Medical Immunology Commons^™

Reversible Male Contraception By Targeted Inhibition Of Serine/Threonine Kinase 33, Angela F Ku, Kiran L Sharma, Hai Minh Ta, Courtney M Sutton, Kurt M Bohren, Yong Wang, Srinivas Chamakuri, Ruihong Chen, John M Hakenjos, Ravikumar Jimmidi, Katarzyna Kent, Feng Li, Jian-Yuan Li, Lang Ma, Chandrashekhar Madasu, Murugesan Palaniappan, Stephen S Palmer, Xuan Qin, Matthew B Robers, Banumathi Sankaran, Zhi Tan, Yasmin M Vasquez, Jian Wang, Jennifer Wilkinson, Zhifeng Yu, Qiuji Ye, Damian W Young, Mingxing Teng, Choel Kim, Martin M Matzuk

Faculty, Staff and Students Publications

Men or mice with homozygous serine/threonine kinase 33 (STK33) mutations are sterile owing to defective sperm morphology and motility. To chemically evaluate STK33 for male contraception with STK33-specific inhibitors, we screened our multibillion-compound collection of DNA-encoded chemical libraries, uncovered potent STK33-specific inhibitors, determined the STK33 kinase domain structure bound with a truncated hit CDD-2211, and generated an optimized hit CDD-2807 that demonstrates nanomolar cellular potency (half-maximal inhibitory concentration = 9.2 nanomolar) and favorable metabolic stability. In mice, CDD-2807 exhibited no toxicity, efficiently crossed the blood-testis barrier, did not accumulate in brain, and induced a reversible contraceptive effect that …

Mv140 Mucosal Vaccine Induces Targeted Immune Response For Enhanced Clearance Of Uropathogenic E Coli In Experimental Urinary Tract Infection, Paula Saz-Leal, Marianne Morris Ligon, Carmen María Diez-Rivero, Diego García-Ayuso, Soumitra Mohanty, Marcos Viñuela, Irene Real-Arévalo, Laura Conejero, Annelie Brauner, José Luis Subiza, Indira Uppugunduri Mysorekar

Faculty, Staff and Students Publications

MV140 is an inactivated whole-cell bacterial mucosal vaccine with proven clinical efficacy against recurrent urinary tract infections (UTIs). These infections are primarily caused by uropathogenic E. coli (UPEC) strains, which are unique in their virulence factors and remarkably diverse. MV140 contains a non-UPEC strain, suggesting that it may induce an immune response against different UPEC-induced UTIs in patients. To verify this, we experimentally evaluated the cellular and humoral responses to UTI89, a prototypical UPEC strain, in mice vaccinated with MV140, as well as the degree of protection achieved in a UPEC UTI89 model of acute cystitis. The results show that …

Downregulation Of Mirlet7 Mirna Family Promotes Tc17 Differentiation And Emphysema Via De-Repression Of Rorγt, Phillip A Erice, Xinyan Huang, Matthew J Seasock, Matthew J Robertson, Hui-Ying Tung, Melissa A Perez-Negron, Shivani L Lotlikar, David B Corry, Farrah Kheradmand, Antony Rodriguez

Faculty, Staff and Students Publications

Environmental air irritants including nanosized carbon black (nCB) can drive systemic inflammation, promoting chronic obstructive pulmonary disease (COPD) and emphysema development. The let-7 microRNA (Mirlet7 miRNA) family is associated with IL-17-driven T cell inflammation, a canonical signature of lung inflammation. Recent evidence suggests the Mirlet7 family is downregulated in patients with COPD, however, whether this repression conveys a functional consequence on emphysema pathology has not been elucidated. Here, we show that overall expression of the Mirlet7 clusters, Mirlet7b/Mirlet7c2 and Mirlet7a1/Mirlet7f1/Mirlet7d, are reduced in the lungs and T cells of smokers with emphysema as well as in mice with …

Correction: Horne Et Al White Matter Correlates Of Domain-Specific Working Memory, Autumn Horne, Junhua Ding, Tatiana T Schnur, Randi C Martin

Faculty, Staff and Student Publications

In the original publication [...].

Investigating The Role Of The Gut Microbiota On Immune Checkpoint Inhibitor-Mediated Colitis, Taylor Halsey, Robert Jenq

Dissertations and Theses (Open Access)

Immune checkpoint inhibitors (ICIs) have been revolutionary in the fight against cancer by recruiting the host immune system as an agent for attack on malignant cells. Unfortunately, immune-related adverse events (irAEs), including ICI-mediated colitis (IMC), are common side effects that result from immune cell mediated damage on healthy tissues. Recent studies have highlighted a role for the gut microbiota in modulating ICI-mediated anti-tumor responses, but less is known regarding how the gut microbiota may impact on irAEs. Considering that the gastrointestinal tract harbors thousands of unique microbial species, many of which are known to modulate the immune system, microbes and …

Cord Blood-Derived Invariant Natural Killer T Cells As A Platform For Allogeneic Chimeric Antigen Receptor Cell Therapy, Maison Grefe

Dissertations and Theses (Open Access)

Chimeric antigen receptor (CAR) T cells have revolutionized the treatment of hematopoietic malignancies achieving >50% complete response rates in numerous refractory/relapsed B cell malignancies. However, there are challenges that hinder CAR-T efficacy and bar the broader use of this therapy in patients. One approach to address these challenges is to create a safe allogeneic CAR cell product by using cells that do not cause graft versus host disease (GvHD). Invariant natural killer T (iNKT) cells are an ideal candidate as they are restricted to the monomorphic CD1d protein in contrast to HLA restricted αβ-T cells and therefore are safe in …

Dissecting The Relationship Between Mucin 5ac And The Lung/Gut Microbiome In The Pathogenesis Of K-Ras Mutant Lung Cancer, Maria T. Grimaldo

Dissertations and Theses (Open Access)

Non-small cell lung cancer, including its most common subtype, lung adenocarcinoma (LUAD), is the leading cause of cancer-related deaths worldwide. In LUAD patients, KRAS mutations are the most common oncogenic driver alteration. Given KRAS is upstream to many signaling pathways involved in cell survival and cytokine production, interventions against KRAS-mutant lung cancers are prone to develop acquired resistance. Thus, there is a need to develop alternate targeting strategies and test combination therapies for improved intervention. Previously, we have found that KRAS-mutant LUAD (KM-LUAD) patients whose tumors harbor high expression of Mucin 5 AC (MUC5AC), a main airway secretory mucin, have …

Kras Allelic Variants In Biliary Tract Cancers, Gordon Taylor Moffat, Zishuo Ian Hu, Funda Meric-Bernstam, Elisabeth Kathleen Kong, Dean Pavlick, Jeffrey S Ross, Karthikeyan Murugesan, Lawrence Kwong, Anaemy Danner De Armas, Anil Korkut, Milind Javle, Jennifer J Knox

Faculty, Staff and Student Publications

IMPORTANCE: Biliary tract cancers (BTCs) contain several actionable molecular alterations, including FGFR2, IDH1, ERBB2 (formerly HER2), and KRAS. KRAS allelic variants are found in 20% to 30% of BTCs, and multiple KRAS inhibitors are currently under clinical investigation.

OBJECTIVES: To describe the genomic landscape, co-sequence variations, immunophenotype, genomic ancestry, and survival outcomes of KRAS-mutated BTCs and to calculate the median overall survival (mOS) for the most common allelic variants.

DESIGN, SETTING, AND PARTICIPANTS: This retrospective, multicenter, pooled cohort study obtained clinical and next-generation sequencing data from multiple databases between January 1, 2017, and December 31, 2022. These databases included Princess …

Synthetic Cationic Helical Polypeptides For The Stimulation Of Antitumour Innate Immune Pathways In Antigen-Presenting Cells, Daeyong Lee, Kristin Huntoon, Yifan Wang, Minjeong Kang, Yifei Lu, Seong Dong Jeong, Todd M Link, Thomas D Gallup, Yaqing Qie, Xuefeng Li, Shiyan Dong, Benjamin R Schrank, Adam J Grippin, Abin Antony, Jonghoon Ha, Mengyu Chang, Yi An, Liang Wang, Dadi Jiang, Jing Li, Albert C Koong, John A Tainer, Wen Jiang, Betty Y S Kim

Faculty, Staff and Student Publications

Intracellular DNA sensors regulate innate immunity and can provide a bridge to adaptive immunogenicity. However, the activation of the sensors in antigen-presenting cells (APCs) by natural agonists such as double-stranded DNAs or cyclic nucleotides is impeded by poor intracellular delivery, serum stability, enzymatic degradation and rapid systemic clearance. Here we show that the hydrophobicity, electrostatic charge and secondary conformation of helical polypeptides can be optimized to stimulate innate immune pathways via endoplasmic reticulum stress in APCs. One of the three polypeptides that we engineered activated two major intracellular DNA-sensing pathways (cGAS-STING (for cyclic guanosine monophosphate-adenosine monophosphate synthase-stimulator of interferon genes) …

Clinical Outcomes After Acute Coronary Syndromes Or Revascularization Among People Living With Hiv: A Systematic Review And Meta-Analysis, Mohammed Haji, Michael Capilupi, Michael Kwok, Nouran Ibrahim, Gerald S Bloomfield, Christopher T Longenecker, Maria C Rodriguez-Barradas, Chester N Ashong, Eric Jutkowitz, Tracey H Taveira, Michelle Richard, Jennifer L Sullivan, James L Rudolph, Wen-Chih Wu, Sebhat Erqou

Faculty, Staff and Students Publications

IMPORTANCE: Clinical outcomes after acute coronary syndromes (ACS) or percutaneous coronary interventions (PCIs) in people living with HIV have not been characterized in sufficient detail, and extant data have not been synthesized adequately.

OBJECTIVE: To better characterize clinical outcomes and postdischarge treatment of patients living with HIV after ACS or PCIs compared with patients in an HIV-negative control group.

DATA SOURCES: Ovid MEDLINE, Embase, and Web of Science were searched for all available longitudinal studies of patients living with HIV after ACS or PCIs from inception until August 2023.

STUDY SELECTION: Included studies met the following criteria: patients living with …

Effectiveness Of Cord Blood As A Strategy To Rule Out Conjugated Hyperbilirubinemia, Miray Kurtca, Sanjiv Harpavat, Sridevi Devaraj

Faculty, Staff and Students Publications

Early detection of biliary atresia is crucial for timely intervention and improved outcomes in infants with elevated conjugated bilirubin levels. This study aims to investigate the viability of cord blood gas analysis as a novel method for assessing conjugated bilirubin levels. Infants with high heel stick levels also showed elevated cord blood bilirubin levels, indicating that cord blood testing could replace the need for repeat heel stick tests, especially benefiting low birth weight infants. Ongoing research, including larger cohorts and alternative bilirubin measurement methods, will further validate this innovative screening approach. Infants with biliary atresia have high conjugated bilirubin levels …

A Review Of Shared Decision-Making, Published Protocols, And Post-Desensitization Strategies In Oral Immunotherapy (Oit), Susan Laubach, Edwin H Kim, Matthew Greenhawt, Sally Bailey, Aikaterini Anagnostou

Faculty, Staff and Students Publications

PURPOSE OF REVIEW: The aim of this review is to highlight key published oral immunotherapy (OIT) protocols and post-desensitization strategies for the major food allergens and to cover important concepts to consider when evaluating OIT for food-allergic patients. Shared decision-making should help identify patient and family values which will help influence the type of evidence-based protocol and maintenance strategy to use.

RECENT FINDINGS: With food OIT emerging as a treatment option, there is a pressing need for patients, physicians, and other providers to have a nuanced understanding of the management choices available to them. There are now randomized controlled trials …

Analytical Challenges In Omics Research On Asthma And Allergy: A National Institute Of Allergy And Infectious Diseases Workshop, Supinda Bunyavanich, Patrice M Becker, Matthew C Altman, Jessica Lasky-Su, Carole Ober, Karsten Zengler, Evgeny Berdyshev, Richard Bonneau, Talal Chatila, Nilanjan Chatterjee, Kian Fan Chung, Colleen Cutcliffe, Wendy Davidson, Gang Dong, Gang Fang, Patricia Fulkerson, Blanca E Himes, Liming Liang, Rasika A Mathias, Shuji Ogino, Joseph Petrosino, Nathan D Price, Eric Schadt, James Schofield, Max A Seibold, Hanno Steen, Lisa Wheatley, Hongmei Zhang, Alkis Togias, Kohei Hasegawa

Center for Medical Ethics and Health Policy Staff Publications

Studies of asthma and allergy are generating increasing volumes of omics data for analysis and interpretation. The National Institute of Allergy and Infectious Diseases (NIAID) assembled a workshop comprising investigators studying asthma and allergic diseases using omics approaches, omics investigators from outside the field, and NIAID medical and scientific officers to discuss the following areas in asthma and allergy research: genomics, epigenomics, transcriptomics, microbiomics, metabolomics, proteomics, lipidomics, integrative omics, systems biology, and causal inference. Current states of the art, present challenges, novel and emerging strategies, and priorities for progress were presented and discussed for each area. This workshop report summarizes …

Grb2 Stabilizes Rad51 At Reversed Replication Forks Suppressing Genomic Instability And Innate Immunity Against Cancer, Zu Ye, Shengfeng Xu, Yin Shi, Xueqian Cheng, Yuan Zhang, Sunetra Roy, Sarita Namjoshi, Michael A Longo, Todd M Link, Katharina Schlacher, Guang Peng, Dihua Yu, Bin Wang, John A Tainer, Zamal Ahmed

Faculty, Staff and Student Publications

Growth factor receptor-bound protein 2 (GRB2) is a cytoplasmic adapter for tyrosine kinase signaling and a nuclear adapter for homology-directed-DNA repair. Here we find nuclear GRB2 protects DNA at stalled replication forks from MRE11-mediated degradation in the BRCA2 replication fork protection axis. Mechanistically, GRB2 binds and inhibits RAD51 ATPase activity to stabilize RAD51 on stalled replication forks. In GRB2-depleted cells, PARP inhibitor (PARPi) treatment releases DNA fragments from stalled forks into the cytoplasm that activate the cGAS-STING pathway to trigger pro-inflammatory cytokine production. Moreover in a syngeneic mouse metastatic ovarian cancer model, GRB2 depletion in the context of PARPi treatment …

Advances In Immunocompetent Mouse And Rat Models, Wen Bu, Yi Li

Center on Aging Staff Publications

Rodent models of breast cancer have played critical roles in our understanding of breast cancer development and progression as well as preclinical testing of cancer prevention and therapeutics. In this article, we first review the values and challenges of conventional genetically engineered mouse (GEM) models and newer iterations of these models, especially those with inducible or conditional regulation of oncogenes and tumor suppressors. Then, we discuss nongermline (somatic) GEM models of breast cancer with temporospatial control, made possible by intraductal injection of viral vectors to deliver oncogenes or to manipulate the genome of mammary epithelial cells. Next, we introduce the …

Treatment Outcomes With Standard Of Care In Relapsed/Refractory Diffuse Large B-Cell Lymphoma: Real-World Data Analysis, Andrew Ip, Alex Mutebi, Tongsheng Wang, Monika Jun, Anupama Kalsekar, Fernando Rivas Navarro, Anthony Wang, Rajesh Kamalakar, Mariana Sacchi, Brian Elliott

Faculty, Staff and Student Publications

INTRODUCTION: Despite new therapies for relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL), treatments with chemotherapy, single-agent rituximab/obinutuzumab, single-agent lenalidomide, or combinations of these agents continue to be commonly used.

METHODS: This retrospective study utilized longitudinal data from 4226 real-world electronic health records to characterize outcomes in patients with R/R DLBCL. Eligible patients were diagnosed with DLBCL between January 2010 and March 2022 and had R/R disease treated with ≥ 1 prior systemic line of therapy (LOT), including ≥ 1 anti-CD20-containing regimen.

RESULTS: A total of 573 patients treated with ≥ 1 prior LOT were included (31.2% and 13.4% …

Validation Of A Whole Blood Machine Learning Strategy For Distinguishing Between Bacterial And Viral Infection In A Pediatric Hospital Setting, Ridwan B Ibrahim, Herda Ona, Anil K Chokkalla, Estella Tam, Sridevi Devaraj

Faculty, Staff and Students Publications

Similar symptoms between viral and bacterial diseases often make diagnosis difficult. This study assessed the clinical performance of the newly cleared whole-blood Bacterial versus Viral Score assay in our pediatric cohort to the previously validated serum assay and emergency department physician diagnosis. This assay shows excellent agreement (R = 0.997) with the serum assay and has great diagnostic accuracy when compared to physician diagnosis.

Dawn-To-Dusk Dry Fasting Decreases Circulating Inflammatory Cytokines In Subjects With Increased Body Mass Index, Zahraa Al Lami, Miray Kurtca, Moin Uddin Atique, Antone R Opekun, Mohamad S Siam, Prasun K Jalal, Bijan Najafi, Sridevi Devaraj, Ayse L Mindikoglu

Faculty, Staff and Students Publications

Background

The circadian rhythm involves numerous metabolic processes, including sleep/awakening, body temperature regulation, hormone secretion, hepatic function, cellular plasticity, and cytokine release (inflammation), that appear to have a dynamic relationship with all the processes above. Studies have linked various cytokines to the chronic state of low-grade inflammation and oxidative stress in obesity. Dawn-to-dusk dry fasting (DDDF) could alleviate the adverse effects of obesity by decreasing inflammation. This study examined the effects of DDDF on circulating inflammatory cytokines in subjects with increased body mass index (BMI).

Methods

The current observational prospective study included adult subjects with a BMI equal to or …

Systemic Lupus Erythematosus And Lupus Nephritis Presenting As Severe Constitutional Symptoms, Ton La, Sahifah Ansari, Ethan Ha, Matthew Novakovic

Faculty, Staff and Students Publications

Systemic lupus erythematosus (SLE) is a remitting-relapsing systemic autoantibody and immune complex disease with a similar clinical presentation to that of malignancy and infection. The authors report a case of newly diagnosed SLE and lupus nephritis in a 48-year-old woman with constitutional symptoms and unintentional weight loss. Her presentation was further complicated by pericardial effusion and methicillin-resistant Staphylococcus aureus (MRSA) facial cellulitis and bacteremia. In the context of nonspecific symptoms and a wide initial differential diagnosis, the early consideration of rheumatologic etiologies and the involvement of consultant services led to appropriate diagnostic testing and a timely diagnosis.

Genomic Data In The All Of Us Research Program, All Of Us Research Program Genomics Investigators

Faculty, Staff and Students Publications

Comprehensively mapping the genetic basis of human disease across diverse individuals is a long-standing goal for the field of human genetics1–4. The All of Us Research Program is a longitudinal cohort study aiming to enrol a diverse group of at least one million individuals across the USA to accelerate biomedical research and improve human health5,6. Here we describe the programme’s genomics data release of 245,388 clinical-grade genome sequences. This resource is unique in its diversity as 77% of participants are from communities that are historically under-represented in biomedical research and 46% are …

Delayed Presentation Of Food Protein-Induced Enterocolitis Syndrome (Fpies) To Okra In A Toddler, Hunter Hall, Sara Anvari, Fallon Schultz, Olubukola Ojuola, Nicholas L Rider

Faculty, Staff and Students Publications

BACKGROUND: Food protein-induced enterocolitis syndrome (FPIES) is a non-immunoglobulin E (IgE) -mediated food allergy predominantly observed in infants and characterized by the delayed onset of vomiting following ingestion of a trigger food. An increase in research and clinical consideration of FPIES has led to the discovery of unique deviations from the standard FPIES triggers and presentations.

CASE PRESENTATION: A 34-month-old female patient with a history of consuming okra daily presented to medical attention after developing classic FPIES symptoms to okra beginning at 14-months of age.

CONCLUSIONS: Recently, awareness about the varied nature of FPIES clinical presentation has come to light. …

Txnrd1 Drives The Innate Immune Response In Senescent Cells With Implications For Age-Associated Inflammation, Xue Hao, Bo Zhao, Martina Towers, Liping Liao, Edgar Luzete Monteiro, Xin Xu, Christina Freeman, Hongzhuang Peng, Hsin-Yao Tang, Aaron Havas, Andrew V Kossenkov, Shelley L Berger, Peter D Adams, David W Speicher, David Schultz, Ronen Marmorstein, Kenneth S Zaret, Rugang Zhang

Faculty, Staff and Student Publications

Sterile inflammation, also known as 'inflammaging', is a hallmark of tissue aging. Cellular senescence contributes to tissue aging, in part, through the secretion of proinflammatory factors collectively known as the senescence-associated secretory phenotype (SASP). The genetic variability of thioredoxin reductase 1 (TXNRD1) is associated with aging and age-associated phenotypes such as late-life survival, activity of daily living and physical performance in old age. TXNRD1's role in regulating tissue aging has been attributed to its enzymatic role in cellular redox regulation. Here, we show that TXNRD1 drives the SASP and inflammaging through the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) …

The Curious Case Of A Painful Leg Ulcer, Jay R Patel, Rubi Montejano, Christina Hopkins, Hanna Siatecka, Theodore Rosen

Faculty, Staff and Students Publications

Sickle cell disease is a condition that can involve numerous organ systems secondary to vascular occlusion. Herein, we present a case of a 21-year-old male with sickle cell disease requiring long-term hydroxyurea therapy. Upon migrating to the United States from Yemen, the patient developed a rapidly progressive, exquisitely painful ulcer on his right lower extremity. Given his country of origin, a broad differential, including select infectious diseases, was essential. Moreover, establishing the unequivocally correct diagnosis was crucial to determine proper and safe therapy. Ultimately, a lesional biopsy demonstrated numerous sickled red blood cells occluding blood vessels, leading to the diagnosis …

Invasive Group A Streptococcus In Infants Less Than 1-Year Of Age From 2012 To 2022: A Single-Center Experience, Taylor Nack, Jesus G Vallejo, James Dunn, Anthony R Flores, J Chase Mcneil

Faculty, Staff and Students Publications

The incidence of invasive Group A Streptococcus (iGAS) has varied throughout the COVID-19 pandemic. We reviewed iGAS infections in infants ≤1 year from 2012 to 2022. Twenty-five percent of cases occurred in the last quarter of 2022. Pneumonia (21.8%) was the most common presentation. Twenty-one patients (65.6%) were successfully transitioned to oral antibiotics.

Epstein-Barr Virus-Based Prognostic Model In Nodular Sclerosis Classic Hodgkin Lymphoma, Chen Jiang, Li-Yun Huang, Ji-Hao Zhou, Zhi-Ming Li, Yu Wang, Shuo Li, Jian-Chang Fu, Qi-Tao Huang, Qin Yan, Yu-Yuan Huang, Min Zuo, Shimin Hu, Robert Peter Gale, Yang Liang, Jing-Ping Yun, Yu-Hua Huang

Faculty, Staff and Student Publications

The role of Epstein-Barr virus (EBV) in lymphoma cells of nodular sclerosis classic Hodgkin lymphoma (NScHL) is controversial. Our aim was to explore this and establish a clinically feasible model for risk stratification. We interrogated data from 542 consecutive subjects with NScHL receiving ABVD therapy and demonstrated EBV-infection in their lymphoma cells with EBV-encoded small RNAs (EBERs) in situ hybridization. Subjects were divided into training and validation datasets. As data from the training dataset suggested EBERs-positivity was the only independent prognostic factor for both progression-free survival (PFS) and overall survival (OS), we developed corresponding prognostic models based on it. Our …

Gad65abs Are Not Associated With Beta-Cell Dysfunction In Patients With T2d In The Grade Study, Christiane S Hampe, Ali Shojaie, Barbara Brooks-Worrell, Sepideh Dibay, Kristina Utzschneider, Steven E Kahn, Mary E Larkin, Mary L Johnson, Naji Younes, Neda Rasouli, Cyrus Desouza, Robert M Cohen, Jean Y Park, Hermes J Florez, Willy Marcos Valencia, Robert Stempel, Jerry P Palmer, Ashok Balasubramanyam

Faculty, Staff and Students Publications

CONTEXT: Autoantibodies directed against the 65-kilodalton isoform of glutamic acid decarboxylase (GAD65Abs) are markers of autoimmune type 1 diabetes (T1D) but are also present in patients with Latent Autoimmune Diabetes of Adults and autoimmune neuromuscular diseases, and also in healthy individuals. Phenotypic differences between these conditions are reflected in epitope-specific GAD65Abs and anti-idiotypic antibodies (anti-Id) against GAD65Abs. We previously reported that 7.8% of T2D patients in the GRADE study have GAD65Abs but found that GAD65Ab positivity was not correlated with beta-cell function, glycated hemoglobin (HbA1c), or fasting glucose levels.

CONTEXT: In this study, we aimed to better characterize islet autoantibodies …

D-Mannose Reduces Cellular Senescence And Nlrp3/Gasdermind/Il-1Β-Driven Pyroptotic Uroepithelial Cell Shedding In The Murine Bladder, Chetanchandra S Joshi, Arnold M Salazar, Caihong Wang, Marianne M Ligon, Rayvanth R Chappidi, Bisiayo E Fashemi, Paul A Felder, Amy Mora, Sandra L Grimm, Cristian Coarfa, Indira U Mysorekar

Faculty, Staff and Students Publications

Aging is a risk factor for disease via increased susceptibility to infection, decreased ability to maintain homeostasis, inefficiency in combating stress, and decreased regenerative capacity. Multiple diseases, including urinary tract infection (UTI), are more prevalent with age; however, the mechanisms underlying the impact of aging on the urinary tract mucosa and the correlation between aging and disease remain poorly understood. Here, we show that, relative to young (8-12 weeks) mice, the urothelium of aged (18-24 months) female mice accumulates large lysosomes with reduced acid phosphatase activity and decreased overall autophagic flux in the aged urothelium, indicative of compromised cellular homeostasis. …

Features Of Acute Covid-19 Associated With Post-Acute Sequelae Of Sars-Cov-2 Phenotypes: Results From The Impacc Study, Al Ozonoff, Naresh Doni Jayavelu, Shanshan Liu, Esther Melamed, Carly E Milliren, Jingjing Qi, Linda N Geng, Grace A Mccomsey, Charles B Cairns, Lindsey R Baden, Joanna Schaenman, Albert C Shaw, Hady Samaha, Vicki Seyfert-Margolis, Florian Krammer, Lindsey B Rosen, Hanno Steen, Caitlin Syphurs, Ravi Dandekar, Casey P Shannon, Rafick P Sekaly, Lauren I R Ehrlich, David B Corry, Farrah Kheradmand, Mark A Atkinson, Scott C Brakenridge, Nelson I Agudelo Higuita, Jordan P Metcalf, Catherine L Hough, William B Messer, Bali Pulendran, Kari C Nadeau, Mark M Davis, Ana Fernandez Sesma, Viviana Simon, Harm Van Bakel, Seunghee Kim-Schulze, David A Hafler, Ofer Levy, Monica Kraft, Chris Bime, Elias K Haddad, Carolyn S Calfee, David J Erle, Charles R Langelier, Walter Eckalbar, Steven E Bosinger, Bjoern Peters, Steven H Kleinstein, Elaine F Reed, Alison D Augustine, Joann Diray-Arce, Holden T Maecker, Matthew C Altman, Ruth R Montgomery, Patrice M Becker, Nadine Rouphael

Faculty, Staff and Students Publications

Post-acute sequelae of SARS-CoV-2 (PASC) is a significant public health concern. We describe Patient Reported Outcomes (PROs) on 590 participants prospectively assessed from hospital admission for COVID-19 through one year after discharge. Modeling identified 4 PRO clusters based on reported deficits (minimal, physical, mental/cognitive, and multidomain), supporting heterogenous clinical presentations in PASC, with sub-phenotypes associated with female sex and distinctive comorbidities. During the acute phase of disease, a higher respiratory SARS-CoV-2 viral burden and lower Receptor Binding Domain and Spike antibody titers were associated with both the physical predominant and the multidomain deficit clusters. A lower frequency of circulating B …

Combinatorial Effects Of Ion Channel Mis-Splicing As A Cause Of Myopathy In Myotonic Dystrophy, Larissa Nitschke, Thomas A Cooper

Faculty, Staff and Students Publications

Myotonic dystrophy type 1 (DM1) is an autosomal dominant disorder caused by an unstable expanded CTG repeat located in the 3'-UTR of the DM1 protein kinase (DMPK) gene. The pathogenic mechanism results in misregulated alternative splicing of hundreds of genes, creating the dilemma of establishing which genes contribute to the mechanism of DM1 skeletal muscle pathology. In this issue of the JCI, Cisco and colleagues systematically tested the combinatorial effects of DM1-relevant mis-splicing patterns in vivo and identified the synergistic effects of mis-spliced calcium and chloride channels as a major contributor to DM1 skeletal muscle impairment. The authors further demonstrated …

Transcriptomics Analysis Reveals Potential Mechanisms Underlying Mitochondrial Dysfunction And T Cell Exhaustion In Astronauts’ Blood Cells In Space, Maria Moreno-Villanueva, Luis E Jimenez-Chavez, Stephanie Krieger, Liang-Hao Ding, Ye Zhang, Adriana Babiak-Vazquez, Mark Berres, Sandra Splinter, Kristen E Pauken, Brian C Schaefer, Brian E Crucian, Honglu Wu

Faculty, Staff and Student Publications

Introduction: The impact of spaceflight on the immune system and mitochondria has been investigated for decades. However, the molecular mechanisms underlying spaceflight-induced immune dysregulations are still unclear.

Methods: In this study, blood from eleven crewmembers was collected before and during International Space Station (ISS) missions. Transcriptomic analysis was performed in isolated peripheral blood mononuclear cells (PBMCs) using RNA-sequencing. Differentially expresses genes (DEG) in space were determined by comparing of the inflight to the preflight samples. Pathways and statistical analyses of these DEG were performed using the Ingenuity Pathway Analysis (IPA) tool.

Results: In comparison to pre-flight, a total of 2030 …