Medicine and Health Sciences Commons^™

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 …

Glp1 Receptor Agonists-Effects Beyond Obesity And Diabetes, Sydney S Wilbon, Mikhail G Kolonin

Faculty, Staff and Student Publications

Glucagon-like peptide-1 receptor agonists (GLP1RA) have been transformative for patients and clinicians in treating type-2 diabetes and obesity. Drugs of this class, the bioavailability of which is continuously improving, enable weight loss and control blood glucose with minimal unwanted side effects. Since adopting GLP1RA for treating metabolic diseases, animal and clinical studies have revealed their beneficial effects on several other pathologies, including cardiovascular diseases, neurodegeneration, kidney disease, and cancer. A notable commonality between these diseases is their association with older age. Clinical trials and preclinical data suggest that GLP1RA may improve outcomes in these aging-related diseases. Some of the benefits …

Effect Of Flecainide And Ibutilide Alone And In Combination To Terminate And Prevent Recurrence Of Atrial Fibrillation, Alexander Burashnikov, José M. Di Diego, Bence Patocskai, Debra S. Echt, Luiz Belardinelli, Charles Antzelevitch

Division of Cardiology Faculty Papers

BACKGROUND: There is a need for improved approaches to rhythm control therapy of atrial fibrillation (AF).

METHODS: The effectiveness of flecainide (1.5 µmol/L) and ibutilide (20 nmol/L), alone and in combination, to cardiovert and prevent AF recurrence was studied in canine-isolated coronary-perfused right atrioventricular preparations. We also examined the safety of the combination of flecainide (1.5 µmol/L) and ibutilide (50 nmol/L) using canine left ventricular wedge preparations.

RESULTS: Sustained AF (>1 hour) was inducible in 100%, 60%, 20%, and 0% of atria in the presence of acetylcholine alone, acetylcholine+ibutilide, acetylcholine+flecainide, and acetylcholine+ibutilide+flecainide, respectively. When used alone, flecainide and ibutilide …

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 …

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

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, …

Enhanced Bmp Signaling In Cathepsin K-Positive Tendon Progenitors Induces Heterotopic Ossification, Hiroyuki Yamaguchi, Margaret Li, Megumi Kitami, Sowmya Swaminathan, Yuji Mishina, Yoshihiro Komatsu

Faculty, Staff and Student Publications

Heterotopic ossification (HO) is abnormal bone growth in soft tissues that results from injury, trauma, and rare genetic disorders. Bone morphogenetic proteins (BMPs) are critical osteogenic regulators which are involved in HO. However, it remains unclear how BMP signaling interacts with other extracellular stimuli to form HO. To address this question, using the Cre-loxP recombination system in mice, we conditionally expressed the constitutively activated BMP type I receptor ALK2 with a Q207D mutation (Ca-ALK2) in Cathepsin K-Cre labeled tendon progenitors (hereafter “Ca-Alk2:Ctsk-Cre”). Ca-Alk2:Ctsk-Cre mice were viable but they formed spontaneous HO in the Achilles tendon. Histological and molecular …

The Function Of Ask1 In Sepsis And Stress-Induced Disorders, John Kostyak, Steven Mckenzie, Ulhas Naik

Cardeza Foundation for Hematologic Research

Apoptosis signal-regulating kinase 1 (ASK1) is a serine-threonine kinase that is ubiquitously expressed in nucleated cells and is responsible for the activation of multiple mitogen-activated protein kinases (MAPK) to regulate cell stress. Activation of ASK1 via cellular stress leads to activation of downstream signaling components, activation of transcription factors, and proinflammatory cytokine production. ASK1 is also expressed in anucleate platelets and is a key player in platelet activation as it is important for signaling. Interestingly, the mechanism of ASK1 activation is cell type-dependent. In this review we will explore how ASK1 regulates a variety of cellular processes from innate immune …

Parallel Neural Pathways Control Sodium Consumption And Taste Valence, Yameng Zhang, Allan-Hermann Pool, Tongtong Wang, Lu Liu, Elin Kang, Bei Zhang, Liang Ding, Kirsten Frieda, Richard Palmiter, Yuki Oka

Faculty, Staff and Student Publications

The hedonic value of salt fundamentally changes depending on the internal state. High concentrations of salt induce innate aversion under sated states, whereas such aversive stimuli transform into appetitive ones under sodium depletion. Neural mechanisms underlying this state-dependent salt valence switch are poorly understood. Using transcriptomics state-to-cell-type mapping and neural manipulations, we show that positive and negative valences of salt are controlled by anatomically distinct neural circuits in the mammalian brain. The hindbrain interoceptive circuit regulates sodium-specific appetitive drive , whereas behavioral tolerance of aversive salts is encoded by a dedicated class of neurons in the forebrain lamina terminalis (LT) …

Ints6 And The Integrator Phosphatase Module Tune The Efficiency Of Select Premature Transcription Termination Events, Rina Fujiwara, Si-Nan Zhai, Dongming Liang, Aayushi P Shah, Matthew Tracey, Xu-Kai Ma, Christopher J Fields, María Saraí Mendoza-Figueroa, Michele C Meline, Deirdre C Tatomer, Li Yang, Jeremy E Wilusz

Children’s Nutrition Research Center Staff Publications

The metazoan-specific Integrator complex catalyzes 3' end processing of small nuclear RNAs (snRNAs) and premature termination that attenuates the transcription of many protein-coding genes. Integrator has RNA endonuclease and protein phosphatase activities, but it remains unclear if both are required for complex function. Here, we show IntS6 (Integrator subunit 6) over-expression blocks Integrator function at a subset of Drosophila protein-coding genes, although having no effect on snRNAs or attenuation of other loci. Over-expressed IntS6 titrates protein phosphatase 2A (PP2A) subunits, thereby only affecting gene loci where phosphatase activity is necessary for Integrator function. IntS6 functions analogous to a PP2A regulatory …

Colonization Of Larval Zebrafish (Danio Rerio) With Adherent-Invasive Escherichia Coli Prevents Recovery Of The Intestinal Mucosa From Drug-Induced Enterocolitis, Erika Flores, Soumita Dutta, Rachel Bosserman, Ambro Van Hoof, Anne-Marie Krachler

Faculty, Staff and Student Publications

Although inflammatory bowel diseases are on the rise, what factors influence IBD risk and severity, and the underlying mechanisms remain to be fully understood. Although host genetics, microbiome, and environmental factors have all been shown to correlate with the development of IBD, cause and effect are difficult to disentangle in this context. For example, AIEC is a known pathobiont found in IBD patients, but it remains unclear if gut inflammation during IBD facilitates colonization with AIEC, or if AIEC colonization makes the host more susceptible to pro-inflammatory stimuli. It is critical to understand the mechanisms that contribute to AIEC infections …

Colonization Of Larval Zebrafish (Danio Rerio) With Adherent-Invasive Escherichia Coli Prevents Recovery Of The Intestinal Mucosa From Drug-Induced Enterocolitis, Erika Flores, Soumita Dutta, Rachel Bosserman, Ambro Van Hoof, Anne-Marie Krachler

Faculty, Staff and Student Publications

Although inflammatory bowel diseases are on the rise, what factors influence IBD risk and severity, and the underlying mechanisms remain to be fully understood. Although host genetics, microbiome, and environmental factors have all been shown to correlate with the development of IBD, cause and effect are difficult to disentangle in this context. For example, AIEC is a known pathobiont found in IBD patients, but it remains unclear if gut inflammation during IBD facilitates colonization with AIEC, or if AIEC colonization makes the host more susceptible to pro-inflammatory stimuli. It is critical to understand the mechanisms that contribute to AIEC infections …

Abnormal Patterns Of Sleep And Waking Behaviors Are Accompanied By Neocortical Oscillation Disturbances In An Ank3 Mouse Model Of Epilepsy-Bipolar Disorder Comorbidity, Juan E Villacres, Nicholas Riveira, Sohmee Kim, Laura L Colgin, Jeffrey L Noebels, Angel Y Lopez

Faculty, Staff and Students Publications

ANK3 is a leading bipolar disorder (BD) candidate gene in humans and provides a unique opportunity for studying epilepsy-BD comorbidity. Previous studies showed that deletion of Ank3-1b, a BD-associated variant of Ank3 in mice leads to increased firing threshold and diminished action potential dynamic range of parvalbumin (PV) interneurons and absence epilepsy, thus providing a biological mechanism linking epilepsy and BD. To explore the behavioral overlap of these disorders, we characterized behavioral patterns of Ank3-1b KO mice during overnight home-cage activity and examined network activity during these behaviors using paired video and EEG recordings. Since PV interneurons contribute to the …

Needle Biopsy Accelerates Pro-Metastatic Changes And Systemic Dissemination In Breast Cancer: Implications For Mortality By Surgery Delay, Hiroyasu Kameyama, Priya Dondapati, Reese Simmons, Macall Leslie, John Langenheim, Yunguang Sun, Misung Yi, Aubrey Rottschaefer, Rashmi Pathak, Shreya Nuguri, Kar-Ming Fung, Shirng-Wern Tsaih, Inna Chervoneva, Hallgeir Rui, Takemi Tanaka

Department of Pharmacology, Physiology, and Cancer Biology Faculty Papers

ncreased breast cancer (BC) mortality risk posed by delayed surgical resection of tumor after diagnosis is a growing concern, yet the underlying mechanisms remain unknown. Our cohort analyses of early-stage BC patients reveal the emergence of a significantly rising mortality risk when the biopsy-to-surgery interval was extended beyond 53 days. Additionally, histology of post-biopsy tumors shows prolonged retention of a metastasis-permissive wound stroma dominated by M2-like macrophages capable of promoting cancer cell epithelial-to-mesenchymal transition and angiogenesis. We show that needle biopsy promotes systemic dissemination of cancer cells through a mechanism of sustained activation of the COX-2/PGE₂/EP2 feedforward loop, …

Pain Management By Chemogenetic Control Of Sensory Neurons, Yize Li, Xin Ge, Ru-Rong Ji

Faculty, Staff and Student Publications

In this study, Perez-Sanchez et al.1 developed a chemogenetic method aimed at alleviating pain in mouse models while dampening excitability in human sensory neurons. This analgesic effect was attained through the introduction of human α7 nicotinic acetylcholine receptor and glycine receptor pore domain via virus-mediated expression in sensory neurons, forming a chloride channel. The activation of this channel was made possible by specific agonists. This study highlights the potential for treating clinical pain by gene therapy.

Neuromuscular Basis Of Drosophila Larval Rolling Escape Behavior, Patricia C Cooney, Yuhan Huang, Wenze Li, Dulanjana M Perera, Richard Hormigo, Tanya Tabachnik, Isuru S Godage, Elizabeth M C Hillman, Wesley B Grueber, Aref A Zarin

Faculty, Staff and Student Publications

To escape from dangerous stimuli, animals execute escape behaviors that are fundamentally different from normal locomotion. The rolling escape behavior of Drosophila larvae consists of C-shaped bending and rolling. However, the muscle contraction patterns that lead to rolling are poorly understood. We find that following the initial body bending, muscles contract in a circumferential wave around the larva as they enter the bend, maintaining unidirectional rolling that resembles a cylinder rolling on a surface. We study the structure of motor circuits for rolling, inhibit different motor neurons to determine which muscles are essential for rolling, and propose circuit and biomechanical …

Interleukin-17-Mediated Protective Cytokine Signaling Against Degeneration Of The Retinal Pigment Epithelium, Yan Chen, Sarah E Bounds, Xiang Ma, James Regun Karmoker, Yin Liu, Jian-Xing Ma, Jiyang Cai

Faculty, Staff and Student Publications

Injuries to the retinal pigment epithelium (RPE) and outer retina often result in the accumulation of retinal microglia within the subretinal space. These subretinal microglia play crucial roles in inflammation and resolution, but the mechanisms governing their functions are still largely unknown. Our previous research highlighted the protective functions of choroidal γδ T cells in response to RPE injury. In the current study, we employed single-cell RNA sequencing approach to characterize the profiles of immune cells in mouse choroid. We found that γδ T cells were the primary producer of interleukin-17 (IL-17) in the choroid. IL-17 signaled through its receptor …

Mirna-211 Maintains Metabolic Homeostasis In Medulloblastoma Through Its Target Gene Long-Chain Acyl-Coa Synthetase 4, Menglang Yuan, Iqbal Mahmud, Keisuke Katsushima, Kandarp Joshi, Olivier Saulnier, Rudramani Pokhrel, Bongyong Lee, Wathsala Liyanage, Haritha Kunhiraman, Stacie Stapleton, Ignacio Gonzalez-Gomez, Rangaramanujam M Kannan, Tanja Eisemann, Elayaraja Kolanthai, Sudipta Seal, Timothy J Garrett, Saed Abbasi, Kimberly Bockley, Justin Hanes, Prem Chapagain, George Jallo, Robert J Wechsler-Reya, Michael D Taylor, Charles G Eberhart, Animesh Ray, Ranjan J Perera

Faculty, Staff and Students Publications

The prognosis of childhood medulloblastoma (MB) is often poor, and it usually requires aggressive therapy that adversely affects quality of life. microRNA-211 (miR-211) was previously identified as an important regulator of cells that descend from neural cells. Since medulloblastomas primarily affect cells with similar ontogeny, we investigated the role and mechanism of miR-211 in MB. Here we showed that miR-211 expression was highly downregulated in cell lines, PDXs, and clinical samples of different MB subgroups (SHH, Group 3, and Group 4) compared to normal cerebellum. miR-211 gene was ectopically expressed in transgenic cells from MB subgroups, and they were subjected …

A Broadly Reactive Antibody Targeting The N-Terminal Domain Of Sars-Cov-2 Spike Confers Fc-Mediated Protection, Lucas J Adams, Laura A Vanblargan, Zhuoming Liu, Pavlo Gilchuk, Haiyan Zhao, Rita E Chen, Saravanan Raju, Zhenlu Chong, Bradley M Whitener, Swathi Shrihari, Prashant N Jethva, Michael L Gross, James E Crowe Jr., Sean P J Whelan, Michael S Diamond, Daved H Fremont

2020-Current year OA Pubs

Most neutralizing anti-SARS-CoV-2 monoclonal antibodies (mAbs) target the receptor binding domain (RBD) of the spike (S) protein. Here, we characterize a panel of mAbs targeting the N-terminal domain (NTD) or other non-RBD epitopes of S. A subset of NTD mAbs inhibits SARS-CoV-2 entry at a post-attachment step and avidly binds the surface of infected cells. One neutralizing NTD mAb, SARS2-57, protects K18-hACE2 mice against SARS-CoV-2 infection in an Fc-dependent manner. Structural analysis demonstrates that SARS2-57 engages an antigenic supersite that is remodeled by deletions common to emerging variants. In neutralization escape studies with SARS2-57, this NTD site accumulates mutations, including …

Autophagy Gene-Dependent Intracellular Immunity Triggered By Interferon-Γ, Michael R Mcallaster, Jaya Bhushan, Dale R Balce, Anthony Orvedahl, Arnold Park, Seungmin Hwang, Meagan E Sullender, L David Sibley, Herbert W Virgin

2020-Current year OA Pubs

Interferon-γ (IFNγ) is a critical mediator of cell-intrinsic immunity to intracellular pathogens. Understanding the complex cellular mechanisms supporting robust interferon-γ-induced host defenses could aid in developing new therapeutics to treat infections. Here, we examined the impact of autophagy genes in the interferon-γ-induced host response. We demonstrate that genes within the autophagy pathway including

Nucleus Accumbens Core Single Cell Ensembles Bidirectionally Respond To Experienced Versus Observed Aversive Events, Oyku Dinckol, Noah Harris Wenger, Jennifer E Zachry, Munir Gunes Kutlu

Rowan-Virtua School of Osteopathic Medicine Departmental Research

Fear learning is a critical feature of survival skills among mammals. In rodents, fear learning manifests itself through direct experience of the aversive event or social transmission of aversive stimuli such as observing and acting on conspecifics' distress. The neuronal network underlying the social transmission of information largely overlaps with the brain regions that mediate behavioral responses to aversive and rewarding stimuli. In this study, we recorded single cell activity patterns of nucleus accumbens (NAc) core neurons using in vivo optical imaging of calcium transients via miniature scopes. This cutting-edge imaging methodology not only allows us to record activity patterns …

Pathway Centric Analysis For Single-Cell Rna-Seq And Spatial Transcriptomics Data With Gsdensity, Qingnan Liang, Yuefan Huang, Shan He, Ken Chen

Faculty, Staff and Student Publications

Advances in single-cell technology have enabled molecular dissection of heterogeneous biospecimens at unprecedented scales and resolutions. Cluster-centric approaches are widely applied in analyzing single-cell data, however they have limited power in dissecting and interpreting highly heterogenous, dynamically evolving data. Here, we present GSDensity, a graph-modeling approach that allows users to obtain pathway-centric interpretation and dissection of single-cell and spatial transcriptomics (ST) data without performing clustering. Using pathway gene sets, we show that GSDensity can accurately detect biologically distinct cells and reveal novel cell-pathway associations ignored by existing methods. Moreover, GSDensity, combined with trajectory analysis can identify curated pathways that are …

Engineering E. Coli Strains Using Antibiotic-Resistance-Gene-Free Plasmids, Matthew B Amrofell, Sunaina Rengarajan, Steven T Vo, Erick S Ramirez Tovar, Larissa Lobello, Gautam Dantas, Tae Seok Moon

2020-Current year OA Pubs

We created a generalizable pipeline for antibiotic-resistance-gene-free plasmid (ARGFP)-based cloning using a dual auxotrophic- and essential-gene-based selection strategy. We use auxotrophic selection to construct plasmids in engineered E. coli DH10B cloning strains and both auxotrophic- and essential-gene-based selection to (1) select for recombinant strains and (2) maintain a plasmid in E. coli Nissle 1917, a common chassis for engineered probiotic applications, and E. coli MG1655, the laboratory "wild-type" E. coli strain. We show that our approach has comparable efficiency to that of antibiotic-resistance-gene-based cloning. We also show that the double-knockout Nissle and MG1655 strains are simple to transform with plasmids …

Tuftelin1 Drives Experimental Pulmonary Fibrosis Progression By Facilitating Stress Fiber Assembly, Caoyuan Niu, Kai Xu, Yanan Hu, Yanling Jia, Yuexia Yang, Xiaoyue Pan, Ruyan Wan, Hui Lian, Qiwen Wang, Juntang Yang, Yajun Li, Ivan Rosas, Lan Wang, Guoying Yu

Children’s Nutrition Research Center Staff Publications

Background: Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease (ILD) with unknown etiology, characterized by sustained damage repair of epithelial cells and abnormal activation of fibroblasts, the underlying mechanism of the disease remains elusive.

Methods: To evaluate the role of Tuftelin1 (TUFT1) in IPF and elucidate its molecular mechanism. We investigated the level of TUFT1 in the IPF and bleomycin-induced mouse models and explored the influence of TUFT1 deficiency on pulmonary fibrosis. Additionally, we explored the effect of TUFT1 on the cytoskeleton and illustrated the relationship between stress fiber and pulmonary fibrosis.

Results: Our results demonstrated a significant …

Gpr84-Mediated Signal Transduction Affects Metabolic Function By Promoting Brown Adipocyte Activity, Xue-Nan Sun, Yu A An, Vivian A Paschoal, Camila O De Souza, May-Yun Wang, Lavanya Vishvanath, Lorena Ma Bueno, Ayanna S Cobb, Joseph A Nieto Carrion, Madison E Ibe, Chao Li, Harrison A Kidd, Shiuhwei Chen, Wenhong Li, Rana K Gupta, Da Young Oh

Faculty, Staff and Student Publications

The G protein-coupled receptor 84 (GPR84), a medium-chain fatty acid receptor, has garnered attention because of its potential involvement in a range of metabolic conditions. However, the precise mechanisms underlying this effect remain elusive. Our study has shed light on the pivotal role of GPR84, revealing its robust expression and functional significance within brown adipose tissue (BAT). Mice lacking GPR84 exhibited increased lipid accumulation in BAT, rendering them more susceptible to cold exposure and displaying reduced BAT activity compared with their WT counterparts. Our in vitro experiments with primary brown adipocytes from GPR84-KO mice revealed diminished expression of thermogenic genes …

Acidosis-Mediated Increase In Ifn-Γ-Induced Pd-L1 Expression On Cancer Cells As An Immune Escape Mechanism In Solid Tumors, Philipp Knopf, Dimitri Stowbur, Sabrina H L Hoffmann, Natalie Hermann, Andreas Maurer, Valentina Bucher, Marilena Poxleitner, Bredi Tako, Dominik Sonanini, Balaji Krishnamachary, Sanhita Sinharay, Birgit Fehrenbacher, Irene Gonzalez-Menendez, Felix Reckmann, David Bomze, Lukas Flatz, Daniela Kramer, Martin Schaller, Stephan Forchhammer, Zaver M Bhujwalla, Leticia Quintanilla-Martinez, Klaus Schulze-Osthoff, Mark D Pagel, Marieke F Fransen, Martin Röcken, André F Martins, Bernd J Pichler, Kamran Ghoreschi, Manfred Kneilling

Faculty, Staff and Student Publications

Immune checkpoint inhibitors have revolutionized cancer therapy, yet the efficacy of these treatments is often limited by the heterogeneous and hypoxic tumor microenvironment (TME) of solid tumors. In the TME, programmed death-ligand 1 (PD-L1) expression on cancer cells is mainly regulated by Interferon-gamma (IFN-γ), which induces T cell exhaustion and enables tumor immune evasion. In this study, we demonstrate that acidosis, a common characteristic of solid tumors, significantly increases IFN-γ-induced PD-L1 expression on aggressive cancer cells, thus promoting immune escape. Using preclinical models, we found that acidosis enhances the genomic expression and phosphorylation of signal transducer and activator of transcription …

Targeting Eif4a Triggers An Interferon Response To Synergize With Chemotherapy And Suppress Triple-Negative Breast Cancer, Na Zhao, Elena B Kabotyanski, Alexander B Saltzman, Anna Malovannaya, Xueying Yuan, Lucas C Reineke, Nadia Lieu, Yang Gao, Diego A Pedroza, Sebastian J Calderon, Alex J Smith, Clark Hamor, Kazem Safari, Sara Savage, Bing Zhang, Jianling Zhou, Luisa M Solis, Susan G Hilsenbeck, Cheng Fan, Charles M Perou, Jeffrey M Rosen

Faculty, Staff and Students Publications

Protein synthesis is frequently dysregulated in cancer and selective inhibition of mRNA translation represents an attractive cancer therapy. Here, we show that therapeutically targeting the RNA helicase eIF4A with zotatifin, the first-in-class eIF4A inhibitor, exerts pleiotropic effects on both tumor cells and the tumor immune microenvironment in a diverse cohort of syngeneic triple-negative breast cancer (TNBC) mouse models. Zotatifin not only suppresses tumor cell proliferation but also directly repolarizes macrophages toward an M1-like phenotype and inhibits neutrophil infiltration, which sensitizes tumors to immune checkpoint blockade. Mechanistic studies revealed that zotatifin reprograms the tumor translational landscape, inhibits the translation of Sox4 …

Mapping Restricted Introgression Across The Genomes Of Admixed Indigenous African Cattle Breeds., Juliane Friedrich, Richard I Bailey, Andrea Talenti, Umer Chaudhry, Qasim Ali, Emmanuel F Obishakin, Chukwunonso Ezeasor, Jessica Powell, Olivier Hanotte, Abdulfatai Tijjani, Karen Marshall, James Prendergast, Pamela Wiener

Faculty Research 2023

BACKGROUND: The genomes of indigenous African cattle are composed of components with Middle Eastern (taurine) and South Asian (indicine) origins, providing a valuable model to study hybridization and to identify genetic barriers to gene flow. In this study, we analysed indigenous African cattle breeds as models of hybrid zones, considering taurine and indicine samples as ancestors. In a genomic cline analysis of whole-genome sequence data, we considered over 8 million variants from 144 animals, which allows for fine-mapping of potential genomic incompatibilities at high resolution across the genome.

RESULTS: We identified several thousand variants that had significantly steep clines ('SCV') …