Medicine and Health Sciences Commons^™

The Uterine Secretome Initiates Growth Of Gynecologic Tissues In Ectopic Locations, Jan Sunde, Morgan Wasickanin, Tiffany A Katz, Laurel Gillette, Sanam Bidadi, Derek O'Neil, Ramya Masand, Richard O Burney, Kathleen A Pennington

Faculty, Staff and Students Publications

Endosalpingiosis (ES) and endometriosis (EM) refer to the growth of tubal and endometrial epithelium respectively, outside of their site of origin. We hypothesize that uterine secretome factors drive ectopic growth. To test this, we developed a mouse model of ES and EM using tdTomato (tdT) transgenic fluorescent mice as donors. To block implantation factors, progesterone knockout (PKO) tdT mice were created. Fluorescent lesions were present after oviduct implantation with and without WT endometrium. Implantation was increased (p<0.05) when tdt oviductal tissue was implanted with endometrium compared to oviductal tissue alone. Implantation was reduced (p<0.0005) in animals implanted with minced tdT oviductal tissue with PKO tdT endometrium compared to WT endometrium. Finally, oviductal tissues was incubated with and without a known implantation factor, leukemia inhibitory factor (LIF) prior to and during implantation. LIF promoted lesion implantation. In conclusion, endometrial derived implantation factors, such as LIF, are necessary to initiate ectopic tissue growth. We have developed an animal model of ectopic growth of gynecologic tissues in a WT mouse which will potentially allow for development of new prevention and treatment modalities.

Lung Infection With Classical Klebsiella Pneumoniae Strains Establishes Robust Macrophage-Dependent Protection Against Heterologous Reinfection, Joseph J Mackel, Casey L G Mick, Emily Guo, David A Rosen

2020-Current year OA Pubs

At present, there is no approved vaccine for prevention of infection by the opportunistic bacterium Klebsiella pneumoniae (Kp); success in treating these infections is increasingly challenged by the spread of antibiotic resistance. Preclinical investigation of adaptive immunity elicited by lung infection with live classical Kp may reveal host mechanisms of protection against this pathogen. Here, we utilize multiple virulent classical Kp strains to demonstrate that following lung infection, surviving wild-type mice develop protective immunity against both homologous and heterologous (heterotypic) reinfection. For Kp strains with low capacity to disseminate from the lung, this immunity is B-cell-independent. We further demonstrate that …

A Structure-Function Analysis Of Hepatocyte Arginase 2 Reveals Mitochondrial Ureahydrolysis As A Determinant Of Glucose Oxidation, Yiming Zhang, Jiameng Sun, Henry D Wasserman, Joshua A Adams, Cassandra B Higgins, Shannon C Kelly, Louise Lantier, Brian J Debosch

2020-Current year OA Pubs

BACKGROUND & AIMS: Restoring hepatic and peripheral insulin sensitivity is critical to prevent or reverse metabolic syndrome and type 2 diabetes. Glucose homeostasis comprises in part the complex regulation of hepatic glucose production and insulin-mediated glucose uptake and oxidation in peripheral tissues. We previously identified hepatocyte arginase 2 (Arg2) as an inducible ureahydrolase that improves glucose homeostasis and enhances glucose oxidation in multiple obese, insulin-resistant models. We therefore examined structure-function determinants through which hepatocyte Arg2 governs systemic insulin action and glucose oxidation.

METHODS: To do this, we generated mice expressing wild-type murine Arg2, enzymatically inactive Arg2 (Arg2

RESULTS: We show …

Folate Regulation Of Planar Cell Polarity Pathway And F-Actin Through Folate Receptor Alpha, Xiao Han, Xuanye Cao, Robert M Cabrera, Paula Andrea Pimienta Ramirez, Ying Linda Lin, Bogdan J Wlodarczyk, Cuilian Zhang, Richard H Finnell, Yunping Lei

Faculty, Staff and Students Publications

Folate deficiency contribute to neural tube defects (NTDs) which could be rescued by folate supplementation. However, the underlying mechanisms are still not fully understood. Besides, there is considerable controversy concerning the forms of folate used for supplementation. To address this controversy, we prepared culture medium with different forms of folate, Folic acid (FA) and 5-methyltetrahydrofolate(5mTHF), at concentration of 5uM, 500nM, 50nM and folate free, respectively. Mouse embryonic fibroblasts (MEFs) were treated with different folates continuously for three passages and cell proliferation and F-actin was monitored. We determined that compared to 5mTHF, FA showed stronger effects on promoting cell proliferation and …

Targeting Of Oncogenic Aaa-Atpase Trip13 Reduces Progression Of Pancreatic Ductal Adenocarcinoma, Farrukh Afaq, Sumit Agarwal, Prachi Bajpai, Sameer Al Diffalha, Hyung-Gyoon Kim, Shajan Peter, Moh'd Khushman, Subhash C Chauhan, Priyabrata Mukherjee, Sooryanarayana Varambally, Upender Manne

2020-Current year OA Pubs

Thyroid hormone receptor-interacting protein 13 (TRIP13) is involved in cancer progression, but its role in pancreatic ductal adenocarcinoma (PDAC) is unknown. Thus, we assessed the expression, functional role, and mechanism of action of TRIP13 in PDAC. We further examined the efficacy of TRIP13 inhibitor, DCZ0415, alone or in combination with gemcitabine on malignant phenotypes, tumor progression, and immune response. We found that TRIP13 was overexpressed in human PDACs relative to corresponding normal pancreatic tissues. TRIP13 knockdown or treatment of PDAC cells with DCZ0415 reduced proliferation and colony formation, and induced G2/M cell cycle arrest and apoptosis. Additionally, TRIP13 knockdown or …

Neurosteroids Mediate And Modulate The Effects Of Pro-Inflammatory Stimulation And Toll-Like Receptors On Hippocampal Plasticity And Learning, Yukitoshi Izumi, Kazuko A. O'Dell, Anil G. Cashikar, Steven M. Paul, Douglas F. Covey, Steven J. Mennerick, Charles F. Zorumski

2020-Current year OA Pubs

Pro-inflammatory changes contribute to multiple neuropsychiatric illnesses. Understanding how these changes are involved in illnesses and identifying strategies to alter inflammatory responses offer paths to potentially novel treatments. We previously found that acute pro-inflammatory stimulation with high (μg/ml) lipopolysaccharide (LPS) for 10-15 min dampens long-term potentiation (LTP) in the hippocampus and impairs learning. Effects of LPS involved non-canonical inflammasome signaling but were independent of toll-like receptor 4 (TLR4), a known LPS receptor. Low (ng/ml) LPS also inhibits LTP when administered for 2-4 h, and here we report that this LPS exposure requires TLR4. We also found that effects of low …

Control Of Acute Myeloid Leukemia And Generation Of Immune Memory In Vivo Using Amv564, A Bivalent Bispecific Cd33 X Cd3 T Cell Engager, Linda G. Eissenberg, Julie K. Ritchey, Michael P. Rettig, Dilan A. Patel, Kiran Vij, Feng Gao, Victoria Smith, Tae H Han, John F. Dipersio

2020-Current year OA Pubs

Off-the-shelf immunotherapeutics that suppress tumor growth and provide durable protection against relapse could enhance cancer treatment. We report preclinical studies on a CD33 x CD3 bivalent bispecific diabody, AMV564, that not only suppresses tumor growth, but also facilitates memory responses in a mouse model of acute myelogenous leukemia (AML). Mechanistically, a single 5-day treatment with AMV564 seems to reduce tumor burden by redirection of T cells, providing a time window for allogeneic or other T cells that innately recognize tumor antigens to become activated and proliferate. When the concentration of bispecific becomes negligible, the effector: target ratio has also shifted, …

Inhibition Of Src-3 As A Potential Therapeutic Strategy For Aggressive Mantle Cell Lymphoma, Imani Bijou, Yang Liu, Dong Lu, Jianwei Chen, Shelby Sloan, Lapo Alinari, David M Lonard, Bert W O'Malley, Michael Wang, Jin Wang

Faculty, Staff and Students Publications

Mantle cell lymphoma (MCL) has a poor prognosis and high relapse rates despite current therapies, necessitating novel treatment regimens. Inhibition of SRC-3 show effectiveness in vivo and in vitro in other B cell lymphomas. Additionally, previous studies have shown that SRC-3 is highly expressed in the lymph nodes of B cell non-Hodgkin's lymphoma patients, suggesting SRC-3 may play a role in the progression of B cell lymphoma. This study aimed to investigate novel SRC-3 inhibitors, SI-10 and SI-12, in mantle cell lymphoma. The cytotoxic effects of SI-10 and SI-12 were evaluated in vitro and demonstrated dose-dependent cytotoxicity in a panel …

Stat1 Employs Myeloid Cell-Extrinsic Mechanisms To Regulate The Neutrophil Response And Provide Protection Against Invasive Klebsiella Pneumoniae Lung Infection, Shekina Gonzalez-Ferrer, Zeyu Xiong, Atish Gheware, Janet S Lee, Et Al.

2020-Current year OA Pubs

Klebsiella pneumoniae (KP) is an extracellular Gram-negative bacterium that causes infections in the lower respiratory and urinary tracts and the bloodstream. STAT1 is a master transcription factor that acts to maintain T cell quiescence under homeostatic conditions. Although STAT1 helps defend against systemic spread of acute KP intrapulmonary infection, whether STAT1 regulation of T cell homeostasis impacts pulmonary host defense during acute bacterial infection and injury is less clear. Using a clinical KP respiratory isolate and a pneumonia mouse model, we found that STAT1 deficiency led to an early neutrophil-dominant transcriptional profile and neutrophil recruitment in the lung preceding widespread …

Cep120 Is Essential For Kidney Stromal Progenitor Cell Growth And Differentiation, Ewa Langner, Tao Cheng, Eirini Kefaloyianni, Charles Gluck, Baolin Wang, Moe R Mahjoub

2020-Current year OA Pubs

Mutations in genes that disrupt centrosome structure or function can cause congenital kidney developmental defects and lead to fibrocystic pathologies. Yet, it is unclear how defective centrosome biogenesis impacts renal progenitor cell physiology. Here, we examined the consequences of impaired centrosome duplication on kidney stromal progenitor cell growth, differentiation, and fate. Conditional deletion of the ciliopathy gene Cep120, which is essential for centrosome duplication, in the stromal mesenchyme resulted in reduced abundance of interstitial lineages including pericytes, fibroblasts and mesangial cells. These phenotypes were caused by a combination of delayed mitosis, activation of the mitotic surveillance pathway leading to apoptosis, …

Age-Associated Temporal Decline In Butyrate-Producing Bacteria Plays A Key Pathogenic Role In The Onset And Progression Of Neuropathology And Memory Deficits In 3×Tg-Ad Mice, Paula M Chilton, Smita S Ghare, Benjamin T Charpentier, Scott A Myers, Aakarsha V Rao, Joseph F Petrosino, Kristi L Hoffman, John C Greenwell, Neetu Tyagi, Jyotirmaya Behera, Yali Wang, Lucy J Sloan, Jingwen Zhang, Christopher B Shields, Gregory E Cooper, Leila Gobejishvili, Scott R Whittemore, Craig J Mcclain, Shirish S Barve

Faculty, Staff and Students Publications

Alterations in the gut-microbiome-brain axis are increasingly being recognized to be involved in Alzheimer's disease (AD) pathogenesis. However, the functional consequences of enteric dysbiosis linking gut microbiota and brain pathology in AD progression remain largely undetermined. The present work investigated the causal role of age-associated temporal decline in butyrate-producing bacteria and butyrate in the etiopathogenesis of AD. Longitudinal metagenomics, neuropathological, and memory analyses were performed in the 3×Tg-AD mouse model. Metataxonomic analyses showed a significant temporal decline in the alpha diversity marked by a decrease in butyrate-producing bacterial communities and a concurrent reduction in cecal butyrate production. Inferred metagenomics analysis …

Neutrophil-Derived Activin-A Moderates Their Pro-Netotic Activity And Attenuates Collateral Tissue Damage Caused By Influenza A Virus Infection, Georgios Divolis, Evgenia Synolaki, Athanasia Doulou, Ariana Gavriil, Christina C Giannouli, Anastasia Apostolidou, Martyn L Foster, Martin M Matzuk, Panagiotis Skendros, Ioanna-Evdokia Galani, Paschalis Sideras

Faculty, Staff and Students Publications

BACKGROUND: Pre-neutrophils, while developing in the bone marrow, transcribe the Inhba gene and synthesize Activin-A protein, which they store and release at the earliest stage of their activation in the periphery. However, the role of neutrophil-derived Activin-A is not completely understood.

METHODS:To address this issue, we developed a neutrophil-specific Activin-A-deficient animal model (S100a8-Cre/Inhba fl/fl mice) and analyzed the immune response to Influenza A virus (IAV) infection. More specifically, evaluation of body weight and lung mechanics, molecular and cellular analyses of bronchoalveolar lavage fluids, flow cytometry and cell sorting of lung cells, as well as histopathological analysis of lung tissues, …

Comparative Exploration Of Mammalian Deafness Gene Homologues In The Drosophila Auditory Organ Shows Genetic Correlation Between Insect And Vertebrate Hearing, Daniel C Sutton, Jonathan C Andrews, Dylan M Dolezal, Ye Jin Park, Hongjie Li, Daniel F Eberl, Shinya Yamamoto, Andrew K Groves

Faculty, Staff and Students Publications

Johnston's organ, the Drosophila auditory organ, is anatomically very different from the mammalian organ of Corti. However, recent evidence indicates significant cellular and molecular similarities exist between vertebrate and invertebrate hearing, suggesting that Drosophila may be a useful platform to determine the function of the many mammalian deafness genes whose underlying biological mechanisms are poorly characterized. Our goal was a comprehensive screen of all known orthologues of mammalian deafness genes in the fruit fly to better understand conservation of hearing mechanisms between the insect and the fly and ultimately gain insight into human hereditary deafness. We used bioinformatic comparisons to …

Human Plcg2 Haploinsufficiency Results In A Novel Natural Killer Cell Immunodeficiency, Joshua B Alinger, Emily M Mace, Justin R Porter, Annelise Y Mah-Som, Allyssa L Daugherty, Stephanie Li, Allison A Throm, Jeanette T Pingel, Nermina Saucier, Albert Yao, Ivan K Chinn, James R Lupski, Mohammad Ehlayel, Michael Keller, Greg R Bowman, Megan A Cooper, Jordan S Orange, Anthony R French

Faculty, Staff and Students Publications

Background:

Although most individuals effectively control herpesvirus infections, some suffer from severe and/or recurrent infections. A subset of these patients possess defects in NK cells, lymphocytes which recognize and lyse herpesvirus-infected cells; however, the genetic etiology is rarely diagnosed. PLCG2 encodes a signaling protein in NK cell and B cell signaling. Dominant-negative or gain-of-function variants in PLCG2 cause cold urticaria, antibody deficiency, and autoinflammation. However, loss-of-function variants and haploinsufficiency have not been reported to date.

Objective:

We aimed to identify the genetic cause of NK cell immunodeficiency in two families, and herein describe the functional consequences of two novel loss-of-function …

Sccad: Cluster Decomposition-Based Anomaly Detection For Rare Cell Identification In Single-Cell Expression Data, Yunpei Xu, Shaokai Wang, Qilong Feng, Jiazhi Xia, Yaohang Li, Hong-Dong Li, Jianxin Wang

Computer Science Faculty Publications

Single-cell RNA sequencing (scRNA-seq) technologies have become essential tools for characterizing cellular landscapes within complex tissues. Large-scale single-cell transcriptomics holds great potential for identifying rare cell types critical to the pathogenesis of diseases and biological processes. Existing methods for identifying rare cell types often rely on one-time clustering using partial or global gene expression. However, these rare cell types may be overlooked during the clustering phase, posing challenges for their accurate identification. In this paper, we propose a Cluster decomposition-based Anomaly Detection method (scCAD), which iteratively decomposes clusters based on the most differential signals in each cluster to effectively separate …

Mapping Of A Hybrid Insulin Peptide In The Inflamed Islet Β-Cells From Nod Mice, Janet M Wenzlau, Orion J Peterson, Anthony N Vomund, James E Dilisio, Anita Hohenstein, Kathryn Haskins, Xiaoxiao Wan

2020-Current year OA Pubs

There is accumulating evidence that pathogenic T cells in T1D recognize epitopes formed by post-translational modifications of β-cell antigens, including hybrid insulin peptides (HIPs). The ligands for several CD4 T-cell clones derived from the NOD mouse are HIPs composed of a fragment of proinsulin joined to peptides from endogenous β-cell granule proteins. The diabetogenic T-cell clone BDC-6.9 reacts to a fragment of C-peptide fused to a cleavage product of pro-islet amyloid polypeptide (6.9HIP). In this study, we used a monoclonal antibody (MAb) to the 6.9HIP to determine when and where HIP antigens are present in NOD islets during disease progression …

Transcriptomic Profiling Of Thymic Dysregulation And Viral Tropism After Neonatal Roseolovirus Infection, Andrei Belean, Eden Xue, Benjamin Cisneros, Elisha D O Roberson, Michael A Paley, Tarin M Bigley

2020-Current year OA Pubs

INTRODUCTION: Herpesviruses, including the roseoloviruses, have been linked to autoimmune disease. The ubiquitous and chronic nature of these infections have made it difficult to establish a causal relationship between acute infection and subsequent development of autoimmunity. We have shown that murine roseolovirus (MRV), which is highly related to human roseoloviruses, induces thymic atrophy and disruption of central tolerance after neonatal infection. Moreover, neonatal MRV infection results in development of autoimmunity in adult mice, long after resolution of acute infection. This suggests that MRV induces durable immune dysregulation.

METHODS: In the current studies, we utilized single-cell RNA sequencing (scRNAseq) to study …

Pd-L1 Has A Heterogeneous And Dynamic Expression In Gastric Cancer With Implications For Immunopet, Dina Ibrahim, Cristina Simó, Emma L Brown, Shayla Shmuel, Sandeep Surendra Panikar, Alex Benton, Rachel Deweerd, Farrokh Dehdashti, Haeseong Park, Patrícia M R Pereira

2020-Current year OA Pubs

INTRODUCTION: This study aimed to investigate the dynamics of programmed death-ligand 1 (PD-L1) expression, spatial heterogeneity, and binding affinity of FDA-approved anti-PD-L1 antibodies (avelumab and atezolizumab) in gastric cancer. Additionally, we determined how PD-L1 glycosylation impacts antibody accumulation in gastric cancer cells.

METHODS: Dynamic PD-L1 expression was examined in NCIN87 gastric cancer cells. Comparative binding studies of avelumab and atezolizumab were conducted in gastric cancer models, both

RESULTS: Consistent findings revealed time-dependent PD-L1 induction in NCIN87 gastric cancer cells and spatial heterogeneity in tumors, as shown by PET imaging and immunofluorescence. Avelumab displayed superior binding affinity to NCIN87 cells compared …

A Novel Crispr/Cas9-Mediated Mouse Model Of Colon Carcinogenesis, Hajime Kashima, Anthony Fischer, Daniel A Veronese-Paniagua, Vered A Gazit, Changqing Ma, Yan Yan, Marc S Levin, Blair B Madison, Deborah C Rubin

2020-Current year OA Pubs

BACKGROUND & AIMS: Human sporadic colorectal cancer (CRC) results from a multistep pathway with sequential acquisition of specific genetic mutations in the colorectal epithelium. Modeling CRC in vivo is critical for understanding the tumor microenvironment. To accurately recapitulate human CRC pathogenesis, mouse models must include these multi-step genetic abnormalities. The aim of this study was to generate a sporadic CRC model that more closely mimics this multi-step process and to use this model to study the role of a novel Let7 target PLAGL2 in CRC pathogenesis.

METHODS: We generated a CRISPR/Cas9 somatic mutagenesis mouse model that is inducible and multiplexed …

Ddr2-Regulated Arginase Activity In Ovarian Cancer-Associated Fibroblasts Promotes Collagen Production And Tumor Progression, Favour A Akinjiyan, Zainab Ibitoye, Peinan Zhao, Leah P Shriver, Gary J Patti, Gregory D Longmore, Katherine C Fuh

2020-Current year OA Pubs

Ovarian cancer has poor survival outcomes particularly for advanced stage, metastatic disease. Metastasis is promoted by interactions of stromal cells, such as cancer-associated fibroblasts (CAFs) in the tumor microenvironment (TME), with tumor cells. CAFs play a key role in tumor progression by remodeling the TME and extracellular matrix (ECM) to result in a more permissive environment for tumor progression. It has been shown that fibroblasts, in particular myofibroblasts, utilize metabolism to support ECM remodeling. However, the intricate mechanisms by which CAFs support collagen production and tumor progression are poorly understood. In this study, we show that the fibrillar collagen receptor, …

Hyperbaric Oxygen Augments Susceptibility To C. Difficile Infection By Impairing Gut Microbiota Ability To Stimulate The Hif-1Α-Il-22 Axis In Ilc3, José L Fachi, Laís P Pral, Helder C Assis, Sarah Oliveira, Vinícius R Rodovalho, Jefferson A C Dos Santos, Mariane F Fernandes, Valquíria A Matheus, Renata Sesti-Costa, Paulo J Basso, Marina Flóro E Silva, Niels O S Câmara, Selma Giorgio, Marco Colonna, Marco A R Vinolo

2020-Current year OA Pubs

Hyperbaric oxygen (HBO) therapy is a well-established method for improving tissue oxygenation and is typically used for the treatment of various inflammatory conditions, including infectious diseases. However, its effect on the intestinal mucosa, a microenvironment known to be physiologically hypoxic, remains unclear. Here, we demonstrated that daily treatment with hyperbaric oxygen affects gut microbiome composition, worsening antibiotic-induced dysbiosis. Accordingly, HBO-treated mice were more susceptible to

Beta Cell Primary Cilia Mediate Somatostatin Responsiveness Via Sstr3, Samantha E Adamson, Zipeng A Li, Jing W Hughes

2020-Current year OA Pubs

Somatostatin is a paracrine modulator of insulin secretion and beta cell function with pleotropic effects on glucose homeostasis. The mechanism of somatostatin-mediated communication between delta and beta cells is not well-understood, which we address in this study via the ciliary somatostatin receptor 3 (SSTR3). Primary cilia are membrane organelles that act as signaling hubs in islets by virtue of their subcellular location and enrichment in signaling proteins such as G-protein coupled receptors (GPCRs). We show that SSTR3, a ciliary GPCR, mediates somatostatin suppression of insulin secretion in mouse islets. Quantitative analysis of calcium flux using a mouse model of genetically …

Genetic Inactivation Of Β-Catenin Is Salubrious, Whereas Its Activation Is Deleterious In Desmoplakin Cardiomyopathy, Melis Olcum, Siyang Fan, Leila Rouhi, Sirisha Cheedipudi, Benjamin Cathcart, Hyun-Hwan Jeong, Zhongming Zhao, Priyatansh Gurha, Ali J Marian

Faculty, Staff and Student Publications

AIMS: Mutations in the DSP gene encoding desmoplakin, a constituent of the desmosomes at the intercalated discs (IDs), cause a phenotype that spans arrhythmogenic cardiomyopathy (ACM) and dilated cardiomyopathy. It is typically characterized by biventricular enlargement and dysfunction, myocardial fibrosis, cell death, and arrhythmias. The canonical wingless-related integration (cWNT)/β-catenin pathway is implicated in the pathogenesis of ACM. The β-catenin is an indispensable co-transcriptional regulator of the cWNT pathway and a member of the IDs. We genetically inactivated or activated β-catenin to determine its role in the pathogenesis of desmoplakin cardiomyopathy.

METHODS AND RESULTS: The Dsp gene was conditionally deleted in …

P53r245w Mutation Fuels Cancer Initiation And Metastases In Nash-Driven Liver Tumorigenesis, Denada Dibra, Mihai Gagea, Yuan Qi, Gilda P Chau, Xiaoping Su, Guillermina Lozano

Faculty, Staff and Student Publications

Obesity is a significant global health concern. Non-alcoholic fatty liver disease and non-alcoholic steatohepatitis (NASH) are common risk factors for hepatocellular carcinoma (HCC) and are closely associated with metabolic comorbidities, including obesity and diabetes. The TP53 tumor suppressor is the most frequently mutated gene in liver cancers, with half of these alterations being missense mutations. These mutations produce highly abundant proteins in cancer cells which have both inhibitory effects on wildtype (WT) p53, and gain-of-function (GOF) activities that contribute to tumor progression. A Western diet increases p53 activity in the liver. To elucidate the functional consequences of Trp53 mutations in …

Triobp Modulates Β-Catenin Signaling By Regulation Of Mir-29b In Idiopathic Pulmonary Fibrosis, Lan Wang, Wenyu Zhao, Cong Xia, Shuaichen Ma, Zhongzheng Li, Ningdan Wang, Linke Ding, Yaxuan Wang, Lianhui Cheng, Huibing Liu, Juntang Yang, Yajun Li, Ivan Rosas, Guoying Yu

Faculty, Staff and Students Publications

Idiopathic pulmonary fibrosis (IPF) is a fatal and devastating lung disease of unknown etiology, described as the result of multiple cycles of epithelial cell injury and fibroblast activation. Despite this impressive increase in understanding, a therapy that reverses this form of fibrosis remains elusive. In our previous study, we found that miR-29b has a therapeutic effect on pulmonary fibrosis. However, its anti-fibrotic mechanism is not yet clear. Recently, our study identified that F-Actin Binding Protein (TRIOBP) is one of the target genes of miR-29b and found that deficiency of TRIOBP increases resistance to lung fibrosis in vivo. TRIOBP knockdown inhibited …

A Distinct Human Cell Type Expressing Mhcii And Rorγt With Dual Characteristics Of Dendritic Cells And Type 3 Innate Lymphoid Cells, Alina Ulezko Antonova, Silvia Lonardi, Matilde Monti, Francesco Missale, Changxu Fan, Matthew L Coates, Mattia Bugatti, Natalia Jaeger, Patrick Fernandes Rodrigues, Simone Brioschi, Tihana Trsan, José L Fachi, Khai M Nguyen, Ryan M Nunley, Daniele Moratto, Stefania Zini, Lingjia Kong, Jacques Deguine, Mark E Peeples, Ramnik J Xavier, Menna R Clatworthy, Ting Wang, Marina Cella, William Vermi, Marco Colonna

The Brown Foundation: Institute of Molecular Medicine

Recent studies have characterized various mouse antigen-presenting cells (APCs) expressing the lymphoid-lineage transcription factor RORγt (Retinoid-related orphan receptor gamma t), which exhibit distinct phenotypic features and are implicated in the induction of peripheral regulatory T cells (Tregs) and immune tolerance to microbiota and self-antigens. These APCs encompass Janus cells and Thetis cell subsets, some of which express the AutoImmune REgulator (AIRE). RORγt+ MHCII+ type 3 innate lymphoid cells (ILC3) have also been implicated in the instruction of microbiota-specific Tregs. While RORγt+ APCs have been actively investigated in mice, the identity and function of these cell subsets in humans remain elusive. …

Co-Transmitting Interneurons In The Mouse Olfactory Bulb Regulate Olfactory Detection And Discrimination, Ariel M Lyons-Warren, Evelyne K Tantry, Elizabeth H Moss, Mikhail Y Kochukov, Benjamin D W Belfort, Joshua Ortiz-Guzman, Zachary Freyberg, Benjamin R Arenkiel

Faculty, Staff and Students Publications

Co-transmission of multiple neurotransmitters from a single neuron increases the complexity of signaling information within defined neuronal circuits. Superficial short-axon cells in the olfactory bulb release both dopamine and γ-aminobutyric acid (GABA), yet the specific targets of these neurotransmitters and their respective roles in olfaction have remained unknown. Here, we implement intersectional genetics in mice to selectively block GABA or dopamine release from superficial short-axon cells to identify their distinct cellular targets, impact on circuit function, and behavioral contribution of each neurotransmitter toward olfactory behaviors. We provide functional and anatomical evidence for divergent superficial short-axon cell signaling onto downstream neurons …

Cd62l Expression Marks A Functionally Distinct Subset Of Memory B Cells, Christopher H Hanson, Brittany Henry, Pradhnesh Andhare, Frank J Lin, Haley Pak, Jackson S Turner, Lucas J Adams, Tom Liu, Daved H Fremont, Ali H Ellebedy, Brian J Laidlaw

2020-Current year OA Pubs

The memory B cell response consists of phenotypically distinct subsets that differ in their ability to respond upon antigen re-encounter. However, the pathways regulating the development and function of memory B cell subsets are poorly understood. Here, we show that CD62L and CD44 are progressively expressed on mouse memory B cells and identify transcriptionally and functionally distinct memory B cell subsets. Bcl6 is important in regulating memory B cell subset differentiation with overexpression of Bcl6 resulting in impaired CD62L

Mecp2 Represses The Activity Of Topoisomerase Iiβ In Long Neuronal Genes, Sabin A Nettles, Yoshiho Ikeuchi, Katheryn B Lefton, Ladan Abbasi, Alyssa Erickson, Chibueze Agwu, Thomas Papouin, Azad Bonni, Harrison W Gabel

2020-Current year OA Pubs

A unique signature of neurons is the high expression of the longest genes in the genome. These genes have essential neuronal functions, and disruption of their expression has been implicated in neurological disorders. DNA topoisomerases resolve DNA topological constraints and facilitate neuronal long gene expression. Conversely, the Rett syndrome protein, methyl-CpG-binding protein 2 (MeCP2), can transcriptionally repress long genes. How these factors regulate long genes is not well understood, and whether they interact is not known. Here, we identify and map a functional interaction between MeCP2 and topoisomerase IIβ (TOP2β) in mouse neurons. We profile neuronal TOP2β activity genome wide, …

A Distinct Human Cell Type Expressing Mhcii And Rorγt With Dual Characteristics Of Dendritic Cells And Type 3 Innate Lymphoid Cells, Alina Ulezko Antonova, Changxu Fan, Natalia Jaeger, Patrick Fernandes Rodrigues, Simone Brioschi, Tihana Trsan, José L Fachi, Khai M Nguyen, Ryan M Nunley, Ting Wang, Marina Cella, William Vermi, Marco Colonna, Et Al.

2020-Current year OA Pubs

Recent studies have characterized various mouse antigen-presenting cells (APCs) expressing the lymphoid-lineage transcription factor RORγt (Retinoid-related orphan receptor gamma t), which exhibit distinct phenotypic features and are implicated in the induction of peripheral regulatory T cells (Tregs) and immune tolerance to microbiota and self-antigens. These APCs encompass Janus cells and Thetis cell subsets, some of which express the AutoImmune REgulator (AIRE). RORγt