Digital Commons Network^™

Dual-Specificity Phosphatases 22-Deficient T Cells Contribute To The Pathogenesis Of Ankylosing Spondylitis, Ming-Han Chen, Huai-Chia Chuang, Yi-Chen Yeh, Chung-Tei Chou, Tse-Hua Tan

Children’s Nutrition Research Center Staff Publications

Background: Dual-specificity phosphatases (DUSPs) can dephosphorylate both tyrosine and serine/threonine residues of their substrates and regulate T cell-mediated immunity and autoimmunity. The aim of this study was to investigate the potential roles of DUSPs in ankylosing spondylitis (AS).

Methods: Sixty AS patients and 45 healthy controls were enrolled in this study. Associations of gene expression of 23 DUSPs in peripheral T cells with inflammatory cytokine gene expression and disease activity of AS were analyzed. Finally, we investigated whether the characteristics of AS are developed in DUSP-knockout mice.

Results: The mRNA levels of DUSP4, DUSP5, DUSP6, DUSP7, and DUSP14 in peripheral …

Micrornas And Gene Regulatory Networks Related To Cleft Lip And Palate, Chihiro Iwaya, Akiko Suzuki, Junichi Iwata

Faculty, Staff and Student Publications

Cleft lip and palate is one of the most common congenital birth defects and has a complex etiology. Either genetic or environmental factors, or both, are involved at various degrees, and the type and severity of clefts vary. One of the longstanding questions is how environmental factors lead to craniofacial developmental anomalies. Recent studies highlight non-coding RNAs as potential epigenetic regulators in cleft lip and palate. In this review, we will discuss microRNAs, a type of small non-coding RNAs that can simultaneously regulate expression of many downstream target genes, as a causative mechanism of cleft lip and palate in humans …

Fgl2-Targeting T Cells Exhibit Antitumor Effects On Glioblastoma And Recruit Tumor-Specific Brain-Resident Memory T Cells, Qingnan Zhao, Jiemiao Hu, Lingyuan Kong, Shan Jiang, Xiangjun Tian, Jing Wang, Rintaro Hashizume, Zhiliang Jia, Natalie Wall Fowlkes, Jun Yan, Xueqing Xia, Sofia F Yi, Long Hoang Dao, David Masopust, Amy B Heimberger, Shulin Li

Faculty, Staff and Student Publications

Although tissue-resident memory T (TRM) cells specific for previously encountered pathogens have been characterized, the induction and recruitment of brain TRM cells following immune therapy has not been observed in the context of glioblastoma. Here, we show that T cells expressing fibrinogen-like 2 (FGL2)–specific single-chain variable fragments (T-αFGL2) can induce tumor-specific CD8+ TRM cells that prevent glioblastoma recurrence. These CD8+ TRM cells display a highly expanded T cell receptor repertoire distinct from that found in peripheral tissue. When adoptively transferred to the brains of either immunocompetent or T cell-deficient naïve mice, these CD8+ TRM cells reject glioma cells. Mechanistically, T-αFGL2 …

In Vivo Gene Delivery Into Mouse Mammary Epithelial Cells Through Mammary Intraductal Injection, Wen Bu, Yi Li

Faculty, Staff and Students Publications

Mouse mammary glands comprise ductal trees, which are lined by epithelial cells and have one opening at the tip of each nipple. The epithelial cells play a major role in mammary gland function and are the origin of most mammary tumors. Introducing genes of interest into mouse mammary epithelial cells is a critical step in evaluating gene function in epithelial cells and generating mouse mammary tumor models. This goal can be accomplished through the intraductal injection of a viral vector carrying the genes of interest into the mouse mammary ductal tree. The injected virus subsequently infects mammary epithelial cells, bringing …

Splicing Factor Srsf1 Deficiency In The Liver Triggers Nash-Like Pathology And Cell Death, Waqar Arif, Bhoomika Mathur, Michael F Saikali, Ullas V Chembazhi, Katelyn Toohill, You Jin Song, Qinyu Hao, Saman Karimi, Steven M Blue, Brian A Yee, Eric L Van Nostrand, Sushant Bangru, Grace Guzman, Gene W Yeo, Kannanganattu V Prasanth, Sayeepriyadarshini Anakk, Carolyn L Cummins, Auinash Kalsotra

Faculty, Staff and Students Publications

Regulation of RNA processing contributes profoundly to tissue development and physiology. Here, we report that serine-arginine-rich splicing factor 1 (SRSF1) is essential for hepatocyte function and survival. Although SRSF1 is mainly known for its many roles in mRNA metabolism, it is also crucial for maintaining genome stability. We show that acute liver damage in the setting of targeted SRSF1 deletion in mice is associated with the excessive formation of deleterious RNA-DNA hybrids (R-loops), which induce DNA damage. Combining hepatocyte-specific transcriptome, proteome, and RNA binding analyses, we demonstrate that widespread genotoxic stress following SRSF1 depletion results in global inhibition of mRNA …

Discovery Of Highly Potent And Bmpr2-Selective Kinase Inhibitors Using Dna-Encoded Chemical Library Screening, Ram K Modukuri, Diana Monsivais, Feng Li, Murugesan Palaniappan, Kurt M Bohren, Zhi Tan, Angela F Ku, Yong Wang, Chandrashekhar Madasu, Jian-Yuan Li, Suni Tang, Gabriella Miklossy, Stephen S Palmer, Damian W Young, Martin M Matzuk

Faculty, Staff and Students Publications

The discovery of monokinase-selective inhibitors for patients is challenging because the 500+ kinases encoded by the human genome share highly conserved catalytic domains. Until now, no selective inhibitors unique for a single transforming growth factor β (TGFβ) family transmembrane receptor kinase, including bone morphogenetic protein receptor type 2 (BMPR2), have been reported. This dearth of receptor-specific kinase inhibitors hinders therapeutic options for skeletal defects and cancer as a result of an overactivated BMP signaling pathway. By screening 4.17 billion “unbiased” and “kinase-biased” DNA-encoded chemical library molecules, we identified hits CDD-1115 and CDD-1431, respectively, that were low-nanomolar selective kinase inhibitors of …

Hepatocytes Demarcated By Ephb2 Contribute To The Progression Of Nonalcoholic Steatohepatitis, Yang Xiao, Kirill Batmanov, Wenxiang Hu, Kun Zhu, Alexander Y Tom, Dongyin Guan, Chunjie Jiang, Lan Cheng, Sam J Mccright, Eric C Yang, Matthew R Lanza, Yifan Liu, David A Hill, Mitchell A Lazar

Faculty, Staff and Students Publications

Current therapeutic strategies for treating nonalcoholic steatohepatitis (NASH) have failed to alleviate liver fibrosis, which is a devastating feature leading to hepatic dysfunction. Here, we integrated single-nucleus transcriptomics and epigenomics to characterize all major liver cell types during NASH development in mice and humans. The bifurcation of hepatocyte trajectory with NASH progression was conserved between mice and humans. At the nonalcoholic fatty liver (NAFL) stage, hepatocytes exhibited metabolic adaptation, whereas at the NASH stage, a subset of hepatocytes was enriched for the signatures of cell adhesion and migration, which were mainly demarcated by receptor tyrosine kinase ephrin type B receptor …

Acute High-Fat Diet Impairs Macrophage-Supported Intestinal Damage Resolution, Andrea A Hill, Myunghoo Kim, Daniel F Zegarra-Ruiz, Lin-Chun Chang, Kendra Norwood, Adrien Assié, Wan-Jung H Wu, Michael C Renfroe, Hyo Wong Song, Angela M Major, Buck S Samuel, Joseph M Hyser, Randy S Longman, Gretchen E Diehl

Faculty, Staff and Students Publications

Chronic exposure to high-fat diets (HFD) worsens intestinal disease pathology, but acute effects of HFD in tissue damage remain unclear. Here, we used short-term HFD feeding in a model of intestinal injury and found sustained damage with increased cecal dead neutrophil accumulation, along with dietary lipid accumulation. Neutrophil depletion rescued enhanced pathology. Macrophages from HFD-treated mice showed reduced capacity to engulf dead neutrophils. Macrophage clearance of dead neutrophils activates critical barrier repair and antiinflammatory pathways, including IL-10, which was lost after acute HFD feeding and intestinal injury. IL-10 overexpression restored intestinal repair after HFD feeding and intestinal injury. Macrophage exposure …

Transfusing Convalescent Plasma As Post-Exposure Prophylaxis Against Severe Acute Respiratory Syndrome Coronavirus 2 (Sars-Cov-2) Infection: A Double-Blinded, Phase 2 Randomized, Controlled Trial, Shmuel Shoham, Evan M Bloch, Arturo Casadevall, Daniel Hanley, Bryan Lau, Kelly Gebo, Edward Cachay, Seble G Kassaye, James H Paxton, Jonathan Gerber, Adam C Levine, Arash Naeim, Judith Currier, Bela Patel, Elizabeth S Allen, Shweta Anjan, Lawrence Appel, Sheriza Baksh, Paul W Blair, Anthony Bowen, Patrick Broderick, Christopher A Caputo, Valerie Cluzet, Marie Elena Cordisco, Daniel Cruser, Stephan Ehrhardt, Donald Forthal, Yuriko Fukuta, Amy L Gawad, Thomas Gniadek, Jean Hammel, Moises A Huaman, Douglas A Jabs, Anne Jedlicka, Nicky Karlen, Sabra Klein, Oliver Laeyendecker, Karen Lane, Nichol Mcbee, Barry Meisenberg, Christian Merlo, Giselle Mosnaim, Han-Sol Park, Andrew Pekosz, Joann Petrini, William Rausch, David M Shade, Janna R Shapiro, J Robinson Singleton, Catherine Sutcliffe, David L Thomas, Anusha Yarava, Martin Zand, Jonathan M Zenilman, Aaron A R Tobian, David J Sullivan

Faculty, Staff and Students Publications

BACKGROUND: The efficacy of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) convalescent plasma (CCP) for preventing infection in exposed, uninfected individuals is unknown. CCP might prevent infection when administered before symptoms or laboratory evidence of infection.

METHODS: This double-blinded, phase 2 randomized, controlled trial (RCT) compared the efficacy and safety of prophylactic high titer (≥1:320 by Euroimmun ELISA) CCP with standard plasma. Asymptomatic participants aged ≥18 years with close contact exposure to a person with confirmed coronavirus disease 2019 (COVID-19) in the previous 120 hours and negative SARS-CoV-2 test within 24 hours before transfusion were eligible. The primary outcome was …

Production Of A Monoclonal Antibody For The Detection Of Forchlorfenuron: Application In An Indirect Enzyme-Linked Immunosorbent Assay And Immunochromatographic Strip, Xingmei Lei, A M Abd El-Aty, Lingyuan Xu, Jing Zhao, Jia Li, Song Gao, Yun Zhao, Yongxin She, Fen Jin, Jing Wang, Lufei Zheng, Maojun Jin, Bruce D Hammock

Faculty, Staff and Student Publications

In this study, a monoclonal antibody (mAb) specific to forchlorfenuron (CPPU) with high sensitivity and specificity was produced and designated (9G9). To detect CPPU in cucumber samples, an indirect enzyme-linked immunosorbent assay (ic-ELISA) and a colloidal gold nanobead immunochromatographic test strip (CGN-ICTS) were established using 9G9. The half-maximal inhibitory concentration (IC50) and the LOD for the developed ic-ELISA were determined to be 0.19 ng/mL and 0.04 ng/mL in the sample dilution buffer, respectively. The results indicate that the sensitivity of the antibodies prepared in this study (9G9 mAb) was higher than those reported in the previous literature. On the other …

Intestinal Toxicity To Ctla-4 Blockade Driven By Il-6 And Myeloid Infiltration, Yifan Zhou, Yusra B Medik, Bhakti Patel, Daniel B Zamler, Sijie Chen, Thomas Chapman, Sarah Schneider, Elizabeth M Park, Rachel L Babcock, Taylor T Chrisikos, Laura M Kahn, Allison M Dyevoich, Josue E Pineda, Matthew C Wong, Aditya K Mishra, Samuel H Cass, Alexandria P Cogdill, Daniel H Johnson, Sarah B Johnson, Khalida Wani, Debora A Ledesma, Courtney W Hudgens, Jingjing Wang, Md Abdul Wadud Khan, Christine B Peterson, Aron Y Joon, Weiyi Peng, Haiyan S Li, Reetakshi Arora, Ximing Tang, Maria Gabriela Raso, Xuegong Zhang, Wai Chin Foo, Michael T Tetzlaff, Gretchen E Diehl, Karen Clise-Dwyer, Elizabeth M Whitley, Matthew M Gubin, James P Allison, Patrick Hwu, Nadim J Ajami, Adi Diab, Jennifer A Wargo, Stephanie S Watowich

Faculty, Staff and Student Publications

Immune checkpoint blockade (ICB) has revolutionized cancer treatment, yet quality of life and continuation of therapy can be constrained by immune-related adverse events (irAEs). Limited understanding of irAE mechanisms hampers development of approaches to mitigate their damage. To address this, we examined whether mice gained sensitivity to anti-CTLA-4 (αCTLA-4)–mediated toxicity upon disruption of gut homeostatic immunity. We found αCTLA-4 drove increased inflammation and colonic tissue damage in mice with genetic predisposition to intestinal inflammation, acute gastrointestinal infection, transplantation with a dysbiotic fecal microbiome, or dextran sodium sulfate administration. We identified an immune signature of αCTLA-4–mediated irAEs, including colonic neutrophil accumulation …

Bone Metastasis Initiation Is Coupled With Bone Remodeling Through Osteogenic Differentiation Of Ng2+ Cells, Weijie Zhang, Zhan Xu, Xiaoxin Hao, Tiancheng He, Jiasong Li, Yichao Shen, Kai Liu, Yang Gao, Jun Liu, David G Edwards, Aaron M Muscarella, Ling Wu, Liqun Yu, Longyong Xu, Xi Chen, Yi-Hsuan Wu, Igor L Bado, Yunfeng Ding, Sergio Aguirre, Hai Wang, Zbigniew Gugala, Robert L Satcher, Stephen T C Wong, Xiang H-F Zhang

Faculty, Staff and Students Publications

The bone microenvironment is dynamic and undergoes remodeling in normal and pathologic conditions. Whether such remodeling affects disseminated tumor cells (DTC) and bone metastasis remains poorly understood. Here, we demonstrated that pathologic fractures increase metastatic colonization around the injury. NG2+ cells are a common participant in bone metastasis initiation and bone remodeling in both homeostatic and fractured conditions. NG2+ bone mesenchymal stem/stromal cells (BMSC) often colocalize with DTCs in the perivascular niche. Both DTCs and NG2+ BMSCs are recruited to remodeling sites. Ablation of NG2+ lineage impaired bone remodeling and concurrently diminished metastatic colonization. In cocultures, NG2+ BMSCs, especially when …

Short-Term Pi3k Inhibition Prevents Breast Cancer In Preclinical Models, Amy T Ku, Adelaide I J Young, Ahmed Atef Ibrahim, Wen Bu, Weiyu Jiang, Meng Lin, Laterrica C Williams, Bryant Lee Mccue, George Miles, Chandandeep Nagi, Fariba Behbod, Yi Li

Faculty, Staff and Students Publications

Antiestrogen medication is the only chemoprevention currently available for women at a high risk of developing breast cancer; however, antiestrogen therapy requires years to achieve efficacy and has adverse side effects. Therefore, it is important to develop an efficacious chemoprevention strategy that requires only a short course of treatment. PIK3CA is commonly activated in breast atypical hyperplasia, the known precancerous precursor of breast cancer. Targeting PI3K signaling in these precancerous lesions may offer a new strategy for chemoprevention. Here, we first established a mouse model that mimics the progression from precancerous lesions to breast cancer. Next, we demonstrated that a …

Long And Short Duration Exposures To The Selective Serotonin Reuptake Inhibitors (Ssris) Fluoxetine, Paroxetine And Sertraline At Environmentally Relevant Concentrations Lead To Adverse Effects On Zebrafish Behaviour And Reproduction, Ananda Baskaran Venkatachalam, Bailey Levesque, John C Achenbach, Jane J Pappas, Lee D Ellis

Faculty, Staff and Student Publications

Selective serotonin reuptake inhibitors (SSRIs) are currently the most prescribed class of psychotropic medications. Their increased global manufacture and use have become growing concerns for aquatic toxicologists and environmental biologists, who assess both the direct and indirect effects of substances on the environment and on human health. In order to assess the potential impact of environmentally relevant levels of SSRIs on fish development, behaviour and reproduction, we exposed juvenile and adult zebrafish to a select group of SSRIs using two separate exposure paradigms. In the first paradigm, juvenile zebrafish were exposed to Fluoxetine (Prozac), Paroxetine (Paxil), Sertraline (Zoloft) or a …

3,3'-Diindolylmethane Augments 5-Fluorouracil-Inducedgrowth Suppression In Gastric Cancer Cells Through Suppression Of The Akt/Gsk-3Β And Wnt/Beta-Catenin, Cong Shan Li, Thi Van Nguyen, Ok Hee Chai, Byung Hyun Park, Ju-Seog Lee, Soo Mi Kim

Faculty, Staff and Student Publications

Gastric cancer (GC) is one of the most lethal cancers in South Korea, and it is a cancer of concern worldwide. 5-fluorouracil (5-Fu) is commonly used as the first-line therapy for advanced GC; however, its side effects often limit the dosage range and impair patients' quality of life. Due to the limitations of current chemotherapy, new anticancer therapies are urgently needed. 3,3'-diindolylmethane (DIM) has been reported to have the ability to protect against various types of cancer. Our study aimed to elucidate the anticancer effect of DIM in GC when treated with the chemotherapeutic agent 5-Fu. In our results, combined …

Long-Lasting Chews Elicit Positive Emotional States In Dogs During Short Periods Of Social Isolation, Hannah E Flint, Megan Atkinson, James Lush, Alysia B G Hunt, Tammie King

Faculty, Staff and Students Publications

Dogs may experience negative emotional states when isolated from human caregivers and conspecifics. This study aimed to evaluate how dogs interact with different enrichments during a short period of social isolation, as a first step towards identifying methods for improving their emotional wellbeing. Using a cross-over design, dogs (n = 20) at the Waltham Petcare Science Institute were exposed to four different food-based enrichments while left alone in a familiar room for 20 min: long-lasting chew (Chew), kibble in a treat-dispensing toy (Toy), and kibble dispensed through a smart treat-dispensing device with (Device + Voice) and without (Device) a …

Lef1 Drives A Central Memory Program And Supports Antitumor Activity Of Natural Killer T Cells, Ho Ngai, Gabriel A Barragan, Gengwen Tian, Julien C Balzeau, Chunchao Zhang, Amy N Courtney, Linjie Guo, Xin Xu, Michael S Wood, Janice M Drabek, Thorsten Demberg, Caroline M Sands, Cynthia N Chauvin-Fleurence, Erica J Di Pierro, Jeffrey M Rosen, Leonid S Metelitsa

Faculty, Staff and Students Publications

Vα24-invariant natural killer T cells (NKT) possess innate antitumor properties that can be exploited for cancer immunotherapy. We have shown previously that the CD62L+ central memory-like subset of these cells drives the in vivo antitumor activity of NKTs, but molecular mediators of NKT central memory differentiation remain unknown. Here, we demonstrate that relative to CD62L- cells, CD62L+ NKTs express a higher level of the gene encoding the Wnt/β-catenin transcription factor lymphoid enhancer binding factor 1 (LEF1) and maintain active Wnt/β-catenin signaling. CRISPR/Cas9-mediated LEF1 knockout reduced CD62L+ frequency after antigenic stimulation, whereas Wnt/β-catenin activator Wnt3a ligand increased CD62L+ frequency. LEF1 overexpression …

Genome-Wide Screening Reveals The Genetic Basis Of Mammalian Embryonic Eye Development, Justine M Chee, Louise Lanoue, Dave Clary, Kendall Higgins, Lynette Bower, Ann Flenniken, Ruolin Guo, David J Adams, Fatima Bosch, Robert E Braun, Steve D M Brown, H-J Genie Chin, Mary E Dickinson, Chih-Wei Hsu, Michael Dobbie, Xiang Gao, Sanjeev Galande, Anne Grobler, Jason D Heaney, Yann Herault, Martin Hrabe De Angelis, Fabio Mammano, Lauryl M J Nutter, Helen Parkinson, Chuan Qin, Toshi Shiroishi, Radislav Sedlacek, J-K Seong, Ying Xu, Brian Brooks, Colin Mckerlie, K C Kent Lloyd, Henrik Westerberg, Ala Moshiri

Faculty, Staff and Students Publications

BACKGROUND: Microphthalmia, anophthalmia, and coloboma (MAC) spectrum disease encompasses a group of eye malformations which play a role in childhood visual impairment. Although the predominant cause of eye malformations is known to be heritable in nature, with 80% of cases displaying loss-of-function mutations in the ocular developmental genes OTX2 or SOX2, the genetic abnormalities underlying the remaining cases of MAC are incompletely understood. This study intended to identify the novel genes and pathways required for early eye development. Additionally, pathways involved in eye formation during embryogenesis are also incompletely understood. This study aims to identify the novel genes and pathways …

Cellular Composition And Circuit Organization Of The Locus Coeruleus Of Adult Mice, Andrew Mckinney, Ming Hu, Amber Hoskins, Arian Mohammadyar, Nabeeha Naeem, Junzhan Jing, Saumil S Patel, Bhavin R Sheth, Xiaolong Jiang

Faculty, Staff and Students Publications

The locus coeruleus (LC) houses the vast majority of noradrenergic neurons in the brain and regulates many fundamental functions, including fight and flight response, attention control, and sleep/wake cycles. While efferent projections of the LC have been extensively investigated, little is known about its local circuit organization. Here, we performed large-scale multipatch recordings of noradrenergic neurons in adult mouse LC to profile their morpho-electric properties while simultaneously examining their interactions. LC noradrenergic neurons are diverse and could be classified into two major morpho-electric types. While fast excitatory synaptic transmission among LC noradrenergic neurons was not observed in our preparation, these …

Tumor-Associated Nonmyelinating Schwann Cell-Expressed Nuclear Export Signal Mutation Of Epidermal Growth Factor Receptor Enhances Malignant Phenotypes Of Cancer Cells, Chengcao Sun, Youqiong Ye, Zhi Tan, Yuan Liu, Yajuan Li, Wei Hu, Ke Liang, Sergey D Egranov, Lisa Angela Huang, Zhao Zhang, Yaohua Zhang, Jun Yao, Tina K Nguyen, Zilong Zhao, Andrew Wu, Jeffrey R Marks, Abigail S Caudle, Aysegul A Sahin, Jianjun Gao, Seth T Gammon, David Piwnica-Worms, Jian Hu, Paul J Chiao, Dihua Yu, Mien-Chie Hung, Michael A Curran, George A Calin, Haoqiang Ying, Leng Han, Chunru Lin, Liuqing Yang

Faculty, Staff and Student Publications

One of the major obstacles to treating pancreatic ductal adenocarcinoma (PDAC) is its immunoresistant microenvironment. The functional importance and molecular mechanisms of Schwann cells in PDAC remains largely elusive. We characterized the gene signature of tumor-associated nonmyelinating Schwann cells (TASc) in PDAC and indicated that the abundance of TASc was correlated with immune suppressive tumor microenvironment and the unfavorable outcome of patients with PDAC. Depletion of pancreatic-specific TASc promoted the tumorigenesis of PDAC tumors. TASc-expressed long noncoding RNA (lncRNA) plasmacytoma variant translocation 1 (

A Dlg1-Arhgap31-Cdc42 Axis Is Essential For The Intestinal Stem Cell Response To Fluctuating Niche Wnt Signaling, David Castillo-Azofeifa, Tomas Wald, Efren A Reyes, Aaron Gallagher, Julia Schanin, Stephanie Vlachos, Nathalie Lamarche-Vane, Carolyn Bomidi, Sarah Blutt, Mary K Estes, Todd Nystul, Ophir D Klein

Faculty, Staff and Students Publications

A central factor in the maintenance of tissue integrity is the response of stem cells to variations in the levels of niche signals. In the gut, intestinal stem cells (ISCs) depend on Wnt ligands for self-renewal and proliferation. Transient increases in Wnt signaling promote regeneration after injury or in inflammatory bowel diseases, whereas constitutive activation of this pathway leads to colorectal cancer. Here, we report that Discs large 1 (Dlg1), although dispensable for polarity and cellular turnover during intestinal homeostasis, is required for ISC survival in the context of increased Wnt signaling. RNA sequencing (RNA-seq) and genetic mouse models demonstrated …

Hemoglobin Concentration Impacts Viscoelastic Hemostatic Assays In Icu Admitted Patients, David J Roh, Tiffany R Chang, Aditya Kumar, Devin Burke, Glenda Torres, Katherine Xu, Winni Yang, Azzurra Cottarelli, Ernest Moore, Angela Sauaia, Kirk Hansen, Angela Velazquez, Amelia Boehme, Athina Vrosgou, Shivani Ghoshal, Soojin Park, Sachin Agarwal, Jan Claassen, E Sander Connolly, Gebhard Wagener, Richard O Francis, Eldad Hod

Faculty, Staff and Student Publications

Objectives: Low hemoglobin concentration impairs clinical hemostasis across several diseases. It is unclear whether hemoglobin impacts laboratory functional coagulation assessments. We evaluated the relationship of hemoglobin concentration on viscoelastic hemostatic assays in intracerebral hemorrhage (ICH) and perioperative patients admitted to an ICU.

Design: Observational cohort study and separate in vitro laboratory study.

Setting: Multicenter tertiary referral ICUs.

Patients: Two acute ICH cohorts receiving distinct testing modalities: rotational thromboelastometry (ROTEM) and thromboelastography (TEG), and a third surgical ICU cohort receiving ROTEM were evaluated to assess the generalizability of findings across disease processes and testing platforms. A separate in vitro ROTEM laboratory …

Alphaviruses Detected In Mosquitoes In The North-Eastern Regions Of South Africa, 2014 To 2018, Milehna M Guarido, Isabel Fourie, Kgothatso Meno, Adriano Mendes, Megan A Riddin, Caitlin Macintyre, Sontaga Manyana, Todd Johnson, Maarten Schrama, Erin E Gorsich, Basil D Brooke, Antonio Paulo G Almeida, Marietjie Venter

Faculty, Staff and Student Publications

The prevalence and distribution of African alphaviruses such as chikungunya have increased in recent years. Therefore, a better understanding of the local distribution of alphaviruses in vectors across the African continent is important. Here, entomological surveillance was performed from 2014 to 2018 at selected sites in north-eastern parts of South Africa where alphaviruses have been identified during outbreaks in humans and animals in the past. Mosquitoes were collected using a net, CDC-light, and BG-traps. An alphavirus genus-specific nested RT-PCR was used for screening, and positive pools were confirmed by sequencing and phylogenetic analysis. We collected 64,603 mosquitoes from 11 genera, …

Panoptosis Is A Prominent Feature Of Desmoplakin Cardiomyopathy, Melis Olcum, Leila Rouhi, Siyang Fan, Maya M Gonzales, Hyun-Hwan Jeong, Zhongming Zhao, Priyatansh Gurha, Ali J Marian

Faculty, Staff and Student Publications

INTRODUCTION: Arrhythmogenic cardiomyopathy (ACM) is hereditary cardiomyopathy caused by pathogenic variants (mutations) in genes encoding the intercalated disc (ID), particularly desmosome proteins. ACM caused by mutations in the

AIM: The aim of this article was to gain insight into the pathogenesis of DSP cardiomyopathy.

METHODS AND RESULTS: The

CONCLUSION: The findings identify PANoptosis as a prominent phenotypic feature of DSP cardiomyopathy and set the stage for delineating the specific molecular mechanisms involved in its pathogenesis. The model also provides the opportunity to test the effects of pharmacological and genetic interventions on myocardial fibrosis and cell death.

Inhibition Of Myeloperoxidase Enhances Immune Checkpoint Therapy For Melanoma, Tracy W Liu, Seth T Gammon, Ping Yang, Wencai Ma, Jing Wang, David Piwnica-Worms

Faculty, Staff and Student Publications

BACKGROUND: The presence of a highly immunosuppressive tumor microenvironment has limited the success of immune checkpoint therapy (ICT). Immune suppressing myeloid cells with increased production of reactive oxygen species are critical drivers of this immunosuppressive tumor microenvironment. Strategies to limit these immune suppressing myeloid cells are needed to enhance response to ICT.

METHODS: To evaluate the contribution of myeloperoxidase (MPO), a myeloid lineage-restricted enzyme and a major source of reactive oxygen species, to mediating ICT response, we compared treatment outcome and immune composition in wild-type, MPO-deficient (

RESULTS: Tumor growth and survival studies demonstrated that either host deficiency (

CONCLUSION: …

Innately Expressed Estrogen-Related Receptors In The Skeletal Muscle Are Indispensable For Exercise Fitness, Danesh H Sopariwala, Andrea S Rios, Guangsheng Pei, Anirban Roy, Meiricris Tomaz Da Silva, Hao Thi Thu Nguyen, Addison Saley, Rachel Van Drunen, Anastasia Kralli, Kristin Mahan, Zhongming Zhao, Ashok Kumar, Vihang A Narkar

Faculty, Staff and Student Publications

Transcriptional determinants in the skeletal muscle that govern exercise capacity, while poorly defined, could provide molecular insights into how exercise improves fitness. Here, we have elucidated the role of nuclear receptors, estrogen-related receptor alpha and gamma (ERRα/γ) in regulating myofibrillar composition, contractility, and exercise capacity in skeletal muscle. We used muscle-specific single or double (DKO) ERRα/γ knockout mice to investigate the effect of ERRα/γ deletion on muscle and exercise parameters. Individual knockout of ERRα/γ did not have a significant impact on the skeletal muscle. On the other hand, DKO mice exhibit pale muscles compared to wild-type (WT) littermates. RNA-seq analysis …

Economic Evaluation Of An Intervention To Prevent Adolescent Dating Violence (Me & You), Ellerie Weber, Melissa F Peskin, Christine M Markham, Ross Shegog, Elizabeth R Baumler, Robert C Addy, Jeff R Temple, Belinda Hernandez, Paula Cuccaro, Melanie A Thiel, Efrat K Gabay, Susan Tortolero Emery

Faculty, Staff and Student Publications

Me & You: Building Healthy Relationships (Me & You) is a multilevel, technology-enhanced adolescent dating violence (DV) prevention program that aimed to reduce DV among ethnic-minority, early adolescent, urban youth. A group-randomized control trial of Me & You, conducted with 10 middle schools from a large urban school district in Southeast Texas in 2014–2015, found it to be effective in reducing DV perpetration and decreasing some forms of DV victimization. Economic evaluations of DV interventions are extremely limited, despite calls for more economic analyses to be incorporated in research. We help fill this gap by evaluating the cost-effectiveness from the …

Relationships Between Urinary Metals And Diabetes Traits Among Mexican Americans In Starr County, Texas, Usa, Margaret C Weiss, Yu-Hsuan Shih, Molly Scannell Bryan, Brian P Jackson, David Aguilar, Craig L Hanis, Maria Argos, Robert M Sargis

Faculty, Staff and Student Publications

Hispanics/Latinos have higher rates of type 2 diabetes (T2D), and the origins of these disparities are poorly understood. Environmental endocrine-disrupting chemicals (EDCs), including some metals and metalloids, are implicated as diabetes risk factors. Data indicate that Hispanics/Latinos may be disproportionately exposed to EDCs, yet they remain understudied with respect to environmental exposures and diabetes. The objective of this study is to determine how metal exposures contribute to T2D progression by evaluating the associations between 8 urinary metals and measures of glycemic status in 414 normoglycemic or prediabetic adults living in Starr County, Texas, a Hispanic/Latino community with high rates of …

Reduced Spag17 Expression In Systemic Sclerosis Triggers Myofibroblast Transition And Drives Fibrosis, Paulene Sapao, Elisha D O Roberson, Bo Shi, Shervin Assassi, Brian Skaug, Fred Lee, Alexandra Naba, Bethany E Perez White, Carlos Córdova-Fletes, Pei-Suen Tsou, Amr H Sawalha, Johann E Gudjonsson, Feiyang Ma, Priyanka Verma, Dibyendu Bhattacharyya, Mary Carns, Jerome F Strauss, Delphine Sicard, Daniel J Tschumperlin, Melissa I Champer, Paul J Campagnola, Maria E Teves, John Varga

Faculty, Staff and Student Publications

Systemic sclerosis (SSc) is a clinically heterogeneous fibrotic disease with no effective treatment. Myofibroblasts are responsible for unresolving synchronous skin and internal organ fibrosis in SSc, but the drivers of sustained myofibroblast activation remain poorly understood. Using unbiased transcriptome analysis of skin biopsies, we identified the downregulation of SPAG17 in multiple independent cohorts of patients with SSc, and by orthogonal approaches, we observed a significant negative correlation between SPAG17 and fibrotic gene expression. Fibroblasts and endothelial cells explanted from SSc skin biopsies showed reduced chromatin accessibility at the SPAG17 locus. Remarkably, mice lacking Spag17 showed spontaneous skin fibrosis with increased …

Positioning The Brainstem Within The Neural Network Of Threat Prediction, Xu O Zhang, Fabricio H Do Monte

Faculty, Staff and Student Publications

In a recent study, Strickland and McDannald dissected the role of brainstem networks in threat prediction. Using probabilistic threat discrimination in rats, the authors demonstrated that brainstem neurons estimate threat probability and generate positive aversive prediction errors after unexpected outcomes. Their findings suggest that, beyond organizing defensive behaviors, brainstem neurons are involved in threat prediction computations.