Medical Sciences Commons^™

Usability Of Abattoir-Acquired Pig Eyes For Refractive Excimer Laser Research, Marius Topka, Yao Zhang, Antonia Bock, Peter Riedel, Johannes Lörner, Alexander Hammer, Eva Maier, Friedrich Paulsen, Christian M Hammer

Faculty, Staff and Student Publications

The purpose of this study was to elucidate, under which conditions abattoir-acquired pig eyes are suitable for refractive excimer laser experiments. Porcine eyes from tunnel-scalded (n = 5) and tank-scalded (n = 10) pigs were compared to unscalded eyes (n = 5) and to eyes scalded in the laboratory (n = 5). The corneal epithelium was removed before an excimer laser was used to perform a - 8.0 D photoablation. Corneal thickness was measured by optical coherence topography before and after photoablation. The ablation depth was determined with a contour measuring station, the morphology of the ablated areas was characterized …

Zfta-Rela Dictates Oncogenic Transcriptional Programs To Drive Aggressive Supratentorial Ependymoma, Amir Arabzade, Yanhua Zhao, Srinidhi Varadharajan, Hsiao-Chi Chen, Selin Jessa, Bryan Rivas, Austin J Stuckert, Minerva Solis, Alisha Kardian, Dana Tlais, Brian J Golbourn, Ann-Catherine J Stanton, Yuen San Chan, Calla Olson, Kristen L Karlin, Kathleen Kong, Robert Kupp, Baoli Hu, Sarah G Injac, Madeline Ngo, Peter R Wang, Luz A De León, Felix Sahm, Daisuke Kawauchi, Stefan M Pfister, Charles Y Lin, H Courtney Hodges, Irtisha Singh, Thomas F Westbrook, Murali M Chintagumpala, Susan M Blaney, Donald W Parsons, Kristian W Pajtler, Sameer Agnihotri, Richard J Gilbertson, Joanna Yi, Nada Jabado, Claudia L Kleinman, Kelsey C Bertrand, Benjamin Deneen, Stephen C Mack

Faculty, Staff and Students Publications

Over 60% of supratentorial (ST) ependymomas harbor a ZFTA-RELA (ZRfus) gene fusion (formerly C11orf95-RELA). To study the biology of ZRfus, we developed an autochthonous mouse tumor model using in utero electroporation (IUE) of the embryonic mouse brain. Integrative epigenomic and transcriptomic mapping was performed on IUE driven ZRfus tumors by CUT&RUN, ChIP, ATAC, and RNA sequencing and compared to human ZRfus driven ependymoma. In addition to direct canonical NF-κB pathway activation, ZRfus dictates a neoplastic transcriptional program and binds to thousands of unique sites across the genome that are enriched with Plagl family transcription factor (TF) motifs. ZRfus activates …

Exogenous Inter-Α Inhibitor Proteins Prevent Cell Death And Improve Ischemic Stroke Outcomes In Mice, Louise D Mccullough, Meaghan Roy-O'Reilly, Yun-Ju Lai, Anthony Patrizz, Yan Xu, Juneyoung Lee, Aleah Holmes, Daniel C Kraushaar, Anjali Chauhan, Lauren H Sansing, Barbara S Stonestreet, Liang Zhu, Julia Kofler, Yow-Pin Lim, Venugopal Reddy Venna

Faculty, Staff and Students Publications

Inter-α inhibitor proteins (IAIPs) are a family of endogenous plasma and extracellular matrix molecules. IAIPs suppress proinflammatory cytokines, limit excess complement activation, and bind extracellular histones to form IAIP-histone complexes, leading to neutralization of histone-associated cytotoxicity in models of sepsis. Many of these detrimental processes also play critical roles in the pathophysiology of ischemic stroke. In this study, we first assessed the clinical relevance of IAIPs in stroke and then tested the therapeutic efficacy of exogenous IAIPs in several experimental stroke models. IAIP levels were reduced in both ischemic stroke patients and in mice subjected to experimental ischemic stroke when …

A Noncoding Rna Modulator Potentiates Phenylalanine Metabolism In Mice, Yajuan Li, Zhi Tan, Yaohua Zhang, Zhao Zhang, Qingsong Hu, Ke Liang, Yao Jun, Youqiong Ye, Yi-Chuan Li, Chunlai Li, Lan Liao, Jianming Xu, Zhen Xing, Yinghong Pan, Sujash S Chatterjee, Tina K Nguyen, Heidi Hsiao, Sergey D Egranov, Nagireddy Putluri, Cristian Coarfa, David H Hawke, Preethi H Gunaratne, Kuang-Lei Tsai, Leng Han, Mien-Chie Hung, George A Calin, Fares Namour, Jean-Louis Guéant, Ania C Muntau, Nenad Blau, V Reid Sutton, Manuel Schiff, François Feillet, Shuxing Zhang, Chunru Lin, Liuqing Yang

Faculty, Staff and Students Publications

The functional role of long noncoding RNAs (lncRNAs) in inherited metabolic disorders, including phenylketonuria (PKU), is unknown. We demonstrated that the mouse lncRNA Pair and human HULC associate with phenylalanine hydroxylase (PAH). Pair-knockout mice exhibited excessive blood phenylalanine, musty odor, hypopigmentation, growth retardation, and progressive neurological symptoms including seizures, which faithfully models human PKU. HULC depletion led to reduced PAH enzymatic activities in human induced pluripotent stem cell (hiPSC)-differentiated hepatocytes. Mechanistically, HULC modulated the enzymatic activities of PAH by facilitating PAH-substrate and PAH-cofactor interactions. To develop a therapeutic strategy for restoring liver lncRNAs, we designed GalNAc-tagged lncRNA mimics that …

Cd148 Deficiency In Fibroblasts Promotes The Development Of Pulmonary Fibrosis, Konstantin Tsoyi, Xiaoliang Liang, Giulia De Rossi, Stefan W Ryter, Kevin Xiong, Sarah G Chu, Xiaoli Liu, Bonna Ith, Lindsay J Celada, Freddy Romero, Matthew J Robertson, Anthony J Esposito, Sergio Poli, Souheil El-Chemaly, Mark A Perrella, Yuanyuan Shi, James Whiteford, Ivan O Rosas

Faculty, Staff and Students Publications

Rationale: CD148/PTRJ (receptor-like protein tyrosine phosphatase η) exerts antifibrotic effects in experimental pulmonary fibrosis via interactions with its ligand syndecan-2; however, the role of CD148 in human pulmonary fibrosis remains incompletely characterized.

Objectives: We investigated the role of CD148 in the profibrotic phenotype of fibroblasts in idiopathic pulmonary fibrosis (IPF).

Methods: Conditional CD148 fibroblast-specific knockout mice were generated and exposed to bleomycin and then assessed for pulmonary fibrosis. Lung fibroblasts (mouse lung and human IPF lung), and precision-cut lung slices from human patients with IPF were isolated and subjected to experimental treatments. A CD148-activating 18-aa mimetic peptide (SDC2-pep) derived from …

Platelet And Erythrocyte Extravasation Across Inflamed Corneal Venules Depend On Cd18, Neutrophils, And Mast Cell Degranulation, Angie De La Cruz, Aubrey Hargrave, Sri Magadi, Justin A Courson, Paul T Landry, Wanyu Zhang, Fong W Lam, Monica A Bray, C Wayne Smith, Alan R Burns, Rolando E Rumbaut

Faculty, Staff and Student Publications

Platelet extravasation during inflammation is under-appreciated. In wild-type (WT) mice, a central corneal epithelial abrasion initiates neutrophil (PMN) and platelet extravasation from peripheral limbal venules. The same injury in mice expressing low levels of the β2-integrin, CD18 (CD18hypo mice) shows reduced platelet extravasation with PMN extravasation apparently unaffected. To better define the role of CD18 on platelet extravasation, we focused on two relevant cell types expressing CD18: PMNs and mast cells. Following corneal abrasion in WT mice, we observed not only extravasated PMNs and platelets but also extravasated erythrocytes (RBCs). Ultrastructural observations of engorged limbal venules showed platelets and RBCs …

Gene Therapy Knockdown Of Hippo Signaling Induces Cardiomyocyte Renewal In Pigs After Myocardial Infarction, Shijie Liu, Ke Li, Leonardo Wagner Florencio, Li Tang, Todd R Heallen, John P Leach, Yidan Wang, Francisco Grisanti, James T Willerson, Emerson C Perin, Sui Zhang, James F Martin

Faculty, Staff and Students Publications

Human heart failure, a leading cause of death worldwide, is a prominent example of a chronic disease that may result from poor cell renewal. The Hippo signaling pathway is an inhibitory kinase cascade that represses adult heart muscle cell (cardiomyocyte) proliferation and renewal after myocardial infarction in genetically modified mice. Here, we investigated an adeno-associated virus 9 (AAV9)–based gene therapy to locally knock down the Hippo pathway gene Salvador (Sav) in border zone cardiomyocytes in a pig model of ischemia/reperfusion-induced myocardial infarction. Two weeks after myocardial infarction, when pigs had left ventricular systolic dysfunction, we administered AAV9-Sav …

Nlrp3 Inflammasome Is A Key Driver Of Obesity-Induced Atrial Arrhythmias, Larry Scott, Anke C Fender, Arnela Saljic, Luge Li, Xiaohui Chen, Xiaolei Wang, Dominik Linz, Jilu Lang, Mathias Hohl, Darragh Twomey, Thuy T Pham, Rodrigo Diaz-Lankenau, Mihail G Chelu, Markus Kamler, Mark L Entman, George E Taffet, Prashanthan Sanders, Dobromir Dobrev, Na Li

Faculty, Staff and Students Publications

AIMS: Obesity, an established risk factor of atrial fibrillation (AF), is frequently associated with enhanced inflammatory response. However, whether inflammatory signaling is causally linked to AF pathogenesis in obesity remains elusive. We recently demonstrated that the constitutive activation of the 'NACHT, LRR, and PYD Domains-containing Protein 3' (NLRP3) inflammasome promotes AF susceptibility. In this study, we hypothesized that the NLRP3 inflammasome is a key driver of obesity-induced AF.

METHODS AND RESULTS: Western blotting was performed to determine the level of NLRP3 inflammasome activation in atrial tissues of obese patients, sheep, and diet-induced obese (DIO) mice. The increased body weight in …

Inactivated Rabies Virus Vectored Sars-Cov-2 Vaccine Prevents Disease In A Syrian Hamster Model., Drishya Kurup, Delphine C Malherbe, Christoph Wirblich, Rachael Lambert, Adam J Ronk, Leila Zabihi Diba, Alexander Bukreyev, Matthias J. Schnell

Department of Microbiology and Immunology Faculty Papers

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an emergent coronavirus that has caused a worldwide pandemic. Although human disease is often asymptomatic, some develop severe illnesses such as pneumonia, respiratory failure, and death. There is an urgent need for a vaccine to prevent its rapid spread as asymptomatic infections accounting for up to 40% of transmission events. Here we further evaluated an inactivated rabies vectored SARS-CoV-2 S1 vaccine CORAVAX in a Syrian hamster model. CORAVAX adjuvanted with MPLA-AddaVax, a TRL4 agonist, induced high levels of neutralizing antibodies and generated a strong Th1-biased immune response. Vaccinated hamsters were protected from …

Phenytoin Inhibits Cell Proliferation Through Microrna-196a-5p In Mouse Lip Mesenchymal Cells, Hiroki Yoshioka, Sai Shankar Ramakrishnan, Akiko Suzuki, Junichi Iwata

Faculty, Staff and Student Publications

Cleft lip (CL) is one of the most common birth defects. It is caused by either genetic mutations or environmental factors. Recent studies suggest that environmental factors influence the expression of noncoding RNAs [e.g., microRNA (miRNA)], which can regulate the expression of genes crucial for cellular functions. In this study, we examined which miRNAs are associated with CL. Among 10 candidate miRNAs (miR-98-3p, miR-101a-3p, miR-101b-3p, miR-141-3p, miR-144-3p, miR-181a-5p, miR-196a-5p, miR-196b-5p, miR-200a-3p, and miR-710) identified through our bioinformatic analysis of CL-associated genes, overexpression of miR-181a-5p, miR-196a-5p, miR-196b-5p, and miR-710 inhibited cell proliferation through suppression of genes associated with CL in cultured …

Sharing Voxelwise Neuroimaging Results From Rhesus Monkeys And Other Species With Neurovault, Andrew S. Fox, Daniel Holley, Peter Christiaan Klink, Spencer A. Arbuckle, Carol A. Barnes, Jörn Diedrichsen, Sze Chai Kwok, Colin Kyle, J. Andrew Pruszynski, Jakob Seidlitz, Xu Feng Zhou, Russell A. Poldrack, Krzysztof J. Gorgolewski

Brain and Mind Institute Researchers' Publications

© 2020 The Authors Animal neuroimaging studies can provide unique insights into brain structure and function, and can be leveraged to bridge the gap between animal and human neuroscience. In part, this power comes from the ability to combine mechanistic interventions with brain-wide neuroimaging. Due to their phylogenetic proximity to humans, nonhuman primate neuroimaging holds particular promise. Because nonhuman primate neuroimaging studies are often underpowered, there is a great need to share data amongst translational researchers. Data sharing efforts have been limited, however, by the lack of standardized tools and repositories through which nonhuman neuroimaging data can easily be archived …

Mouse Models To Study The Pathophysiology Of Combined Methylmalonic Acidemia And Homocystinuria, Cblc Type, Tiffany Chern, Annita Achilleos, Xuefei Tong, Chih-Wei Hsu, Leeyean Wong, Ross A Poché

Faculty, Staff and Students Publications

Combined methylmalonic acidemia and homocystinuria, cblC type, is the most common inherited disorder of cobalamin metabolism and is characterized by severe fetal developmental defects primarily impacting the central nervous system, hematopoietic system, and heart. CblC was previously shown to be due to mutations in the MMACHC gene, which encodes a protein thought to function in intracellular cobalamin trafficking and biosynthesis of adenosylcobalamin (AdoCbl) and methylcobalamin (MeCbl). These coenzymes are required for the production of succinyl-CoA and methionine, respectively. However, it is currently unclear whether additional roles for MMACHC exist outside of cobalamin metabolism. Furthermore, due to a lack of sufficient …

Ampk Regulation Of Raptor And Tsc2 Mediate Metformin Effects On Transcriptional Control Of Anabolism And Inflammation, Jeanine L Van Nostrand, Kristina Hellberg, En-Ching Luo, Eric L Van Nostrand, Alina Dayn, Jingting Yu, Maxim N Shokhirev, Yelena Dayn, Gene W Yeo, Reuben J Shaw

Faculty, Staff and Students Publications

Despite being the frontline therapy for type 2 diabetes, the mechanisms of action of the biguanide drug metformin are still being discovered. In particular, the detailed molecular interplays between the AMPK and the mTORC1 pathway in the hepatic benefits of metformin are still ill defined. Metformin-dependent activation of AMPK classically inhibits mTORC1 via TSC/RHEB, but several lines of evidence suggest additional mechanisms at play in metformin inhibition of mTORC1. Here we investigated the role of direct AMPK-mediated serine phosphorylation of RAPTOR in a new

Mtor-Initiated Metabolic Switch And Degeneration In The Retinal Pigment Epithelium, Young-Mi Go, Jing Zhang, Jolyn Fernandes, Christopher Litwin, Rui Chen, Theodore G Wensel, Dean P Jones, Jiyang Cai, Yan Chen

Faculty, Staff and Students Publications

The retinal pigment epithelium (RPE) is a particularly vulnerable tissue to age-dependent degeneration. Over the life span, the RPE develops an expanded endo-lysosomal compartment to maintain the high efficiency of phagocytosis and degradation of photoreceptor outer segments (POS) necessary for photoreceptor survival. As the assembly and activation of the mechanistic target of rapamycin complex 1 (mTORC1) occur on the lysosome surface, increased lysosome mass with aging leads to higher mTORC1 activity. The functional consequences of hyperactive mTORC1 in the RPE are unclear. In the current study, we used integrated high-resolution metabolomic and genomic approaches to examine mice with RPE-specific deletion …

A Global Slc7a7 Knockout Mouse Model Demonstrates Characteristic Phenotypes Of Human Lysinuric Protein Intolerance, Bridget M Stroup, Ronit Marom, Xiaohui Li, Chih-Wei Hsu, Cheng-Yen Chang, Luan D Truong, Brian Dawson, Ingo Grafe, Yuqing Chen, Ming-Ming Jiang, Denise Lanza, Jennie Rose Green, Qin Sun, J P Barrish, Safa Ani, Audrey E Christiansen, John R Seavitt, Mary E Dickinson, Farrah Kheradmand, Jason D Heaney, Brendan Lee, Lindsay C Burrage

Faculty, Staff and Students Publications

Lysinuric protein intolerance (LPI) is an inborn error of cationic amino acid (arginine, lysine, ornithine) transport caused by biallelic pathogenic variants in SLC7A7, which encodes the light subunit of the y+LAT1 transporter. Treatments for the complications of LPI, including growth failure, renal disease, pulmonary alveolar proteinosis, autoimmune disorders and osteoporosis, are limited. Given the early lethality of the only published global Slc7a7 knockout mouse model, a viable animal model to investigate global SLC7A7 deficiency is needed. Hence, we generated two mouse models with global Slc7a7 deficiency (Slc7a7em1Lbu/em1Lbu; Slc7a7Lbu/Lbu and Slc7a7em1(IMPC)Bay/em1(IMPC)Bay; Slc7a7Bay/Bay) using CRISPR/Cas9 technology by introducing a deletion of exons …

Modulation Of Hedgehog Signaling By Kappa Opioids To Attenuate Osteoarthritis, Alexander E Weber, Omid Jalali, Sean Limfat, Ruzanna Shkhyan, Robert Van Der Horst, Siyoung Lee, Yucheng Lin, Liangliang Li, Erik N Mayer, Liming Wang, Nancy Q Liu, Frank A Petrigliano, Jay R Lieberman, Denis Evseenko

Faculty, Staff and Students Publications

OBJECTIVE: Inhibition of hedgehog (HH) signaling prevents cartilage degeneration and promotes repair in animal models of osteoarthritis (OA). This study, undertaken in OA models and in human OA articular cartilage, was designed to explore whether kappa opioid receptor (KOR) modulation via the inhibition of HH signaling may have therapeutic potential for achieving disease-modifying activity in OA.

METHODS: Primary human articular cartilage and synovial tissue samples from patients with knee OA undergoing total joint replacement and from healthy human subjects were obtained from the National Disease Research Interchange. For in vivo animal studies, a partial medial meniscectomy (PMM) model of knee …

Nr2f1 Heterozygous Knockout Mice Recapitulate Neurological Phenotypes Of Bosch-Boonstra-Schaaf Optic Atrophy Syndrome And Show Impaired Hippocampal Synaptic Plasticity, Chun-An Chen, Wei Wang, Steen E Pedersen, Ayush Raman, Michelle L Seymour, Fernanda R Ruiz, Anping Xia, Meike E Van Der Heijden, Li Wang, Jiani Yin, Joanna Lopez, Megan E Rech, Richard A Lewis, Samuel M Wu, Zhandong Liu, Fred A Pereira, Robia G Pautler, Huda Y Zoghbi, Christian P Schaaf

Faculty, Staff and Students Publications

Bosch-Boonstra-Schaaf optic atrophy syndrome (BBSOAS) has been identified as an autosomal-dominant disorder characterized by a complex neurological phenotype, with high prevalence of intellectual disability and optic nerve atrophy/hypoplasia. The syndrome is caused by loss-of-function mutations in NR2F1, which encodes a highly conserved nuclear receptor that serves as a transcriptional regulator. Previous investigations to understand the protein's role in neurodevelopment have mostly used mouse models with constitutive and tissue-specific homozygous knockout of Nr2f1. In order to represent the human disease more accurately, which is caused by heterozygous NR2F1 mutations, we investigated a heterozygous knockout mouse model and found that this model …

Losartan Rescues Inflammation-Related Mucociliary Dysfunction In Relevant Models Of Cystic Fibrosis, Michael D Kim, Nathalie Baumlin, Makoto Yoshida, Deepika Polineni, Sebastian F Salathe, Joseph K David, Charles A Peloquin, Adam Wanner, John S Dennis, Juliette Sailland, Philip Whitney, Frank T Horrigan, Juan R Sabater, William M Abraham, Matthias Salathe

Faculty, Staff and Students Publications

Rationale: Despite therapeutic progress in treating cystic fibrosis (CF) airway disease, airway inflammation with associated mucociliary dysfunction remains largely unaddressed. Inflammation reduces the activity of apically expressed large-conductance Ca²⁺-activated and voltage-dependent K⁺ (BK) channels, critical for mucociliary function in the absence of CFTR (CF transmembrane conductance regulator).

Objectives: To test losartan as an antiinflammatory therapy in CF using CF human bronchial epithelial cells and an ovine model of CF-like airway disease.

Methods: Losartan’s antiinflammatory effectiveness to rescue BK activity and thus mucociliary function was tested in vitro using primary, fully redifferentiated human airway epithelial cells homozygous for …

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 …

Rhoa-Rock Signaling As A Therapeutic Target In Traumatic Brain Injury, Shalaka Mulherkar, Kimberley F Tolias

Faculty, Staff and Students Publications

Traumatic brain injury (TBI) is a leading cause of death and disability worldwide. TBIs, which range in severity from mild to severe, occur when a traumatic event, such as a fall, a traffic accident, or a blow, causes the brain to move rapidly within the skull, resulting in damage. Long-term consequences of TBI can include motor and cognitive deficits and emotional disturbances that result in a reduced quality of life and work productivity. Recovery from TBI can be challenging due to a lack of effective treatment options for repairing TBI-induced neural damage and alleviating functional impairments. Central nervous system (CNS) …

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 …

Defining The Layers Of A Sensory Cilium With Storm And Cryoelectron Nanoscopy, Michael A Robichaux, Valencia L Potter, Zhixian Zhang, Feng He, Jun Liu, Michael F Schmid, Theodore G Wensel

Faculty, Staff and Students Publications

Primary cilia carry out numerous signaling and sensory functions, and defects in them, "ciliopathies," cause a range of symptoms, including blindness. Understanding of their nanometer-scale ciliary substructures and their disruptions in ciliopathies has been hindered by limitations of conventional microscopic techniques. We have combined cryoelectron tomography, enhanced by subtomogram averaging, with superresolution stochastic optical reconstruction microscopy (STORM) to define subdomains within the light-sensing rod sensory cilium of mouse retinas and reveal previously unknown substructures formed by resident proteins. Domains are demarcated by structural features such as the axoneme and its connections to the ciliary membrane, and are correlated with molecular …

Interleukin 1 Alpha Administration Is Neuroprotective And Neuro-Restorative Following Experimental Ischemic Stroke, Kathleen E. Salmeron, Michael E. Maniskas, Danielle N. Edwards, Raymond Wong, Ivana Rajkovic, Amanda L. Trout, Abir A. Rahman, Samantha Hamilton, Justin F. Fraser, Emmanuel Pinteaux, Gregory J. Bix

Sanders-Brown Center on Aging Faculty Publications

BACKGROUND: Stroke remains a leading cause of death and disability worldwide despite recent treatment breakthroughs. A primary event in stroke pathogenesis is the development of a potent and deleterious local and peripheral inflammatory response regulated by the pro-inflammatory cytokine interleukin-1 (IL-1). While the role of IL-1β (main released isoform) has been well studied in stroke, the role of the IL-1α isoform remains largely unknown. With increasing utilization of intravenous tissue plasminogen activator (t-PA) or thrombectomy to pharmacologically or mechanically remove ischemic stroke causing blood clots, respectively, there is interest in pairing successful cerebrovascular recanalization with neurotherapeutic pharmacological interventions (Fraser et …

A Consensus Guide To Capturing The Ability To Inhibit Actions And Impulsive Behaviors In The Stop-Signal Task., Frederick Verbruggen, Adam R Aron, Guido Ph Band, Christian Beste, Patrick G Bissett, Adam T Brockett, Joshua W Brown, Samuel R Chamberlain, Christopher D Chambers, Hans Colonius, Lorenza S Colzato, Brian D Corneil, James P Coxon, Annie Dupuis, Dawn M Eagle, Hugh Garavan, Ian Greenhouse, Andrew Heathcote, René J Huster, Sara Jahfari, J Leon Kenemans, Inge Leunissen, Chiang-Shan R Li, Gordon D Logan, Dora Matzke, Sharon Morein-Zamir, Aditya Murthy, Martin Paré, Russell A Poldrack, K Richard Ridderinkhof, Trevor W Robbins, Matthew Roesch, Katya Rubia, Russell J Schachar, Jeffrey D Schall, Ann-Kathrin Stock, Nicole C Swann, Katharine N Thakkar, Maurits W Van Der Molen, Luc Vermeylen, Matthijs Vink, Jan R Wessel, Robert Whelan, Bram B Zandbelt, C Nico Boehler

Brain and Mind Institute Researchers' Publications

Response inhibition is essential for navigating everyday life. Its derailment is considered integral to numerous neurological and psychiatric disorders, and more generally, to a wide range of behavioral and health problems. Response-inhibition efficiency furthermore correlates with treatment outcome in some of these conditions. The stop-signal task is an essential tool to determine how quickly response inhibition is implemented. Despite its apparent simplicity, there are many features (ranging from task design to data analysis) that vary across studies in ways that can easily compromise the validity of the obtained results. Our goal is to facilitate a more accurate use of the …

Translational Evaluation Of Acid/Base And Electrolyte Alterations In Rodent Model Of Focal Ischemia, Sarah R. Martha, Lisa A. Collier, Stephanie M. Davis, Hilary A. Seifert, Christopher C. Leonardo, Craig T. Ajmo, Elspeth A. Foran, Justin F. Fraser, Keith R. Pennypacker

Neurology Faculty Publications

BACKGROUND AND PURPOSE: Acid/base and electrolytes could provide clinically valuable information about cerebral infarct core and penumbra. We evaluated associations between acid/base and electrolyte changes and outcomes in 2 rat models of stroke, permanent, and transient middle cerebral artery occlusion.

METHODS: Three-month old Sprague-Dawley rats underwent permanent or transient middle cerebral artery occlusion. Pre- and post-middle cerebral artery occlusion venous samples for permanent and transient models provided pH, carbon dioxide, oxygen, glucose, and electrolyte values of ionized calcium, potassium, and sodium. Multiple regression determined predictors of infarct volume from these values, and Kaplan-Meier curve analyzed morality between permanent and transient …

Chronic Lymphocytic Leukemia-Derived Il-10 Suppresses Antitumor Immunity., Sara S Alhakeem, Mary K Mckenna, Karine Z Oben, Sunil K Noothi, Jacqueline R Rivas, Gerhard C Hildebrandt, Roger A Fleischman, Vivek M Rangnekar, Natarajan Muthusamy, Subbarao Bondada

Microbiology, Immunology, and Molecular Genetics Faculty Publications

Chronic lymphocytic leukemia (CLL) patients progressively develop an immunosuppressive state. CLL patients have more plasma IL-10, an anti-inflammatory cytokine, than healthy controls. In vitro human CLL cells produce IL-10 in response to BCR cross-linking. We used the transgenic Eμ-T cell leukemia oncogene-1 (

Cortical And Thalamic Connectivity To The Second Auditory Cortex Of The Cat Is Resilient To The Onset Of Deafness., Blake E Butler, Alexandra De La Rua, Taylor Ward-Able, Stephen G Lomber

Brain and Mind Institute Researchers' Publications

It has been well established that following sensory loss, cortical areas that would normally be involved in perceiving stimuli in the absent modality are recruited to subserve the remaining senses. Despite this compensatory functional reorganization, there is little evidence to date for any substantial change in the patterns of anatomical connectivity between sensory cortices. However, while many auditory areas are contracted in the deaf, the second auditory cortex (A2) of the cat undergoes a volumetric expansion following hearing loss, suggesting this cortical area may demonstrate a region-specific pattern of structural reorganization. To address this hypothesis, and to complement existing literature …

Nfatc2 Modulates Microglial Activation In The Aβpp/Ps1 Mouse Model Of Alzheimer's Disease, Gunjan D. Manocha, Atreyi Ghatak, Kendra L. Puig, Susan D. Kraner, Christopher M. Norris, Colin K. Combs

Pharmacology and Nutritional Sciences Faculty Publications

Alzheimer’s disease (AD) brains are characterized by fibrillar amyloid-β (Aβ) peptide containing plaques and associated reactive microglia. The proinflammatory phenotype of the microglia suggests that they may negatively affect disease course and contribute to behavioral decline. This hypothesis predicts that attenuating microglial activation may provide benefit against disease. Prior work from our laboratory and others has characterized a role for the transcription factor, nuclear factor of activated T cells (NFAT), in regulating microglial phenotype in response to different stimuli, including Aβ peptide. We observed that the NFATc2 isoform was the most highly expressed in murine microglia cultures, and inhibition or …

Sensory Processing In Autism Spectrum Disorders And Fragile X Syndrome-From The Clinic To Animal Models., D Sinclair, B Oranje, K A Razak, S J Siegel, S Schmid

Brain and Mind Institute Researchers' Publications

Brains are constantly flooded with sensory information that needs to be filtered at the pre-attentional level and integrated into endogenous activity in order to allow for detection of salient information and an appropriate behavioral response. People with Autism Spectrum Disorder (ASD) or Fragile X Syndrome (FXS) are often over- or under-reactive to stimulation, leading to a wide range of behavioral symptoms. This altered sensitivity may be caused by disrupted sensory processing, signal integration and/or gating, and is often being neglected. Here, we review translational experimental approaches that are used to investigate sensory processing in humans with ASD and FXS, and …

Adolescent Cannabinoid Exposure Induces A Persistent Sub-Cortical Hyper-Dopaminergic State And Associated Molecular Adaptations In The Prefrontal Cortex., Justine Renard, Laura G Rosen, Michael Loureiro, Cleusa De Oliveira, Susanne Schmid, Walter J Rushlow, Steven R Laviolette

Brain and Mind Institute Researchers' Publications

Considerable evidence suggests that adolescent exposure to delta-9-tetrahydrocanabinol (THC), the psychoactive component in marijuana, increases the risk of developing schizophrenia-related symptoms in early adulthood. In the present study, we used a combination of behavioral and molecular analyses with in vivo neuronal electrophysiology to compare the long-term effects of adolescent versus adulthood THC exposure in rats. We report that adolescent, but not adult, THC exposure induces long-term neuropsychiatric-like phenotypes similar to those observed in clinical populations. Thus, adolescent THC exposure induced behavioral abnormalities resembling positive and negative schizophrenia-related endophenotypes and a state of neuronal hyperactivity in the mesocorticolimbic dopamine (DA) pathway. …