Digital Commons Network^™

Impaired Meningeal Lymphatic Vessel Development Worsens Stroke Outcome, Pavel Yanev, Katherine Poinsatte, Devon Hominick, Noor Khurana, Kielen R. Zuurbier, Marcus Berndt, Erik J. Plautz, Michael T. Dellinger, Ann M. Stowe

Neurology Faculty Publications

The discovery of meningeal lymphatic vessels (LVs) has sparked interest in identifying their role in diseases of the central nervous system. Similar to peripheral LVs, meningeal LVs depend on vascular endothelial growth factor receptor-3 (VEGFR3) signaling for development. Here we characterize the effect of stroke on meningeal LVs, and the impact of meningeal lymphatic hypoplasia on post-stroke outcomes. We show that photothrombosis (PT), but not transient middle cerebral artery occlusion (tMCAo), induces meningeal lymphangiogenesis in young male C57Bl/J6 mice. We also show that Vegfr3^wt/mut mice develop significantly fewer meningeal LVs than Vegfr3^wt/wt mice. Again, meningeal lymphangiogenesis occurs in …

Assessing Lymphatic Route Of Csf Outflow And Peripheral Lymphatic Contractile Activity During Head-Down Tilt Using Near-Infrared Fluorescence Imaging, John C Rasmussen, Sunkuk Kwon, Amanda Pinal, Alexander Bareis, Fred C Velasquez, Christopher F Janssen, John R Morrow, Caroline E Fife, Ron J Karni, Eva M Sevick-Muraca

Faculty, Staff and Student Publications

Evidence overwhelmingly suggests that the lymphatics play a critical role in the clearance of cerebrospinal fluid (CSF) from the cranial space. Impairment of CSF outflow into the lymphatics is associated with a number of pathological conditions including spaceflight-associated neuro-ocular syndrome (SANS), a problem that limits long-duration spaceflight. We used near-infrared fluorescence lymphatic imaging (NIRFLI) to dynamically visualize the deep lymphatic drainage pathways shared by CSF outflow and disrupted during head-down tilt (HDT), a method used to mimic the cephalad fluid shift that occurs in microgravity. After validating CSF clearance into the lymph nodes of the neck in swine, a pilot …

Hypothalamic Orexin And Mechanistic Target Of Rapamycin Activation Mediate Sleep Dysfunction In A Mouse Model Of Tuberous Sclerosis Complex, Bo Zhang, Dongjun Guo, Lirong Han, Nicholas Rensing, Akiko Satoh, Michael Wong

2020-Current year OA Pubs

Tuberous sclerosis complex (TSC) is a genetic disease related to hyperactivation of the mechanistic target of rapamycin (mTOR) pathway and manifested by neurological symptoms, such as epilepsy and sleep disorders. The pathophysiology of sleep dysfunction is poorly understood and is likely multifactorial, but may involve intrinsic biological regulators in the brain. Here, we characterized a mouse model of sleep disorders in TSC and investigated mechanisms of sleep dysfunction in this conditional knockout model involving inactivation of the Tsc1 gene in neurons and astrocytes (Tsc1

Short-Chain Fatty Acids Improve Poststroke Recovery Via Immunological Mechanisms, Rebecca Sadler, Julia V. Cramer, Steffanie Heindl, Sarantos Kostidis, Dene Betz, Kielen R. Zuurbier, Bernd H. Northoff, Marieke Heijink, Mark P. Goldberg, Erik J. Plautz, Stefan Roth, Rainer Malik, Martin Dichgans, Lesca M. Holdt, Corinne Benakis, Martin Giera, Ann M. Stowe, Arthur Liesz

Neurology Faculty Publications

Recovery after stroke is a multicellular process encompassing neurons, resident immune cells, and brain-invading cells. Stroke alters the gut microbiome, which in turn has considerable impact on stroke outcome. However, the mechanisms underlying gut–brain interaction and implications for long-term recovery are largely elusive. Here, we tested the hypothesis that short-chain fatty acids (SCFAs), key bioactive microbial metabolites, are the missing link along the gut–brain axis and might be able to modulate recovery after experimental stroke. SCFA supplementation in the drinking water of male mice significantly improved recovery of affected limb motor function. Using in vivo wide-field calcium imaging, we observed …

Metabolic Dysregulation In The Atp7b-/- Wilson's Disease Mouse Model, Clavia Ruth Wooton-Kee, Matthew Robertson, Ying Zhou, Bingning Dong, Zhen Sun, Kang Ho Kim, Hailan Liu, Yong Xu, Nagireddy Putluri, Pradip Saha, Cristian Coarfa, David D Moore, Alli M Nuotio-Antar

Faculty, Staff and Students Publications

Inactivating mutations in the copper transporter Atp7b result in Wilson’s disease. The Atp7b−/− mouse develops hallmarks of Wilson’s disease. The activity of several nuclear receptors decreased in Atp7b−/− mice, and nuclear receptors are critical for maintaining metabolic homeostasis. Therefore, we anticipated that Atp7b−/− mice would exhibit altered progression of diet-induced obesity, fatty liver, and insulin resistance. Following 10 wk on a chow or Western-type diet (40% kcal fat), parameters of glucose and lipid homeostasis were measured. Hepatic metabolites were measured by liquid chromatography–mass spectrometry and correlated with transcriptomic data. Atp7b−/− mice fed a chow diet presented …

Fenugreek Counters The Effects Of High Fat Diet On Gut Microbiota In Mice: Links To Metabolic Benefit, Annadora J. Bruce-Keller, Allison J. Richard, Sun-Ok Fernandez-Kim, David M. Ribnicky, J Michael Salbaum, Susan Newman Phd, Rn, Crrn, Faan, Richard Carmouche, Jacqueline M. Stephens

Publications

Fenugreek (Trigonella foenum-graecum) is an annual herbaceous plant and a staple of traditional health remedies for metabolic conditions including high cholesterol and diabetes. While the mechanisms of the beneficial actions of fenugreek remain unknown, a role for intestinal microbiota in metabolic homeostasis is likely. To determine if fenugreek utilizes intestinal bacteria to offset the adverse effects of high fat diets, C57BL/6J mice were fed control/low fat (CD) or high fat (HFD) diets each supplemented with or without 2% (w/w) fenugreek for 16 weeks. The effects of fenugreek and HFD on gut microbiota were comprehensively mapped and then statistically assessed in …

Infection-Induced Signals Generated At The Plasma Membrane Epigenetically Regulate Wnt Signaling In Vitro And In Vivo, Ishfaq Ahmed, Badal Chandra Roy, Laxmi Uma Maheswar Rao Jakkula, Dharmalingam Subramaniam, Prasad Dandawate, Shrikant Anant, Venkatesh Sampath, Shahid Umar

Manuscripts, Articles, Book Chapters and Other Papers

Wnt signaling regulates immunomodulatory functions during infection and inflammation. Employing NCCIT and HCT116 cells, having high endogenous Wnt signaling, we observed elevated levels of low-density lipoprotein receptor-related protein 5/6 (LRP5/6) and Frizzled class receptor 10 (FZD10) and increases in β-catenin, doublecortin-like kinase 1 (DCLK1), CD44 molecule (CD44), and aldehyde dehydrogenase 1 family member A1 (ALDH1A1). siRNA-induced knockdown of these receptors antagonized TOPflash reporter activity and spheroid growth in vitro and elevated Wnt-inhibitory factor 1 (WIF1) activity. Elevated mRNA and protein levels of LRP5/6 and FZD10 paralleled expression of WNT2b and WNT4 in colonic crypts at days 6 and 12 post-infection …

A Randomized Trial Of Erythropoietin For Neuroprotection In Preterm Infants, Sandra E Juul, Bryan A Comstock, Rajan Wadhawan, Dennis E Mayock, Sherry E Courtney, Tonya Robinson, Kaashif A Ahmad, Ellen Bendel-Stenzel, Mariana Baserga, Edmund F Lagamma, L Corbin Downey, Raghavendra Rao, Nancy Fahim, Andrea Lampland, Ivan D Frantz Iii, Janine Y Khan, Michael Weiss, Maureen M Gilmore, Robin K Ohls, Nishant Srinivasan, Jorge E Perez, Victor Mckay, Phuong T Vu, Jean Lowe, Karl Kuban, T Michael O'Shea, Adam L Hartman, Patrick J Heagerty, Penut Trial Consortium

Pediatrics Research and Scholarship

BACKGROUND: High-dose erythropoietin has been shown to have a neuroprotective effect in preclinical models of neonatal brain injury, and phase 2 trials have suggested possible efficacy; however, the benefits and safety of this therapy in extremely preterm infants have not been established.

METHODS: In this multicenter, randomized, double-blind trial of high-dose erythropoietin, we assigned 941 infants who were born at 24 weeks 0 days to 27 weeks 6 days of gestation to receive erythropoietin or placebo within 24 hours after birth. Erythropoietin was administered intravenously at a dose of 1000 U per kilogram of body weight every 48 hours for …

Integrative Qtl Analysis Of Gene Expression And Chromatin Accessibility Identifies Multi-Tissue Patterns Of Genetic Regulation., Gregory R Keele, Bryan C Quach, Jennifer W Israel, Grace A Chappell, Lauren Lewis, Alexias Safi, Jeremy M Simon, Paul Cotney, Gregory E Crawford, William Valdar, Ivan Rusyn, Terrence S Furey

Faculty Research 2020

Gene transcription profiles across tissues are largely defined by the activity of regulatory elements, most of which correspond to regions of accessible chromatin. Regulatory element activity is in turn modulated by genetic variation, resulting in variable transcription rates across individuals. The interplay of these factors, however, is poorly understood. Here we characterize expression and chromatin state dynamics across three tissues-liver, lung, and kidney-in 47 strains of the Collaborative Cross (CC) mouse population, examining the regulation of these dynamics by expression quantitative trait loci (eQTL) and chromatin QTL (cQTL). QTL whose allelic effects were consistent across tissues were detected for 1,101 …

Memory Function And Brain Functional Connectivity Adaptations Following Multiple-Modality Exercise And Mind-Motor Training In Older Adults At Risk Of Dementia: An Exploratory Sub-Study., Narlon C Boa Sorte Silva, Lindsay S Nagamatsu, Dawn P. Gill, Adrian M Owen, Robert J Petrella

Family Medicine Publications

BACKGROUND: Multiple-modality exercise improves brain function. However, whether task-based brain functional connectivity (FC) following exercise suggests adaptations in preferential brain regions is unclear. The objective of this study was to explore memory function and task-related FC changes following multiple-modality exercise and mind-motor training in older adults with subjective cognitive complaints.

METHODS: We performed secondary analysis of memory function data in older adults [

RESULTS: Our findings indicated that the M4 group showed greater improvements in the Paired Associates tasks compared to the M2 group at 24 weeks [mean difference: 0.47, 95% confidence interval (CI): 0.08 to 0.86,

CONCLUSION: Our findings …

Parasitic Infections Represent A Significant Health Threat Among Recent Immigrants In Chicago, Jesica A. Herrick, Monica Nordstrom, Patrick M. Maloney, Miguel Rodriguez, Kevin Naceanceno, Gloria Gallo, Rojelio Mejia, Ron Hershow

Journal Articles: Epidemiology

Parasitic infections are likely under-recognized among immigrant populations in the USA. We conducted a cross-sectional study to evaluate if such infections have health impacts among recent immigrants in Chicago and to identify predictive factors for parasitic infections. A total of 133 recent immigrants were enrolled, filling out a standardized medical questionnaire and providing blood and stool samples. Appriximately 12% of subjects (15/125) who provided a blood or stool sample for testing were found to have evidence of current or prior infection with a pathogenic parasite, of which Toxocara spp. (8 subjects, 6.4%) and Strongyloides stercoralis (5 subjects, 4%) were most …

Exogenous Flupirtine As Potential Treatment For Cln3 Disease, Katia Maalouf, Joelle Makoukji, Sara Saab, Nadine J. Makhoul, Angelica V. Carmona, Nihar Kinarivala, Noël Ghanem, Paul C. Trippier, Rose-Mary Boustany

Journal Articles: Pharmaceutical Sciences

CLN3 disease is a fatal neurodegenerative disorder affecting children. Hallmarks include brain atrophy, accelerated neuronal apoptosis, and ceramide elevation. Treatment regimens are supportive, highlighting the importance of novel, disease-modifying drugs. Flupirtine and its new allyl carbamate derivative (compound 6) confer neuroprotective effects in CLN3-deficient cells. This study lays the groundwork for investigating beneficial effects in Cln3^Δex7/8 mice. WT/Cln3^Δex7/8 mice received flupirtine/compound 6/vehicle for 14 weeks. Short-term effect of flupirtine or compound 6 was tested using a battery of behavioral testing. For flupirtine, gene expression profiles, astrogliosis, and neuronal cell counts were determined. Flupirtine improved neurobehavioral parameters in …

Single Cell Transcriptomics Implicate Novel Monocyte And T Cell Immune Dysregulation In Sarcoidosis, Lori Garman, Richard C. Pelikan, Astrid Rasmussen, Caleb A. Lareau, Kathryn A. Savoy, Umesh S. Deshmukh, Harini Bagavant, Albert M. Levin, Salim Daouk, Wonder P. Drake, Courtney G. Montgomery

Public Health Sciences Articles

Sarcoidosis is a systemic inflammatory disease characterized by infiltration of immune cells into granulomas. Previous gene expression studies using heterogeneous cell mixtures lack insight into cell-type-specific immune dysregulation. We performed the first single-cell RNA-sequencing study of sarcoidosis in peripheral immune cells in 48 patients and controls. Following unbiased clustering, differentially expressed genes were identified for 18 cell types and bioinformatically assessed for function and pathway enrichment. Our results reveal persistent activation of circulating classical monocytes with subsequent upregulation of trafficking molecules. Specifically, classical monocytes upregulated distinct markers of activation including adhesion molecules, pattern recognition receptors, and chemokine receptors, as well …

Motile Onchocerca Volvulus Microfilariae In The Anterior Chamber Of The Eye, Michael E Gyasi, Augustine R Hong, Gary J Weil

Open Access Publications

No abstract provided.

The Relationship Between Chronic Health Conditions And Cognitive Deficits In Children, Adolescents, And Young Adults With Down Syndrome: A Systematic Review, Kellen C Gandy, Heidi A Castillo, Lara Ouellette, Jonathan Castillo, Philip J Lupo, Lisa M Jacola, Karen R Rabin, Kimberly P Raghubar, Maria M Gramatges

Library Staff Publications

BACKGROUND: Individuals with Down syndrome are predisposed to a number of chronic health conditions, but the relationship between these conditions and cognitive ability is not clear. The primary objective of this systematic review is to assess this relationship by evaluating studies that measure cognitive performance in the context of Down syndrome-associated chronic health conditions.

METHODS: A systematic review was conducted in accordance with the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) guidelines. Studies included in this review (1) included children, adolescent, and young adult participants with Down syndrome and one or more co-occurring health conditions; (2) were quantitative; …

The Effect Of Sleep Restriction, With Or Without High-Intensity Interval Exercise, On Myofibrillar Protein Synthesis In Healthy Young Men, Nicholas J. Saner, Matthew J. -C. Lee, Nathan W. Pitchford, Jujiao Kuang, Gregory D. Roach, Andrew Garnham, Tanner Stokes, Stuart M. Phillips, David J. Bishop, Jonathan D. Bartlett

Research outputs 2014 to 2021

Key points: Sleep restriction has previously been associated with the loss of muscle mass in both human and animal models. The rate of myofibrillar protein synthesis (MyoPS) is a key variable in regulating skeletal muscle mass and can be increased by performing high-intensity interval exercise (HIIE), although the effect of sleep restriction on MyoPS is unknown. In the present study, we demonstrate that participants undergoing a sleep restriction protocol (five nights, with 4 h in bed each night) had lower rates of skeletal muscle MyoPS; however, rates of MyoPS were maintained at control levels by performing HIIE during this period. …

Systemic Th17 Response In The Presence Of Periodontal Inflammation, Lina J Suárez, Daniel E Vargas, Adriana Rodríguez, Roger M Arce, Nelly S Roa

Faculty, Staff and Student Publications

BACKGROUND: The relationship between periodontitis and the pathogenesis of other inflammatory diseases, such as diabetes, rheumatoid arthritis and obesity has been an important topic of study in recent decades. The Th17 pathway plays a significant role in how local inflammation can influence systemic inflammation in the absence of systemic pathology.

OBJECTIVE: To determine Th17 biased-cells in systemically healthy patients in the presence of generalized chronic periodontitis.

METHODOLOGY: A total of 28 patients were recruited without systemic inflammatory pathology, which was determined by clinical history, the Health Assessment Questionnaire (HAQ) and rheumatoid factor detection. Of these patients, 13 were diagnosed as …

Combined Abdominal Heterotopic Heart And Aorta Transplant Model In Mice, Hao Dun, Li Ye, Yuehui Zhu, Brian W Wong

Open Access Publications

BACKGROUND: Allograft vasculopathy (AV) remains a major obstacle to long-term allograft survival. While the mouse aortic transplantation model has been proven as a useful tool for study of the pathogenesis of AV, simultaneous transplantation of the aorta alongside the transplantation of another organ may reveal more clinically relevant mechanisms that contribute to the pathogenesis of chronic allograft rejection. Therefore, we developed a combined abdominal heart and aorta transplantation model in mice which benefits from reducing animal and drug utilization, while providing an improved model to study the progressive nature of AV.

METHODS: The middle of the infrarenal aorta of the …

Identification And Characterization Of Novel Trpm1 Autoantibodies From Serum Of Patients With Melanoma-Associated Retinopathy, Juliette Varin, Margaret M. Reynolds, Nassima Bouzidi, Sarah Tick, Juliette Wohlschlegel, Ondine Becquart, Christelle Michiels, Olivier Dereure, Robert M. Duvoisin, Catherine W. Morgans, José-Alain Sahel, Quentin Samaran, Bernard Guillot, José S. Pulido, Isabelle Audo, Christina Zeitz

Open Access Publications

Melanoma-associated retinopathy (MAR) is a rare paraneoplastic retinal disorder usually occurring in the context of metastatic melanoma. Patients present with night blindness, photopsias and a constriction of the visual field. MAR is an auto-immune disorder characterized by the production of autoantibodies targeting retinal proteins, especially autoantibodies reacting to the cation channel TRPM1 produced in melanocytes and ON-bipolar cells. TRPM1 has at least three different isoforms which vary in the N-terminal region of the protein. In this study, we report the case of three new MAR patients presenting different anti-TRPM1 autoantibodies reacting to the three isoforms of TRPM1 with variable binding …

Canonical Signaling By Tgf Family Members In Mesenchymal Stromal Cells Is Dispensable For Hematopoietic Niche Maintenance Under Basal And Stress Conditions, Joseph Ryan Krambs, Grazia Abou Ezzi, Juo-Chin Yao, Daniel C. Link

Open Access Publications

Mesenchymal stromal cells are an important component of the bone marrow hematopoietic niche. Prior studies showed that signaling from members of the transforming growth factor (TGF) superfamily in mesenchymal stromal cells is required for normal niche development. Here, we assessed the impact of TGF family signaling on niche maintenance and stress responses by deleting Smad4 in mesenchymal stromal cells at birth, thereby abrogating canonical TGF signaling. No alteration in the number or spatial organization of CXCL12-abundant reticular (CAR) cells, osteoblasts, or adipocytes was observed in Osx-Cre, Smad4fl/fl mice, and expression of key niche factors was normal. Basal hematopoiesis and stress …

Campylobacter Colonization, Environmental Enteric Dysfunction, Stunting, And Associated Risk Factors Among Young Children In Rural Ethiopia: A Cross-Sectional Study From The Campylobacter Genomics And Environmental Enteric Dysfunction (Caged) Project, Dehao Chen, Mark J Manary, Et Al

Open Access Publications

Livestock farming provides a possible mechanism by which smallholder farmers can meet their household need for animal source foods (ASF), which may reduce the risk of stunting. However, direct/indirect contacts with domestic animals may increase colonization by

Ige And T Cell Reactivity To A Comprehensive Panel Of Cockroach Allergens In Relation To Disease, Anna Pomés, Véronique Schulten, Jill Glesner, Ricardo Da Silva Antunes, Aaron Sutherland, Leonard B Bacharier, Avraham Beigelman, Paula Busse, April Frazier, Alessandro Sette

Open Access Publications

IgE sensitization to cockroach allergens is associated with development of allergic diseases, such as asthma. To understand the relevance of different cockroach allergens for diagnosis and immunotherapy, a comprehensive analysis of IgE antibody levels and T cell reactivity to an expanded set of cockroach allergens and their relationship to disease was performed in a cohort of USA cockroach sensitized patients. IgE antibody levels to recombinant chitinase and hemocyanin were measured for 23 subjects by custom-made ImmunoCAPs and compared with IgE levels to eight cockroach allergens we previously reported for the same cohort.

Targeting The Tumor Core: Hypoxia-Responsive Nanoparticles For The Delivery Of Chemotherapy To Pancreatic Tumors, Matthew I. Confeld, Babak Mamnoon, Li Feng, Heather Jensen Smith, Priyanka Ray, James Froberg, Jiha Kim, Michael A. Hollingsworth, Mohiuddin Quadir, Yongki Choi, Sanku Mallik

Journal Articles: Eppley Institute

In pancreatic ductal adenocarcinoma (PDAC), early onset of hypoxia triggers remodeling of the extracellular matrix, epithelial-to-mesenchymal transition, increased cell survival, the formation of cancer stem cells, and drug resistance. Hypoxia in PDAC is also associated with the development of collagen-rich, fibrous extracellular stroma (desmoplasia), resulting in severely impaired drug penetration. To overcome these daunting challenges, we created polymer nanoparticles (polymersomes) that target and penetrate pancreatic tumors, reach the hypoxic niches, undergo rapid structural destabilization, and release the encapsulated drugs. In vitro studies indicated a high cellular uptake of the polymersomes and increased cytotoxicity of the drugs under hypoxia compared to …

The Vimentin Rod Domain Blocks P-Selectin-P-Selectin Glycoprotein Ligand 1 Interactions To Attenuate Leukocyte Adhesion To Inflamed Endothelium, Fong Wilson Lam, Cameron August Brown, Christian Valladolid, Dabel Cynthia Emebo, Timothy Gerald Palzkill, Miguel Angel Cruz

Faculty, Staff and Students Publications

Acute inflammation begins with leukocyte P-selectin glycoprotein ligand-1 (PSGL-1) binding to P-selectin on inflamed endothelium and platelets. In pathologic conditions, this process may contribute to secondary organ damage, like sepsis-induced liver injury. Therefore, developing novel therapies to attenuate inflammation may be beneficial. We previously reported that recombinant human vimentin (rhVim) binds P-selectin to block leukocyte adhesion to endothelium and platelets. In this study, we used SPOT-peptide arrays to identify the rod domain as the active region within rhVim that interacts with P-selectin. Indeed, recombinant human rod domain of vimentin (rhRod) binds to P-selectin with high affinity, with in silico modeling …

Sirt3 Promotes Lipophagy And Chaperon-Mediated Autophagy To Protect Hepatocytes Against Lipotoxicity, Tian Zhang, Jingxin Liu, Shengnan Shen, Qiang Tong, Xiaojun Ma, Ligen Lin

Faculty, Staff and Students Publications

Lipophagy is a lysosomal lipolytic pathway that complements the actions of cytosolic neutral lipases. Chaperon-mediated autophagy (CMA) triggers lipid droplets (LDs) breakdown, to initiate lipolysis via either cytosolic lipases or macroautophagy. SIRT3, a mitochondrial NAD+-dependent deacetylase, regulates the acetylation status and activity of many substrates involving in energy metabolism. However, the role of SIRT3 in regulating lipophagy is controversial. The current study showed that SIRT3 expression was decreased and the macroautophagy flux was blocked in the primary hepatocytes from high-fat diet fed mice and P/O (palmitic acid and oleic acid mixture) treated AML12 mouse hepatocytes, compared with the corresponding controls. …

Hypogonadism, Type-2 Diabetes Mellitus, And Bone Health: A Narrative Review, Vittoria Russo, Rui Chen, Reina Armamento-Villareal

Faculty, Staff and Students Publications

One of the complications from chronic hyperglycemia and insulin resistance due to type 2 diabetes mellitus (T2DM) on the hypothalamic-pituitary-gonadal axis in men is the high prevalence of hypogonadotropic hypogonadism (HH). Both T2DM and hypogonadism are associated with impaired bone health and increased fracture risk but whether the combination results in even worse bone disease than either one alone is not well-studied. It is possible that having both conditions predisposes men to an even greater risk for fracture than either one alone. Given the common occurrence of HH or hypogonadism in general in T2DM, a significant number of men could …

Small Molecules That Inhibit Tnf Signalling By Stabilising An Asymmetric Form Of The Trimer, James O'Connell, John Porter, Boris Kroeplien, Tim Norman, Stephen Rapecki, Rachel E. Davis, David Mcmillan, Tracy Arakaki, Alex Burgin, David Fox Iii, Tom Ceska, Fabien Lecomte, Alison Maloney, Alex Vugler, Bruce Carrington, Benjamin P. Cossins, Tim Bourne, Alastair Lawson

Faculty Publications

Tumour necrosis factor (TNF) is a cytokine belonging to a family of trimeric proteins; it has been shown to be a key mediator in autoimmune diseases such as rheumatoid arthritis and Crohn's disease. While TNF is the target of several successful biologic drugs, attempts to design small molecule therapies directed to this cytokine have not led to approved products. Here we report the discovery of potent small molecule inhibitors of TNF that stabilise an asymmetrical form of the soluble TNF trimer, compromising signalling and inhibiting the functions of TNF in vitro and in vivo. This discovery paves the way for …

Single-Nuclei Rna-Seq On Human Retinal Tissue Provides Improved Transcriptome Profiling, Qingnan Liang, Rachayata Dharmat, Leah Owen, Akbar Shakoor, Yumei Li, Sangbae Kim, Albert Vitale, Ivana Kim, Denise Morgan, Shaoheng Liang, Nathaniel Wu, Ken Chen, Margaret M Deangelis, Rui Chen

Faculty, Staff and Students Publications

Single-cell RNA-seq is a powerful tool in decoding the heterogeneity in complex tissues by generating transcriptomic profiles of the individual cell. Here, we report a single-nuclei RNA-seq (snRNA-seq) transcriptomic study on human retinal tissue, which is composed of multiple cell types with distinct functions. Six samples from three healthy donors are profiled and high-quality RNA-seq data is obtained for 5873 single nuclei. All major retinal cell types are observed and marker genes for each cell type are identified. The gene expression of the macular and peripheral retina is compared to each other at cell-type level. Furthermore, our dataset shows an …

Clearance Of Chikungunya Virus Infection In Lymphoid Tissues Is Promoted By Treatment With An Agonistic Anti-Cd137 Antibody, Jun P Hong, Mary K Mccarthy, Bennett J Davenport, Thomas E Morrison, Michael S Diamond

Open Access Publications

CD137, a member of the tumor necrosis factor receptor superfamily of cell surface proteins, acts as a costimulatory receptor on T cells, natural killer cells, B cell subsets, and some dendritic cells. Agonistic anti-CD137 monoclonal antibody (MAb) therapy has been combined with other chemotherapeutic agents in human cancer trials. Based on its ability to promote tumor clearance, we hypothesized that anti-CD137 MAb might activate immune responses and resolve chronic viral infections. We evaluated anti-CD137 MAb therapy in a mouse infection model of chikungunya virus (CHIKV), an alphavirus that causes chronic polyarthritis in humans and is associated with reservoirs of CHIKV …

Distinct Roles Of Interferon Alpha And Beta In Controlling Chikungunya Virus Replication And Modulating Neutrophil-Mediated Inflammation, Lindsey E Cook, Marissa C Locke, Alissa R Young, Kristen Monte, Matthew L Hedberg, Raeann M Shimak, Kathleen C F Sheehan, Deborah J Veis, Michael S Diamond, Deborah J Lenschow

Open Access Publications

Type I interferons (IFNs) are key mediators of the innate immune response. Although members of this family of cytokines signal through a single shared receptor, biochemical and functional variation exists in response to different IFN subtypes. While previous work has demonstrated that type I IFNs are essential to control infection by chikungunya virus (CHIKV), a globally emerging alphavirus, the contributions of individual IFN subtypes remain undefined. To address this question, we evaluated CHIKV pathogenesis in mice lacking IFN-β (IFN-β knockout [IFN-β-KO] mice or mice treated with an IFN-β-blocking antibody) or IFN-α (IFN regulatory factor 7 knockout [IRF7-KO] mice or mice …