Digital Commons Network^™

Intratracheal Interleukin-10 Administration Reduces Acute Lung Injury Induced By Sulfur Dioxide Exposure In Mice, Amy J. Nelson, Todd A. Wyatt, Bradley W. Richmond, Belinda Diaz, Angela Gleason, Michael J. Duryee, Geoffrey M. Thiele, Ted R. Mikuls, Jill A. Poole

Journal Articles: Environmental, Agricultural & Occupational Health

Therapies capable of reducing acute high-consequence airborne chemical exposure-induced lung disease are lacking. This study seeks to determine the therapeutic potential of interleukin (IL)-10 administered following acute sulfur dioxide (SO₂) exposure in mice. C57BL/6 male and female mice were exposed to SO₂ gas at 125 ppm for 4 h and subsequently treated 2-3 h later with IL-10 (1 μg) or vehicle control by intratracheal instillation for a total of 3 doses over 2 days with comparisons to sham-treated mice (N = 20 mice/group). IL-10 treatment reduced SO₂-induced weight loss with corresponding reductions in SO_{2 …}

Mucin 5ac Modulates Cancer-Associated Fibroblast Heterogeneity Through Epigenetic Reprogramming Of Precursor Cells, Rachel J. Kehrberg, Namita Bhyravbhatla, Zahraa Wajih Alsafwani, Xiaoqi Li, Gopalakrishnan Natarajan, Imran Khan, Randall E. Brand, Maneesh Jain, Surinder K. Batra, Sushil Kumar

Journal Articles: Biochemistry & Molecular Biology

Pancreatic cancer (PC) is characterized by extensive desmoplasia, with heterogeneous cancer-associated fibroblasts (CAFs) as a major component. However, the contribution of distinct precursor cells to CAF heterogeneity remains poorly defined. This study investigated the role of Muc5ac in modulating CAF heterogeneity by maturing precursor cells, including adipose-derived mesenchymal stem cells (AD-MSCs), bone marrow-derived MSCs (BM-MSCs), and pancreatic stellate cells (PSCs), into different CAF subsets. RNA sequencing of precursor cells treated with conditioned media from Muc5ac-proficient or -deficient cancer cells revealed distinct transcriptional profiles. Muc5ac significantly modulated the expression of Dnmts and Tets in AD-MSCs, promoting the acquisition of extracellular matrix …

Prolonged Qt Interval In Hiv-1 Infected Humanized Mice Treated Chronically With Dolutegravir/Tenofovir Disoproxil Fumarate/Emtricitabine, Ali Namvaran, Julian V. Garcia, Mahendran Ramasamy, Kayla Nguyen, Farzaneh Tavakkoli Ghazani, Bryan T. Hackfort, Prasanta Dash, Reagan E. Fisher, Benson J. Edagwa, Santhi Gorantla, Keshoer R. Bidasee

Journal Articles: Cellular & Integrative Physiology

The REPRIEVE Trial recently reported high rates of sudden cardiac death (SCD) middle-aged people living with HIV-1 infection (PWH) using the WHO/NIH-recommended two nucleoside reverse transcriptase inhibitors (NRTIs)/one integrase strand inhibitor (INSTI) regimen to manage HIV-1 viremia. To date, clinically relevant animal models to delineate underlying causes for this remain limited. Here, we assessed if HIV-1-infected NOD.Cg-Prkdc^scidIl2rg^tm1Wjl/SzJ humanized mice (Hu-mice) treated with the WHO/NIH-recommended antiretroviral regimen, dolutegravir (DTG, INSTI)/tenofovir disoproxil fumarate (TDF, NRTIs)/emtricitabine (FTC, NRTIs), can recapitulate abnormalities in the ECG and subclinical structural heart disease that serve as harbingers of SCD in middle-aged PWH. …

Noradrenergic Innervation Across Brain Regions Is Altered By Aging And By Disease Progression In A Mouse Model Of Alzheimer’S Disease Neuropathology, Nicole M Hernandez, Manuel Silva-Pérez, Jeannie Chin

Faculty, Staff and Students Publications

Norepinephrine plays critical roles in modulating arousal and attention, is highly dynamic in awake, behaving individuals, and has anti-inflammatory and neuroprotective actions. Notably, the locus coeruleus (LC), the primary source of norepinephrine in the central nervous system, is among the first brain regions to show pathological alterations in early stages of Alzheimer's disease (AD). LC neuronal loss and associated reductions in norepinephrine in the brain have therefore been postulated to play a key role in AD pathophysiology. LC neurons and their axons have been studied in several mouse models of AD-related neuropathology to investigate their contribution to brain dysfunction in …

Inhibition Of Histone Demethylase Lsd1 Suppresses Cd47 Expression And Enhances Efficacy Of Cd47 Blockade In Breast Cancer, Fengjie Jiang, Yu Shen, Bing Li, Michael Henry, Nancy Davidson, Yi Huang

Department of Biomedical and Translational Sciences Faculty Publications

Background CD47 functions as a “don’t eat me” checkpoint, inhibiting macrophage-mediated phagocytosis in triple-negative breast cancer (TNBC). While anti-CD47 therapies can restore immune surveillance, their efficacy in TNBC is often limited by immune evasion and drug development challenges.

Methods We investigated the crosstalk between the histone demethylase lysine-specific demethylase 1 (LSD1) and CD47 signaling in TNBC using in silico datasets, isogenic cell lines, conditional BRCA1 knockout models, and syngeneic mouse models. Techniques such as immunohistochemistry, multiplex immunofluorescence, immunoprecipitation, protein ubiquitination, chromatin immunoprecipitation, chemotaxis, flow cytometry, and phagocytosis assays were employed to examine the epigenetic regulation of CD47 by LSD1 and …

Mir-302 Regulates Pancreatic Progenitor Pool And Pancreatic Size, Ziyue Z Yang, Caroline G Snider, Ronald J Parchem

Faculty, Staff and Students Publications

Disruptions in pancreatic development can lead to health issues such as pancreatic agenesis and congenital diabetes mellitus. Understanding pancreatic organogenesis is critical for elucidating disease mechanisms and developing regenerative therapies. The pancreas consists of endocrine and exocrine cells, both of which are derived from multipotent progenitor cells (MPCs). MPC proliferation and differentiation are tightly controlled by multiple mechanisms, including post-transcriptional regulation by miRNAs. However, these regulatory factors are not fully understood. Here, we profiled miRNA expression in MPCs and identified that mir-302 was highly enriched during the earliest stages of pancreatic development. Loss of mir-302 resulted in reduced pancreatic size …

Cerebellar Deep Brain Stimulation Rescues Purkinje Cell Mitochondrial Density In A Genetic Mouse Model Of Cerebellar Ataxia, Lauren N Miterko-Myers, Lauren E Peacoe, Lita Duraine, Zhongyuan Zuo, Roy V Sillitoe

Faculty, Staff and Students Publications

Deep brain stimulation (DBS) improves motor function in a growing list of movement diseases including Parkinson's disease, dystonia, and tremor. There is evidence that DBS may also be effective in ataxia. It is not known why DBS is effective, but modulating cell activity and conferring neuroprotection are hypothesized to underlie its benefits. Understanding the effects of DBS on neurons is paramount to extending its clinical use in the treatment of various motor and non-motor diseases. Here, we stimulated the cerebellum of Car8 waddles (Car8wdl) mice, given the cerebellum's important role in ataxia pathophysiology. Using transmission electron microscopy, we tested the …

Surface Marker Identification To Capture Live Circulating Tumor Cells In Metastatic Triple-Negative Breast Cancer, Bree M Lege, Khushali J Patel, Brendan Panici, Ping Gong, Michael T Lewis, Matthew J Ellis, Chonghui Cheng

Faculty, Staff and Students Publications

Metastatic triple-negative breast cancer (TNBC) is highly aggressive and lacks targeted therapies. Circulating tumor cells (CTC) are invaluable for monitoring metastatic tumor progression and treatment response but are difficult to capture because of their rarity and heterogeneity. Surface-based staining for live CTCs is essential to preserve RNA quality in single cells, but current markers tend to perform poorly on more mesenchymal tumor cells such as TNBCs. To enhance live TNBC CTC detection, we developed a workflow for live CTC capture and single-cell RNA sequencing (scRNA-seq). Using a mouse model of metastatic TNBC, we identified four new CTC surface markers, AHNAK2, …

Senolytic-Resistant Senescent Cells Have A Distinct Sasp Profile And Functional Impact: The Path To Developing Senosensitizers, Utkarsh Tripathi, Masayoshi Suda, Vagisha Kulshreshtha, Bryan T Piatkowski, Allyson K Palmer, Nino Giorgadze, Christina Inman, Nathan Gasek, Ming Xu, Kurt O Johnson, Tamar Pirtskhalava, Selim Chaib, Larissa P G Langhi Prata, Yi Zhu, Renuka Kandhaya-Pillai, Stefan G Tullius, Saranya P Wyles, Rambabu Majji, Hari Krishna Yalamanchili, David B Allison, Tamar Tchkonia, James L Kirkland

Faculty, Staff and Students Publications

The senescent cell (SC) fate is linked to aging, multiple disorders and diseases, and physical dysfunction. Senolytics, agents that selectively eliminate 30%-70% of SCs, act by transiently disabling the senescent cell antiapoptotic pathways (SCAPs), which defend those SCs that are proapoptotic and pro-inflammatory from their own senescence-associated secretory phenotype (SASP). Consistent with this, a JAK/STAT inhibitor, Ruxolitinib, which attenuates the pro-inflammatory SASP of senescent human preadipocytes, caused them to become "senolytic-resistant". Administering senolytics to obese mice selectively decreased the abundance of the subset of SCs that is pro-inflammatory. In cell cultures, the 30%-70% of human senescent preadipocytes or human umbilical …

Wnt4 Deficiency Impacts Heart, Diaphragm, And Palate Development: Insights From Human Genetics, Machine Learning, And Mouse Models, Andrés Hernández-García, Bum Jun Kim, David Chitayat, Patrick Shannon, Stephanie Hedges, Maria Al Bandari, Maria J Guillen Sacoto, Emily Anne Bates, Yunus H Ozekin, Victor Faundes, Pamela N Luna, Chad A Shaw, Tara L Rasmussen, Chih-Wei Hsu, Daryl A Scott

Faculty, Staff and Students Publications

WNT4 is a secreted protein that plays a critical role in the regulation of cell fate and embryogenesis. Biallelic variants in WNT4 have been linked to SERKAL syndrome, an autosomal recessive disorder characterized by 46,XX sex reversal and dysgenesis of the kidneys, adrenals, and lungs. SERKAL syndrome has only been described in a single consanguineous kindred with four affected fetuses. Additional features seen in a subset of affected fetuses included ventricular septal defect (VSD), congenital diaphragmatic hernia (CDH), and orofacial clefting (OFC). To determine if these additional features were likely to be caused by WNT4 deficiency, we used machine learning …

Ptpn1 Regulation Via Ybx1-Ptbp1 Interaction Promotes Fibroblast Activation And Fibrotic Remodeling In The Lung, Huibing Liu, Cong Xia, Yingying Zhang, Yulong Gan, Lianhui Cheng, Xuqian Wang, Airu Chang, Wenyu Zhao, Bin Li, Yaxuan Wang, Yajun Li, Ivan Rosas, Juntang Yang, Guoying Yu, Lan Wang

Faculty, Staff and Students Publications

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive interstitial pneumonia of unknown etiology. Its pathogenesis involves complex multicellular interactions and signaling pathways, with fibroblast-to-myofibroblast transition (FMT) being critical for fibrogenesis. Although the transcription factor Y-box binding protein 1 (YBX1) regulates processes such as cell proliferation, transcription, translation, and DNA repair, its role in IPF remains undefined. Here, we demonstrate that YBX1 overexpression significantly promotes transforming growth factor-β1 (TGF-β1)-induced pulmonary FMT, leading to substantially increased extracellular matrix (ECM) deposition in primary human (PHLFs) and mouse (PMLFs) lung fibroblasts. Conversely, YBX1 inhibition markedly suppresses TGF-β1-driven aberrant fibroblast migration and activation. Mechanistically, YBX1 …

Therapeutic Potential Of Hookworm Proteins In Promoting Regulatory Immune Responses To Modulate Trypanosoma Cruzi Induced Liver Inflammation And Oxidative Stress, Maria Jose Villar, Cristina Poveda, Bin Zhan, Maya Gonsoulin, Kathryn M Jones

Faculty, Staff and Students Publications

Background: Chronic Trypanosoma cruzi infection causes significant liver pathology, and current antiparasitic treatments often worsen hepatic damage. Hookworm-derived proteins have shown immunomodulatory effects in inflammatory diseases, including T. cruzi-induced myocarditis.

Objective: This study evaluates recombinant hookworm proteins AIP-1 and AIP-2 for treating liver inflammation in a murine model of chronic Chagas disease (CD).

Methods: Female BALB/c mice infected with T. cruzi were treated with AIP-1 or AIP-2 (1 mg/kg) for seven days. Controls were untreated or received aspirin (25 mg/kg) for 14 days. Liver tissues were analyzed for parasite burden (quantitative polymerase chain reaction - qPCR), histopathology (H&E, Picrosirius Red), …

Astrocytic Sox9 Overexpression In Alzheimer’S Disease Mouse Models Promotes Aβ Plaque Phagocytosis And Preserves Cognitive Function, Dong-Joo Choi, Sanjana Murali, Wookbong Kwon, Junsung Woo, Eun-Ah Christine Song, Yeunjung Ko, Debosmita Sardar, Brittney Lozzi, Yi-Ting Cheng, Michael R Williamson, Teng-Wei Huang, Kaitlyn Sanchez, Joanna Jankowsky, Benjamin Deneen

Faculty, Staff and Students Publications

Astrocytes play essential roles in the brain, and their dysfunction is associated with nearly every form of neurological disease. Despite their ubiquity, knowledge of how astrocytes contribute to disease pathogenesis is incomplete; accordingly, harnessing their biology toward therapeutics remains a major challenge. Here we show that the transcription factor Sox9 plays a context-specific role in maintaining astrocyte function and circuit activity in the aging hippocampus and Alzheimer's disease (AD) models. We found that Sox9 overexpression in astrocytes in AD models clears existing amyloid beta (Aβ) plaques and preserves cognitive function. Mechanistically, Sox9 promotes the phagocytosis of Aβ plaques by astrocytes …

Dynamic Progression Of Ectopic Lymphoid Structure Formation In Lacrimal Glands Of A Sjögren’S Disease Murine Model, Sara Abdelhamid, Alison V Ramirez, Emre Aksan, Elizaveta A Demianova, Cintia S De Paiva, Maria C Edman, J Andrew Mackay, Sarah F Hamm-Alvarez

Faculty, Staff and Students Publications

Background: Sjögren's Disease (SjD) is a chronic autoimmune condition characterized by lymphocytic infiltration of lacrimal glands (LG) and salivary glands (SG). In SG, these immune structures have properties of ectopic lymphoid structures (ELS) and appear to play a critical role in disease pathology. While the presence of ELS in patients' SG biopsies is linked to disease severity, their presence and composition in LG has not been well characterized.

Methods: The properties and time course of apparent ELS development in LG from the male non-obese diabetes free (NOR) sub-strain of the Non-Obese Diabetic (NOD) mice was investigated at stages encompassing early …

Limosilactobacillus Reuteri Alleviates Proinflammatory T-Cell-Mediated Liver Injury And Transcriptomic Changes In Immunocompromised Mice, Ana Fadhel Alvarez, Zheng Yin, Beanna Okeugo, Alexander Banerjee, Meng Luo, Christopher M Taylor, Salomea Giorgberidze, Vaishali Harne, Rambabu Majji, Melissa N Munroe, Ji Ho Suh, Stephen T C Wong, Kang Ho Kim, Hari Krishna Yalamanchili, Suhair Al Salihi, Jon Marc Rhoads, Yuying Liu

Children’s Nutrition Research Center Staff Publications

Background: A deficiency of immunosuppressive regulatory T cells, as seen in scurfy (SF) mice or in IPEX syndrome in humans, can lead to multiorgan inflammation. Oral administration of the probiotic Limosilactobacillus reuteri Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH (DSM) 17938 prolongs survival and reduces Th1- and Th2-associated inflammation in SF mice. It remains unclear how DSM 17938-educated SF-CD4+ T cells modulate T-cell-liver communication.

Methods: To characterize CD4+ T cells from SF mice orally administered DSM 17938 (Prob-SF-CD4+ T cells) and to compare them with CD4+ T cells from SF mice (SF-CD4+ T cells), cells isolated from SF spleens were …

Pharmacogenetic Hslco1b1*14-Guided Dosing Of Methotrexate In Transgenic Arthritic Mice Normalizes Exposure And Response., Felicia Gooden, Brennan D. Meier, Griffin D. Shaffer, Kim Gibson, Paul Toren, Nieko C. Punt, Sandhya Subash, Dilip K. Singh, Bhagwat Prasad, Laura Ramsey, Zachary L. Taylor

Manuscripts, Articles, Book Chapters and Other Papers

Juvenile idiopathic arthritis (JIA) is a chronic autoimmune disease that negatively affects ~100,000 children under the age of 16 in the United States. About ~30% of these patients fail first-line drug therapy with low-dose methotrexate (MTX) due to poor tolerability or lack of efficacy. The SLCO1B1*14 allele is associated with increased MTX clearance and has been linked to reduced overall drug exposure and nonresponse to MTX in JIA patients. Herein, we describe transgenic hSLCO1B1*14 and hSLCO1B1*1 DBA1/J mSlco1b2 knock-out mice, which we used to assess arthritic response to MTX using the collagen-induced arthritis model. Mass spectrometry-based proteomics analysis revealed that …

Eata Mediated Degradation Of Intestinal Mucus Is Species-Specific And Driven By Muc2 Structural Features, Sergio Trillo-Muyo, Brendan Dolan, Frida Svensson, Tim J Vickers, Liisa Arike, Maria-Jose García-Bonete, Jenny K Gustafsson, Mathias I Nielsen, Hans H Wandall, James M Fleckenstein, Gunnar C Hansson, Sjoerd Van Der Post

2020-Current year OA Pubs

Enterotoxigenic Escherichia coli (ETEC) infections are a leading cause of diarrheal illness, responsible for an estimated 100,000 deaths annually. ETEC pathogenesis is driven by various virulence factors, including toxins, adhesins, and noncanonical factors such as the protease EatA. The first line of host defense against intestinal pathogenic bacterial infections is the protective intestinal mucus layer. Here, we demonstrate the mechanism by which EatA degrades the core mucus component MUC2, thereby facilitating access to the epithelial cell surface and promoting infection. We identify the specific cleavage site region localized at the C-terminal of MUC2. EatA's protease activity depends on the interaction …

Chemotherapy-Induced Adipo-Lineage Cell Senescence Drives Bone Loss, Ganesh Kumar Raut, Taylor Malachowski, Anupama Melam, Renata Ramalho-Oliveira, Taylor Holt, Xianmin Luo, Zhangting Yao, Douglas V Faget, Qihao Ren, David G Denardo, Sheila A Stewart

2020-Current year OA Pubs

Chemotherapy-induced bone loss is a debilitating and common side effect of cancer treatment, though its underlying mechanisms remain poorly understood. Here, we show that, despite the systemic administration of chemotherapy, cellular senescence is restricted to bone marrow adipo-lineage cells specifically Cxcl12-abundant reticular (CAR) cells and bone marrow adipocytes (BMAds). Induction of senescence within these populations promotes RANK ligand (RANKL)-mediated osteoclastogenesis, leading to significant bone loss. Notably, we find that inhibition of the p38MAPK-MK2 pathway suppresses the senescence-associated secretory phenotype (SASP), including RANKL production abrogating bone loss. Furthermore, treatment with the senolytic combination dasatinib and quercetin (D + Q) selectively eliminates …

Sex Differences In Bile Acid Homeostasis And Excretion Underlie The Disparity In Liver Cancer Incidence Between Males And Females, Megan E Patton, Sherwin Kelekar, Lauren J Taylor, Angela E Dean, Qianying Zuo, Rhishikesh N Thakare, Sung Hwan Lee, Emily C Gentry, Morgan Panitchpakdi, Pieter Dorrestein, Yazen Alnouti, Zeynep Madak-Erdogan, Ju-Seog Lee, Milton J Finegold, Sayeepriyadarshini Anakk

Faculty, Staff and Student Publications

Hepatocellular carcinoma (HCC), the common liver cancer, exhibits higher incidence in males. Here, we report that mice lacking bile acid (BA) regulators, Farnesoid X Receptor (FXR also termed NR1H4) and Small Heterodimer Partner (SHP also termed NR0B2), recapitulate the sex difference in liver cancer risk. Since few therapeutic options are available, we focused on understanding the intrinsic protection afforded to female livers. Transcriptomic analysis in control and NR1H4 and NR0B2 double knockout livers identified female-specific changes in metabolism, including amino acids, lipids, and steroids. To assess translational relevance, we examined if transcriptomic signatures obtained from this murine HCC model correlate …

Batf2 Is A Glutamine-Responsive Tumour Suppressor Required For Type-I Interferon-Dependent Anti-Tumour Immunity, Wang Gong, Hülya F Taner, Yuesong Wu, Yumin He, Xingwu Zhou, Zaiye Li, Xin Hu, Charisse Ursin, Kala Chand Debnath, Kohei Okuyama, Qiang Hu, Christopher R Donnelly, Felipe Nör, Chamila D Perera, Emily Bellile, Arash Yunesi, Zhiqian Zhai, Mei Zhao, Wanqing Cheng, Zackary R Fitzsimonds, Luke Broses, Jiaqian Li, Shadmehr Demehri, Deepak Nagrath, Gregory T Wolf, Andrew G Sikora, Yanbao Yu, Haitao Wen, Lei Wei, Steven B Chinn, Jeffrey N Myers, Shizuo Akira, Yuying Xie, James J Moon, Yu Leo Lei

Faculty, Staff and Student Publications

Recent evidence highlights the significance of a new type of tumour suppressors, which are not frequently mutated but inhibited by metabolic cues in cancers. Here, we identify BATF2 as a tumour suppressor whose expression is epigenetically silenced by glutamine in Head and Neck Squamous Cell Carcinomas (HNSCC). BATF2 correlates with type-I interferon and Th1 signatures in human HNSCC, with correlation coefficients even stronger than those of the positive control, STING. The phosphorylation of BATF2 at serine 227 promotes the oligomerization of STING. BATF2 deficiency or high glutamine levels result in higher oxygen consumption rates and metabolic profiles unfavorable for …

Distinct Populations Of Lung Capillary Endothelial Cells And Their Functional Significance, Joel James, Dan Yi, Zhiyu Dai, Et Al.

2020-Current year OA Pubs

The role of the lung's microcirculation and capillary endothelial cells in normal physiology and the pathobiology of pulmonary diseases is obviously vital. The recent discovery of molecularly distinct aerocytes and general capillary (gCaps) endothelial cells by single-cell transcriptomics (scRNAseq) advanced the field in understanding microcirculatory milieu and cellular communications. However, increasing evidence from different groups indicated the possibility of a more heterogeneous nature of lung capillaries. Therefore, we investigated enriched lung endothelial cells by scRNAseq and identified five novel populations of gCaps with distinct molecular signatures and roles. Our analysis suggests that two major populations of gCaps that express Scn7a(Na

Phospholipid Scramblase 1 (Plscr1) Regulates Interferon-Lambda Receptor 1 (Ifn-Λr1) And Ifn-Λ Signaling In Influenza A Virus (Iav) Infection, Alina Xiaoyu Yang, Lisa Ramos-Rodriguez, Parand Sorkhdini, Dongqin Yang, Carmelissa Norbrun, Sonoor Majid, Sanghyun Lee, Yong Zhang, Michael Holtzman, David F Boyd, Yang Zhou

2020-Current year OA Pubs

Phospholipid scramblase 1 (PLSCR1) is an interferon-stimulated gene (ISG) that has several known anti-influenza functions. However, the mechanisms in relation to its expression compartment and enzymatic activity have not been completely explored. Moreover, only limited animal models have been studied to delineate its role at the tissue level in influenza infections. Our results showed that influenza A virus (IAV)-infected

Micu2 Controls Mitochondrial Calcium Signaling And Migration In Neurons During Development, Elena Berezhnaya, Benjamín Cartes-Saavedra, Raghavendra Singh, Macarena Rodríguez-Prados, Orly Reiner, Fowzan S Alkuraya, György Hajnóczky

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Neurological disorders are linked to mitochondrial dysfunction and calcium overload. Mitochondrial calcium uptake is mediated by the mitochondrial calcium uniporter (mtCU), regulated by MICU1, which can be either homodimerized or heterodimerized with MICU2 or MICU3. Though MICU2 is scarce in the adult brain, MICU2 loss in patients leads to a neurodevelopmental disorder. We hypothesized that MICU2 is required for developmental calcium signaling and neuronal migration. MICU2 is present in the developing mouse brain but disappears by maturation, contrasting with other mtCU subunits that increase. MICU2 loss in mice does not affect cytoplasmic calcium but augments the mitochondrial matrix calcium rise …

Ribosomal Protein Control Of Hematopoietic Stem Cell Transformation Through Regulation Of Metabolism, Bryan Harris, Stephen Sykes, Et Al.

2020-Current year OA Pubs

We report here that expression of the ribosomal protein RPL22 is frequently reduced in human myelodysplastic syndrome (MDS) and acute myelogenous leukemia (AML), and reduced RPL22 expression is associated with worse outcomes. Mice null for Rpl22 display characteristics of an MDS-like syndrome and develop leukemia at an accelerated rate. Rpl22-deficient mice also display enhanced hematopoietic stem cell (HSC) self-renewal and obstructed differentiation potential, which arises not from reduced protein synthesis but from altered metabolism, including increased fatty acid oxidation (FAO) and a striking induction of the stemness factor Lin28b in the resulting leukemia. Lin28b promotes a substantial increase in lipid …

Sox11 Modulates Bcr Signaling Through The Pax5/Cd19 Axis For Therapeutic Targeting In Btk-Resistant Mantle Cell Lymphoma, Rudra Prasad Dutta, Heng-Huan Lee, Violetta V Leshchenko, Ravi Prakash Shukla, Fangfang Yan, Yang Liu, H Ümit Kaniskan, Xing Qiu, Jian Jin, Lapo Alinari, Michael Wang, Samir Parekh

Faculty, Staff and Student Publications

Mantle cell lymphoma (MCL) is an incurable subtype of B-cell non-Hodgkin lymphoma. Despite multiple approved Bruton tyrosine kinase inhibitors (BTKis), resistance to BTKi continues to pose a major clinical challenge. The transcription factor sex determining region Y-box 11 (SOX11) is expressed in most patients with MCL and is associated with poor outcomes. We have previously demonstrated SOX11-dependent B-cell receptor (BCR) signaling in transgenic models of MCL. Here, we report that SOX11 drives BCR signaling via the transcriptional activation of the PAX5/CD19 axis. The translational potential of these results is significant as single-cell RNA sequencing data show that SOX11 is overexpressed …

Coordinated Changes In Stromal And Hematopoietic Cells That Define The Perinatal To Juvenile Transition In The Mouse Thymus, Anusha Vasudev, Colin R Moore, Aparna Calindi, Seung Woo Kang, Bryan R Helm, Jayashree Srinivasan, Siddhartha Shah, Erin Baker, Ruiting Zong, Nandini Singarapu, Scott Casey, Andrew N Macintyre, Ken S Lau, Laura P Hale, Qi Liu, Nancy R Manley, Lauren I R Ehrlich, Ellen R Richie

Faculty, Staff and Student Publications

Perinatal T cells have distinctive phenotypes and functions that may be due in part to age-associated features of stromal cells in the perinatal thymus. We identify age-associated changes in mouse thymic epithelial cells, mesenchyme, endothelium, and hematopoietic antigen-presenting cells from birth to one month of age using single-cell transcriptional profiling, flow cytometry, and imaging. Coordinated cellular and molecular changes occur at 7-14 days of age, designated "transitional ages," as thymus growth switches to homeostasis. E2F target gene expression declines, and the expression of type I interferon response genes increases across diverse cell types at transitional ages. Alterations in thymic stromal …

A Protein Complex In The Extreme Distal Tip Of Vertebrate Motile Cilia Controls Their Organization, Length, And Function, Juyeon Hong, Jiehong Pan, Amjad Horani, Steven L Brody, Et Al.

2020-Current year OA Pubs

The beating of cilia on multi-ciliated cells (MCCs) is essential for normal development and homeostasis in animals. But while the structure and function of basal bodies and axonemes have received significant attention recently, the distal tips of MCC cilia remain relatively poorly defined. Here, we characterize the molecular organization of the distal tip of vertebrate MCC cilia, characterizing two distinct domains occupied by distinct protein constituents. Using frog, mouse, and human MCCs, we find that two largely uncharacterized proteins, Ccdc78 and Ccdc33, occupy a previously undefined region at the extreme distal tip, and these are required for the normal organization …

Metabolomic Profiling Reveals Brain Lipid Alterations In Pex7-Deficient Models Of Rhizomelic Chondrodysplasia Punctata, Riya Sankhe, Meredith I Williams, Wedad Fallatah, Laura Mackay, Mary Layne Brown, Pranjali Bhagwat, Sarah H Elsea, Nancy Braverman, Michael F Wangler

Duncan NRI Faculty and Staff Publications

Rhizomelic chondrodysplasia punctata type 1 (RCDP1) is a peroxisomal disorder characterized by skeletal shortening, intellectual disability, seizures, cataracts, and reduced lifespans. RCDP1 is caused by biallelic loss-of-function variants in PEX7, which encodes a protein required for importing select enzymes into the peroxisome matrix, including those essential for ether lipid synthesis (e.g., plasmalogens) and the branched-chain fatty acid catabolism. Plasmalogen deficiency is a hallmark of RCDP1 and other peroxisomal disorders, including RCDP types 2-5 (RCDP2-5) and Zellweger spectrum disorders (ZSD). Here, we performed comprehensive metabolomic profiling of clinical samples from RCDP patients and Pex7-deficient mouse models. We identified profound …

Surgical Revision In The Presence Of An S. Aureus Infection Increases Virulence Factor Expression And Activates A Multi-Tissue Inflammatory Response, Carly J. Smith, Arianna J. Moniodes, Amanda R. Watkins, Autumn G. Melvage, Thomas P. Thompson, Eirene Choi, Abigail A. Lucas, Brendan F. Gilmore, Thomas P. Schaer, Noreen J. Hickok, Theresa A. Freeman

Department of Orthopaedic Surgery Faculty Papers

Replacing implanted medical hardware due to infection often requires one or more revision surgeries. Each surgery triggers a tissue injury response and disrupts the established bacterial biofilm. However, the complex tissue response to reinjury and biofilm disturbance is not well understood. Our results show that with an existing infection, immunological niches such as the bone marrow, lymph nodes, and circulating blood further upregulate pro-inflammatory programs in response to revision. Rather than reducing bacterial burden, this heightened inflammation provokes virulence factor expression and tissue damage, including bone osteolysis and muscle fibrosis. While muscle fibrosis appears transient and begins resolving by 14 …

A Proteogenomic Gene Signature Defines Prognostic Subgroups Highlighting Pi3k/Akt/Mtor Signaling Pathway As A Therapeutic Vulnerability In Myeloid Malignancies, Fan He, Shuyang Lin, Bei Gao, Varun Ramesh, Alexander B Kim, Tim Kong, Daniel A C Fisher, Christopher T Letson, Molly Brakhane, Mary Fulbright, Yanbo Yu, Marco Sardiello, Jorge Di Paola, Stephen M Sykes, Stephen T Oh

2020-Current year OA Pubs

INTRODUCTION: Myeloid malignancies, including acute myeloid leukemia (AML) and myeloproliferative neoplasms (MPN), exhibit overlapping pathophysiology. Chronic MPNs can transform into secondary AML (sAML), which is associated with poor prognosis and limited treatment options. However, the process and prognostic significance of leukemic transformation remain incompletely understood.

METHOD: Through a two-sample bidirectional Mendelian randomization (MR) analysis, we showed that genetic liability to MPN significantly predicts the risk of developing AML, establishing MPN as the precursor to leukemia. To identify mediators of this risk, we integrated population-level plasma proteomics data, identifying 55 proteins associated with MPN. Upon integrative analysis with the BEAT-AML cohort, …