laudes, Silvio Waschina, Hinrich Schulenburg, Christoph Kaleta

Faculty, Staff and Students Publications

While numerous health-beneficial interactions between host and microbiota have been identified, there is still a lack of targeted approaches for modulating these interactions. Thus, we here identify precision prebiotics that specifically modulate the abundance of a microbiome member species of interest. In the first step, we show that defining precision prebiotics by compounds that are only taken up by the target species but no other species in a community is usually not possible due to overlapping metabolic niches. Subsequently, we use metabolic modeling to identify precision prebiotics for a two-member Caenorhabditis elegans microbiome community comprising the immune-protective target species Pseudomonas …

Large-Scale Proteomics Identifies Novel Biomarkers And Circulating Risk Factors For Aortic Stenosis, Khaled Shelbaya, Victoria Arthur, Yimin Yang, Pranav Dorbala, Leo Buckley, Brian Claggett, Hicham Skali, Line Dufresne, Ta-Yu Yang, James C Engert, George Thanassoulis, James Floyd, Thomas R Austin, Anna Bortnick, Jorge Kizer, Renata C C Freitas, Sasha A Singh, Elena Aikawa, Ron C Hoogeveen, Christie Ballantyne, Bing Yu, Josef Coresh, Michael J Blaha, Kunihiro Matsushita, Amil M Shah

Faculty, Staff and Student Publications

Background: Limited data exist regarding risk factors for aortic stenosis (AS). The plasma proteome is a promising phenotype for discovery of novel biomarkers and potentially causative mechanisms.

Objectives: The aim of this study was to discover novel biomarkers with potentially causal associations with AS.

Methods: We measured 4,877 plasma proteins (SomaScan aptamer-affinity assay) among ARIC (Atherosclerosis Risk In Communities) study participants in mid-life (visit 3 [V3]; n = 11,430; age 60 ± 6 years) and in late-life (V5; n = 4,899; age 76 ± 5 years). We identified proteins cross-sectionally associated with aortic valve (AV) peak velocity (AVmax) and dimensionless …

Chimeric Antigen Receptor Macrophages Target And Resorb Amyloid Plaques, Alexander B. Kim, Qingli Xiao, Ping Yan, Qiuyun Pan, Gaurav Pandey, Susie Grathwohl, Ernesto Gonzales, Isabella Xu, Yoonho Cho, Hans Haecker, Slava Epelman, Abhinav Diwan, Jin-Moo Lee, Carl J Deselm

2020-Current year OA Pubs

Substantial evidence suggests a role for immunotherapy in treating Alzheimer's disease (AD). While the precise pathophysiology of AD is incompletely understood, clinical trials of antibodies targeting aggregated forms of β amyloid (Aβ) have shown that reducing amyloid plaques can mitigate cognitive decline in patients with early-stage AD. Here, we describe what we believe to be a novel approach to target and degrade amyloid plaques by genetically engineering macrophages to express an Aβ-targeting chimeric antigen receptor (CAR-Ms). When injected intrahippocampally, first-generation CAR-Ms have limited persistence and fail to significantly reduce plaque load, which led us to engineer next-generation CAR-Ms that secrete …

Streamlined Identification Of Clinically And Functionally Relevant Genetic Regulators Of Lower-Tract Urogenital Development, Meade Haller, Yan Yin, Gabe Haller, Tian Li, Qiufang Li, Laura E Lamb, Liang Ma

2020-Current year OA Pubs

Congenital anomalies of the lower genitourinary (LGU) tract are frequently comorbid due to genetically linked developmental pathways, and are among the most common yet most socially stigmatized congenital phenotypes. Genes involved in sexual differentiation are prime candidates for developmental anomalies of multiple LGU organs, but insufficient prospective screening tools have prevented the rapid identification of causative genes. Androgen signaling is among the most influential modulators of LGU development. The present study uses SpDamID technology in vivo to generate a comprehensive map of the pathways actively regulated by the androgen receptor (AR) in the genitalia in the presence of the p300 …

Fluvoxamine Inhibits Th1 And Th17 Polarization And Function By Repressing Glycolysis To Attenuate Autoimmune Progression In Type 1 Diabetes, Yuan Zou, Jing Zhang, Fei Sun, Qianqian Xu, Longmin Chen, Xi Luo, Ting Wang, Qing Zhou, Shu Zhang, Fei Xiong, Wen Kong, Ping Yang, Qilin Yu, Shiwei Liu, Cong-Yi Wang

Faculty, Staff and Student Publications

BACKGROUND: Fluvoxamine is one of the selective serotonin reuptake inhibitors (SSRIs) that are regarded as the first-line drugs to manage mental disorders. It has been also recognized with the potential to treat inflammatory diseases and viral infection. However, the effect of fluvoxamine on autoimmune diseases, particularly type 1 diabetes (T1D) and the related cellular and molecular mechanisms, are yet to be addressed.

METHOD: Herein in this report, we treated NOD mice with fluvoxamine for 2 weeks starting from 10-week of age to dissect the impact of fluvoxamine on the prevention of type 1 diabetes. We compared the differences of immune …

Efficacy Of Novel Agents Against Cellular Models Of Familial Platelet Disorder With Myeloid Malignancy (Fpd-Mm), Christopher P Mill, Warren C Fiskus, Courtney D Dinardo, Patrick Reville, John A Davis, Christine E Birdwell, Kaberi Das, Hanxi Hou, Koichi Takahashi, Lauren Flores, Xinjia Ruan, Xiaoping Su, Sanam Loghavi, Joseph D Khoury, Kapil N Bhalla

Faculty, Staff and Student Publications

Germline, mono-allelic mutations in RUNX1 cause familial platelet disorder (RUNX1-FPD) that evolves into myeloid malignancy (FPD-MM): MDS or AML. FPD-MM commonly harbors co-mutations in the second RUNX1 allele and/or other epigenetic regulators. Here we utilized patient-derived (PD) FPD-MM cells and established the first FPD-MM AML cell line (GMR-AML1). GMR-AML1 cells exhibited active super-enhancers of MYB, MYC, BCL2 and CDK6, augmented expressions of c-Myc, c-Myb, EVI1 and PLK1 and surface markers of AML stem cells. In longitudinally studied bone marrow cells from a patient at FPD-MM vs RUNX1-FPD state, we confirmed increased chromatin accessibility and mRNA expressions of MYB, MECOM and …

Aneuploid Embryonic Stem Cells Drive Teratoma Metastasis, Rong Xiao, Deshu Xu, Meili Zhang, Zhanghua Chen, Li Cheng, Songjie Du, Mingfei Lu, Tonghai Zhou, Ruoyan Li, Fan Bai, Yue Huang

Faculty, Staff and Student Publications

Aneuploidy, a deviation of the chromosome number from euploidy, is one of the hallmarks of cancer. High levels of aneuploidy are generally correlated with metastasis and poor prognosis in cancer patients. However, the causality of aneuploidy in cancer metastasis remains to be explored. Here we demonstrate that teratomas derived from aneuploid murine embryonic stem cells (ESCs), but not from isogenic diploid ESCs, disseminated to multiple organs, for which no additional copy number variations were required. Notably, no cancer driver gene mutations were identified in any metastases. Aneuploid circulating teratoma cells were successfully isolated from peripheral blood and showed high capacities …

The Novel Phosphatase Nudt5 Is A Critical Regulator Of Triple-Negative Breast Cancer Growth, Jing Qian, Yanxia Ma, William M Tahaney, Cassandra L Moyer, Amanda Lanier, Jamal Hill, Darian Coleman, Negar Koupaei, Susan G Hilsenbeck, Michelle I Savage, Brent D G Page, Abhijit Mazumdar, Powel H Brown

Faculty, Staff and Student Publications

BACKGROUND: The most aggressive form of breast cancer is triple-negative breast cancer (TNBC), which lacks expression of the estrogen receptor (ER) and progesterone receptor (PR), and does not have overexpression of the human epidermal growth factor receptor 2 (HER2). Treatment options for women with TNBC tumors are limited, unlike those with ER-positive tumors that can be treated with hormone therapy, or those with HER2-positive tumors that can be treated with anti-HER2 therapy. Therefore, we have sought to identify novel targeted therapies for TNBC. In this study, we investigated the potential of a novel phosphatase, NUDT5, as a potential therapeutic target …

Immune Response To Sars-Cov-2 Variants After Immunization With Different Vaccines In Mexico, Erika Garay, Sean P J Whelan, Rebecca M Dubois, Sara M O'Rourke, Angel Eduardo Salgado-Escobar, José Esteban Muñoz-Medina, Carlos F Arias, Susana López

2020-Current year OA Pubs

There is limited information on the antibody responses against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in subjects from developing countries with populations having a high incidence of co-morbidities. Here, we analysed the immunogenicity of homologous schemes using the ChAdOx1-S, Sputnik V, or BNT162b2 vaccines and the effect of a booster dose with ChAdOx1-S in middle-aged adults who were seropositive or seronegative to the SARS-CoV-2 spike protein before vaccination. The study was conducted post-vaccination with a follow-up of 4 months for antibody titre using enzyme-linked immunosorbent assay (ELISA) and pseudovirus (PV) neutralization assays (PNAs). All three vaccines elicited a superior …

Gestational Diabetes Augments Group B Streptococcus Infection By Disrupting Maternal Immunity And The Vaginal Microbiota, Vicki Mercado-Evans, Marlyd E Mejia, Jacob J Zulk, Samantha Ottinger, Zainab A Hameed, Camille Serchejian, Madelynn G Marunde, Clare M Robertson, Mallory B Ballard, Simone H Ruano, Natalia Korotkova, Anthony R Flores, Kathleen A Pennington, Kathryn A Patras

Faculty, Staff and Student Publications

Group B Streptococcus (GBS) is a pervasive perinatal pathogen, yet factors driving GBS dissemination in utero are poorly defined. Gestational diabetes mellitus (GDM), a complication marked by dysregulated immunity and maternal microbial dysbiosis, increases risk for GBS perinatal disease. Using a murine GDM model of GBS colonization and perinatal transmission, we find that GDM mice display greater GBS in utero dissemination and subsequently worse neonatal outcomes. Dual-RNA sequencing reveals differential GBS adaptation to the GDM reproductive tract, including a putative glycosyltransferase (yfhO), and altered host responses. GDM immune disruptions include reduced uterine natural killer cell activation, impaired recruitment to placentae, …

Nlgn4x Tcr Transgenic T Cells To Treat Gliomas., Christoper Krämer, Michael Kilian, Yu-Chan Chih, Alexandros Kourtesakis, Dirk C Hoffmann, Tamara Boschert, Philipp Koopmann, Khwab Sanghvi, Alice De Roia, Stefanie Jung, Kristine Jähne, Bryan Day, Leonard D. Shultz, Miriam Ratliff, Richard Harbottle, Edward W Green, Rainer Will, Wolfgang Wick, Michael Platten, Lukas Bunse

Faculty Research 2024

BACKGROUND: Neuroligin 4 X-linked (NLGN4X) harbors a human leukocyte antigen (HLA)-A*02-restricted tumor-associated antigen, overexpressed in human gliomas, that was found to induce specific cytotoxic T cell responses following multi-peptide vaccination in patients with newly diagnosed glioblastoma.

METHODS: T cell receptor (TCR) discovery was performed using droplet-based single-cell TCR sequencing of NLGN4X-tetramer-sorted T cells postvaccination. The identified TCR was delivered to Jurkat T cells and primary human T cells (NLGN4X-TCR-T). Functional profiling of NLGN4X-TCR-T was performed by flow cytometry and cytotoxicity assays. Therapeutic efficacy of intracerebroventricular NLGN4X-TCR-T was assessed in NOD scid gamma (NSG) major histocompatibility complex (MHC) I/II knockout (KO) …