Medicine and Health Sciences Commons^™

Genetic Variant Effects On Gene Expression In Human Pancreatic Islets And Their Implications For T2d., Ana Viñuela, Arushi Varshney, Martijn Van De Bunt, Rashmi B Prasad, Olof Asplund, Amanda Bennett, Michael Boehnke, Andrew A Brown, Michael R Erdos, João Fadista, Ola Hansson, Gad Hatem, Cédric Howald, Apoorva K Iyengar, Paul Johnson, Ulrika Krus, Patrick E Macdonald, Anubha Mahajan, Jocelyn E Manning Fox, Narisu Narisu, Vibe Nylander, Peter Orchard, Nikolay Oskolkov, Nikolaos I Panousis, Anthony Payne, Michael L. Stitzel, Swarooparani Vadlamudi, Ryan Welch, Francis S Collins, Karen L Mohlke, Anna L Gloyn, Laura J Scott, Emmanouil T Dermitzakis, Leif Groop, Stephen C J Parker, Mark I Mccarthy

Faculty Research 2020

Most signals detected by genome-wide association studies map to non-coding sequence and their tissue-specific effects influence transcriptional regulation. However, key tissues and cell-types required for functional inference are absent from large-scale resources. Here we explore the relationship between genetic variants influencing predisposition to type 2 diabetes (T2D) and related glycemic traits, and human pancreatic islet transcription using data from 420 donors. We find: (a) 7741 cis-eQTLs in islets with a replication rate across 44 GTEx tissues between 40% and 73%; (b) marked overlap between islet cis-eQTL signals and active regulatory sequences in islets, with reduced eQTL effect size observed in …

Tissue-Specific Usage Of Transposable Element-Derived Promoters In Mouse Development, Benpeng Miao, Shuhua Fu, Cheng Lyu, Paul Gontarz, Ting Wang, Bo Zhang

2020-Current year OA Pubs

BACKGROUND: Transposable elements (TEs) are a significant component of eukaryotic genomes and play essential roles in genome evolution. Mounting evidence indicates that TEs are highly transcribed in early embryo development and contribute to distinct biological functions and tissue morphology.

RESULTS: We examine the epigenetic dynamics of mouse TEs during the development of five tissues: intestine, liver, lung, stomach, and kidney. We found that TEs are associated with over 20% of open chromatin regions during development. Close to half of these accessible TEs are only activated in a single tissue and a specific developmental stage. Most accessible TEs are rodent-specific. Across …

Atrial Myocyte Nlrp3/Camkii Nexus Forms A Substrate For Postoperative Atrial Fibrillation, Jordi Heijman, Azinwi Phina Muna, Tina Veleva, Cristina E Molina, Henry Sutanto, Marcel Tekook, Qiongling Wang, Issam H Abu-Taha, Marcel Gorka, Stephan Künzel, Ali El-Armouche, Hermann Reichenspurner, Markus Kamler, Viacheslav Nikolaev, Ursula Ravens, Na Li, Stanley Nattel, Xander H T Wehrens, Dobromir Dobrev

Faculty, Staff and Students Publications

RATIONALE: Postoperative atrial fibrillation (POAF) is a common and troublesome complication of cardiac surgery. POAF is generally believed to occur when postoperative triggers act on a preexisting vulnerable substrate, but the underlying cellular and molecular mechanisms are largely unknown.

OBJECTIVE: To identify cellular POAF mechanisms in right atrial samples from patients without a history of atrial fibrillation undergoing open-heart surgery.

METHODS AND RESULTS: Multicellular action potentials, membrane ion-currents (perforated patch-clamp), or simultaneous membrane-current (ruptured patch-clamp) and [Ca

CONCLUSIONS: Preexisting Ca

Loss Of Speg Inhibitory Phosphorylation Of Ryanodine Receptor Type-2 Promotes Atrial Fibrillation, Hannah M Campbell, Ann P Quick, Issam Abu-Taha, David Y Chiang, Carlos F Kramm, Tarah A Word, Sören Brandenburg, Mohit Hulsurkar, Katherina M Alsina, Hui-Bin Liu, Brian Martin, Dennis Uhlenkamp, Oliver M Moore, Satadru K Lahiri, Eleonora Corradini, Markus Kamler, Albert J R Heck, Stephan E Lehnart, Dobromir Dobrev, Xander H T Wehrens

Faculty, Staff and Students Publications

BACKGROUND: Enhanced diastolic calcium (Ca

METHODS: Western blotting was performed with right atrial biopsies from patients with paroxysmal AF. SPEG atrial knockout mice were generated using adeno-associated virus 9. In mice, AF inducibility was determined using intracardiac programmed electric stimulation, and diastolic Ca

RESULTS: Western blotting revealed decreased SPEG protein levels in atrial biopsies from patients with paroxysmal AF in comparison with patients in sinus rhythm. SPEG atrial-specific knockout mice exhibited increased susceptibility to pacing-induced AF by programmed electric stimulation and enhanced Ca

CONCLUSIONS: Unlike other kinases (PKA, CaMKII) that increase RyR2 activity, SPEG phosphorylation reduces RyR2-mediated sarcoplasmic reticulum Ca

Swell1 Regulates Skeletal Muscle Cell Size, Intracellular Signaling, Adiposity And Glucose Metabolism, Ashutosh Kumar, Litao Xie, Chau My Ta, Antentor O Hinton, Susheel K Gunasekar, Rachel A Minerath, Karen Shen, Joshua M Maurer, Chad E Grueter, E Dale Abel, Gretchen Meyer, Rajan Sah

2020-Current year OA Pubs

Maintenance of skeletal muscle is beneficial in obesity and Type 2 diabetes. Mechanical stimulation can regulate skeletal muscle differentiation, growth and metabolism; however, the molecular mechanosensor remains unknown. Here, we show that SWELL1 (

Dual Roles Of Neutrophils In Metastatic Colonization Are Governed By The Host Nk Cell Status., Peishan Li, Mingyang Lu, Jiayuan Shi, Li Hua, Zheng Gong, Qing Li, Leonard D. Shultz, Guangwen Ren

Faculty Research 2020

The role of neutrophils in solid tumor metastasis remains largely controversial. In preclinical models of solid tumors, both pro-metastatic and anti-metastatic effects of neutrophils have been reported. In this study, using mouse models of breast cancer, we demonstrate that the metastasis-modulating effects of neutrophils are dictated by the status of host natural killer (NK) cells. In NK cell-deficient mice, granulocyte colony-stimulating factor-expanded neutrophils show an inhibitory effect on the metastatic colonization of breast tumor cells in the lung. In contrast, in NK cell-competent mice, neutrophils facilitate metastatic colonization in the same tumor models. In an ex vivo neutrophil-NK cell-tumor cell …

Aluminum Reproductive Toxicity: A Summary And Interpretation Of Scientific Reports, Robert A. Yokel

Pharmaceutical Sciences Faculty Publications

Publications addressing aluminum (Al)-induced reproductive toxicity were reviewed. Key details were compiled in summary tables. Approximate systemic Al exposure, a measure of bioavailability, was calculated for each exposure, based on the Al percentage in the dosed Al species, Al bioavailability, and absorption time course reports for the exposure route. This was limited to laboratory animal studies because no controlled-exposure human studies were found. Intended Al exposure was compared to unintended dietary Al exposure. The considerable and variable Al content of laboratory animal diets creates uncertainty about reproductive function in the absence of Al. Aluminum-induced reproductive toxicity in female mice and …

Long Noncoding Rna H19x Is A Key Mediator Of Tgf-Β-Driven Fibrosi, Elena Pachera, Shervin Assassi, Gloria A Salazar, Mara Stellato, Florian Renoux, Adam Wunderlin, Przemyslaw Blyszczuk, Robert Lafyatis, Fina Kurreeman, Jeska De Vries-Bouwstra, Tobias Messemaker, Carol A Feghali-Bostwick, Gerhard Rogler, Wouter T Van Haaften, Gerard Dijkstra, Fiona Oakley, Maurizio Calcagni, Janine Schniering, Britta Maurer, Jörg Hw Distler, Gabriela Kania, Mojca Frank-Bertoncelj, Oliver Distler

Faculty, Staff and Student Publications

TGF-β is a master regulator of fibrosis, driving the differentiation of fibroblasts into apoptosis-resistant myofibroblasts and sustaining the production of extracellular matrix (ECM) components. Here, we identified the nuclear long noncoding RNA (lncRNA) H19X as a master regulator of TGF-β-driven tissue fibrosis. H19X was consistently upregulated in a wide variety of human fibrotic tissues and diseases and was strongly induced by TGF-β, particularly in fibroblasts and fibroblast-related cells. Functional experiments following H19X silencing revealed that H19X was an obligatory factor for TGF-β-induced ECM synthesis as well as differentiation and survival of ECM-producing myofibroblasts. We showed that H19X regulates DDIT4L gene …

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 …

Characterization Of Retinal Biomechanical Properties Using Brillouin Microscopy, Yogeshwari S Ambekar, Manmohan Singh, Giuliano Scarcelli, Elda M Rueda, Benjamin M Hall, Ross A Poché, Kirill V Larin

Faculty, Staff and Students Publications

SIGNIFICANCE: The retina is critical for vision, and several diseases may alter its biomechanical properties. However, assessing the biomechanical properties of the retina nondestructively is a challenge due to its fragile nature and location within the eye globe. Advancements in Brillouin spectroscopy have provided the means for nondestructive investigations of retina biomechanical properties.

AIM: We assessed the biomechanical properties of mouse retinas using Brillouin microscopy noninvasively and showed the potential of Brillouin microscopy to differentiate the type and layers of retinas based on stiffness.

APPROACH: We used Brillouin microscopy to quantify stiffness of fresh and paraformaldehyde (PFA)-fixed retinas. As further …

Immune And Microrna Responses To Infection And Indole-3-Carbinol During Colitis, Rasha Raheem Alkarkoushi, Yvonne Hui, Abbas S. Tavakoli, Udai Singh, Prakash Nagarkatti, Mitzi Nagarkatti, Ioulia Chatzistamou, Marpe Bam, Traci L. Testerman

Faculty Publications

BACKGROUND: Indole-3-carbinol (I3C) and other aryl hydrocarbon receptor agonists are known to modulate the immune system and ameliorate various inflammatory and autoimmune diseases in animal models, including colitis induced by dextran sulfate sodium (DSS). MicroRNAs (miRNAs) are also gaining traction as potential therapeutic agents or diagnostic elements. Enterohepatic (EHH) species are associated with an increased risk of inflammatory bowel disease, but little is known about how these species affect the immune system or response to treatment. AIM: To determine whether infection with an EHH species alters the response to I3C and how the immune and miRNA responses of an EHH …

Structure And Mechanism Of A Unique Diiron Center In Mammalian Stearoyl-Coa Desaturase, Jiemin Shen, Gang Wu, Ah-Lim Tsai, Ming Zhou

Faculty, Staff and Students Publications

Stearoyl-CoA desaturase 1 (SCD1) is a membrane-embedded metalloenzyme that catalyzes formation of a double-bond on a saturated acyl-CoA. SCD1 has a diiron center and its proper function requires an electron transport chain composed of NADH (or NADPH), cytochrome b5 reductase (b5R), and cytochrome b5 (cyt b5). Since SCD1 is a key regulator in fat metabolism and is required for survival of cancer cells, there is intense interest in targeting SCD1 for various metabolic diseases and cancers. Crystal structures of human and mouse SCD1 were reported recently, however, both proteins have two zinc ions instead of two iron ions in the …

Tonic Tcr Signaling Inversely Regulates The Basal Metabolism Of Cd4+ T Cells, Ashley A Viehmann Milam, Juliet M Bartleson, Michael D Buck, Chih-Hao Chang, Alexey Sergushichev, David L Donermeyer, Wing Y Lam, Erika L Pearce, Maxim N Artyomov, Paul M Allen

2020-Current year OA Pubs

The contribution of self-peptide-MHC signaling in CD4

Enantiomerically Pure Quinoline-Based Κ-Opioid Receptor Agonists: Chemoenzymatic Synthesis And Pharmacological Evaluation, Benedikt Martin, Dirk Schepmann, Freddy A Bernal, Thomas J Schmidt, Tao Che, Karin Loser, Bernhard Wünsch

2020-Current year OA Pubs

Racemic

Metabolism Of Jq1, An Inhibitor Of Bromodomain And Extra Terminal Bromodomain Proteins, In Human And Mouse Liver Microsomes†, Feng Li, Kevin R Mackenzie, Prashi Jain, Conrad Santini, Damian W Young, Martin M Matzuk

Faculty, Staff and Students Publications

JQ1 is a small-molecule inhibitor of the bromodomain and extra terminal (BET) protein family that potently inhibits the bromodomain testis-specific protein (BRDT), which is essential for spermatogenesis. JQ1 treatment produces a reversible contraceptive effect by targeting the activity of BRDT in mouse male germ cells, validating BRDT as a male contraceptive target. Although JQ1 possesses favourable physical properties, it exhibits a short half-life. Because the details of xenobiotic metabolism play important roles in the optimization of drug candidates and in determining the role of metabolism in drug efficacy, we investigated the metabolism of JQ1 in human and mouse liver microsomes. …

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 …

Nanoceria Distribution And Effects Are Mouse-Strain Dependent, Robert A. Yokel, Michael T. Tseng, D. Allan Butterfield, Matthew L. Hancock, Eric A. Grulke, Jason M. Unrine, Arnold J. Stromberg, Alan K. Dozier, Uschi M. Graham

Pharmaceutical Sciences Faculty Publications

Prior studies showed nanoparticle clearance was different in C57BL/6 versus BALB/c mice, strains prone to Th1 and Th2 immune responses, respectively. Objective: Assess nanoceria (cerium oxide, CeO₂ nanoparticle) uptake time course and organ distribution, cellular and oxidative stress, and bioprocessing as a function of mouse strain. Methods: C57BL/6 and BALB/c female mice were i.p. injected with 10 mg/kg nanoceria or vehicle and terminated 0.5 to 24 h later. Organs were collected for cerium analysis; light and electron microscopy with elemental mapping; and protein carbonyl, IL-1β, and caspase-1 determination. Results: Peripheral organ cerium significantly increased, generally more …

Profound And Redundant Functions Of Arcuate Neurons In Obesity Development, Canjun Zhu, Zhiying Jiang, Yuanzhong Xu, Zhao-Lin Cai, Qingyan Jiang, Yong Xu, Mingshan Xue, Benjamin R Arenkiel, Qi Wu, Gang Shu, Qingchun Tong

Children’s Nutrition Research Center Staff Publications

The current obesity epidemic faces a lack of mechanistic insights. It is known that the acute activity changes of a growing number of brain neurons rapidly alter feeding behaviour; however, how these changes translate to obesity development and the fundamental mechanism underlying brain neurons in controlling body weight remain elusive. Here, we show that chronic activation of hypothalamic arcuate GABAergic (GABA

Symmetric Inverse Consistent Nonlinear Registration Driven By Mutual Information, Wen Fury, Keun Woo Park, Zhuhao Wu, Eunhee Kim, Moon-Sook Woo, Yu Bai, Lynn E Macdonald, Susan D Croll, Sunghee Cho

Faculty, Staff and Student Publications

BACKGROUND AND PURPOSE: Stroke is a major cause of chronic neurological disability. There is considerable interest in understanding how acute transcriptome changes evolve into subacute and chronic patterns that facilitate or limit spontaneous recovery. Here we mapped longitudinal changes in gene expression at multiple time points after stroke in mice out to 6 months.

METHODS: Adult C57BL/6 mice were subjected to transient middle cerebral artery occlusion. Longitudinal transcriptome levels were measured at 10 time points after stroke from acute to recovery phases of ischemic stroke. Localization and the number of mononuclear phagocytes were determined in the postischemic brain. Whole-mount brain …

Gut Microbiota-Derived Short-Chain Fatty Acids Promote Poststroke Recovery In Aged Mice, Juneyoung Lee, John D'Aigle, Louise Atadja, Victoria Quaicoe, Pedram Honarpisheh, Bhanu P Ganesh, Ahmad Hassan, Joerg Graf, Joseph Petrosino, Nagireddy Putluri, Liang Zhu, David J Durgan, Robert M Bryan, Louise D Mccullough, Venugopal Reddy Venna

Faculty, Staff and Students Publications

RATIONALE: The elderly experience profound systemic responses after stroke, which contribute to higher mortality and more severe long-term disability. Recent studies have revealed that stroke outcomes can be influenced by the composition of gut microbiome. However, the potential benefits of manipulating the gut microbiome after injury is unknown.

OBJECTIVE: To determine if restoring youthful gut microbiota after stroke aids in recovery in aged subjects, we altered the gut microbiome through young fecal transplant gavage in aged mice after experimental stroke. Further, the effect of direct enrichment of selective bacteria producing short-chain fatty acids (SCFAs) was tested as a more targeted …

Paraventricular Hypothalamus Mediates Diurnal Rhythm Of Metabolism, Eun Ran Kim, Yuanzhong Xu, Ryan M Cassidy, Yungang Lu, Yongjie Yang, Jinbin Tian, De-Pei Li, Rachel Van Drunen, Aleix Ribas-Latre, Zhao-Lin Cai, Mingshan Xue, Benjamin R Arenkiel, Kristin Eckel-Mahan, Yong Xu, Qingchun Tong

Children’s Nutrition Research Center Staff Publications

Defective rhythmic metabolism is associated with high-fat high-caloric diet (HFD) feeding, ageing and obesity; however, the neural basis underlying HFD effects on diurnal metabolism remains elusive. Here we show that deletion of BMAL1, a core clock gene, in paraventricular hypothalamic (PVH) neurons reduces diurnal rhythmicity in metabolism, causes obesity and diminishes PVH neuron activation in response to fast-refeeding. Animal models mimicking deficiency in PVH neuron responsiveness, achieved through clamping PVH neuron activity at high or low levels, both show obesity and reduced diurnal rhythmicity in metabolism. Interestingly, the PVH exhibits BMAL1-controlled rhythmic expression of GABA-A receptor γ2 subunit, and dampening …

Whole Exome Sequencing In Patients With Williams-Beuren Syndrome Followed By Disease Modeling In Mice Points To Four Novel Pathways That May Modify Stenosis Risk, Phoebe C R Parrish, Delong Liu, Russell H Knutsen, Charles J Billington, Robert P Mecham, Yi-Ping Fu, Beth A Kozel

2020-Current year OA Pubs

Supravalvular aortic stenosis (SVAS) is a narrowing of the aorta caused by elastin (ELN) haploinsufficiency. SVAS severity varies among patients with Williams-Beuren syndrome (WBS), a rare disorder that removes one copy of ELN and 25-27 other genes. Twenty percent of children with WBS require one or more invasive and often risky procedures to correct the defect while 30% have no appreciable stenosis, despite sharing the same basic genetic lesion. There is no known medical therapy. Consequently, identifying genes that modify SVAS offers the potential for novel modifier-based therapeutics. To improve statistical power in our rare-disease cohort (N = 104 exomes), …

Critical Micrornas And Regulatory Motifs In Cleft Palate Identified By A Conserved Mirna-Tf-Gene Network Approach In Humans And Mice, Aimin Li, Peilin Jia, Saurav Mallik, Rong Fei, Hiroki Yoshioka, Akiko Suzuki, Junichi Iwata, Zhongming Zhao

Faculty, Staff and Student Publications

Cleft palate (CP) is the second most common congenital birth defect. The etiology of CP is complicated, with involvement of various genetic and environmental factors. To investigate the gene regulatory mechanisms, we designed a powerful regulatory analytical approach to identify the conserved regulatory networks in humans and mice, from which we identified critical microRNAs (miRNAs), target genes and regulatory motifs (miRNA-TF-gene) related to CP. Using our manually curated genes and miRNAs with evidence in CP in humans and mice, we constructed miRNA and transcription factor (TF) co-regulation networks for both humans and mice. A consensus regulatory loop (miR17/miR20a-FOXE1-PDGFRA) and eight …

Electrically Coupled Inhibitory Interneurons Constrain Long-Range Connectivity Of Cortical Networks, Andrew W Kraft, Anish Mitra, Zachary P Rosenthal, Nico U F Dosenbach, Adam Q Bauer, Abraham Z Snyder, Marcus E Raichle, Joseph P Culver, Jin-Moo Lee

2020-Current year OA Pubs

Spontaneous infra-slow brain activity (ISA) exhibits a high degree of temporal synchrony, or correlation, between distant brain regions. The spatial organization of ISA synchrony is not explained by anatomical connections alone, suggesting that active neural processes coordinate spontaneous activity. Inhibitory interneurons (IINs) form electrically coupled connections via the gap junction protein connexin 36 (Cx36) and networks of interconnected IINs are known to influence neural synchrony over short distances. However, the role of electrically coupled IIN networks in regulating spontaneous correlation over the entire brain is unknown. In this study, we performed OIS imaging on Cx36-/- mice to examine the role …

Disrupted Hypothalamic Crh Neuron Responsiveness Contributes To Diet-Induced Obesity, Canjun Zhu, Yuanzhong Xu, Zhiying Jiang, Jin Bin Tian, Ryan M Cassidy, Zhao-Lin Cai, Gang Shu, Yong Xu, Mingshan Xue, Benjamin R Arenkiel, Qingyan Jiang, Qingchun Tong

Children’s Nutrition Research Center Staff Publications

The current obesity epidemic mainly results from high-fat high-caloric diet (HFD) feeding and may also be contributed by chronic stress; however, the neural basis underlying stress-related diet-induced obesity remains unknown. Corticotropin-releasing hormone (CRH) neurons in the paraventricular hypothalamus (PVH), a known body weight-regulating region, represent one key group of stress-responsive neurons. Here, we found that HFD feeding blunted PVH CRH neuron response to nutritional challenges as well as stress stimuli and dexamethesone, which normally produce rapid activation and inhibition on these neurons, respectively. We generated mouse models with the activity of these neurons clamped at high or low levels, both …

C1q/Tnf-Related Protein 5 Contributes To Diabetic Vascular Endothelium Dysfunction Through Promoting Nox-1 Signaling., Jing Liu, Zhijun Meng, Lu Gan, Rui Guo, Jia Gao, Caihong Liu, Di Zhu, Demin Liu, Ling Zhang, Zhen Zhang, Dina Xie, Xiangying Jiao, Wayne Bond Lau, Bernard L. Lopez, Theodore A. Christopher, Xin-Liang Ma, Jimin Cao, Yajing Wang

Department of Emergency Medicine Faculty Papers

OBJECTIVE: Dysregulated adipokine profiles contribute to the pathogenesis of diabetic cardiovascular complications. Endothelial cell (EC) dysfunction, a common pathological alteration in cardiovascular disorders, is exaggerated in diabetes. However, it is unclear whether and how dysregulated adipokines may contribute to diabetic EC dysfunction.

METHODS AND RESULTS: Serum C1q/TNF-Related Protein 5 (CTRP5) were determined in control/diabetes patients, and control/diabetic mice (high-fat diet, HFD). We observed for the first time that serum total CTRP5 was increased, high molecular weight (HMW) form was decreased, but the globular form (gCTRP5) was significantly increased in diabetic patients. These pathological alterations were reproduced in diabetic mice. To …

Microbial Experience Influences Tumor- Infiltrating T Lymphocytes, Hanna Groeber

Masters Theses

Immune cells, including T cells, have been used for anti-cancer therapy with varying degrees of success. One potential reason for immunotherapy failures in clinical trials may be that typical specific pathogen free (SPF) mice do not accurately replicate human microbial experience, which has important influence on shaping the adaptive immune response. Recently, several previous studies have shown that the immune system of SPF mice more closely resembles newborn human immunity, whereas immune systems from mice exposed to diverse pathogens more closely reflect adult human immunity.

To study the impact of microbial experience on the immune response, we have adopted a …

Atrx Deletion In Neurons Leads To Sexually Dimorphic Dysregulation Of Mir-137 And Spatial Learning And Memory Deficits., Renee J. Tamming, Vanessa Dumeaux, Yan Jiang, Sarfraz Shafiq, Luana Langlois, Jacob Ellegood, Lily R. Qiu, Jason P. Lerch, Nathalie G. Bérubé

Paediatrics Publications

ATRX gene mutations have been identified in syndromic and non-syndromic intellectual disabilities in humans. ATRX is known to maintain genomic stability in neuroprogenitor cells, but its function in differentiated neurons and memory processes remains largely unresolved. Here, we show that the deletion of neuronal Atrx in mice leads to distinct hippocampal structural defects, fewer presynaptic vesicles, and an enlarged postsynaptic area at CA1 apical dendrite-axon junctions. We identify male-specific impairments in long-term contextual memory and in synaptic gene expression, linked to altered miR-137 levels. We show that ATRX directly binds to the miR-137 locus and that the enrichment of the …

Nuclear Localization Of A Novel Calpain-2 Mediated Junctophilin-2 C-Terminal Cleavage Peptide Promotes Cardiomyocyte Remodeling, Satadru K Lahiri, Ann P Quick, Benoit Samson-Couterie, Mohit Hulsurkar, Ies Elzenaar, Ralph J Van Oort, Xander H T Wehrens

Faculty, Staff and Students Publications

Heart failure (HF) is a leading cause of morbidity and mortality worldwide. Patients with HF exhibit a loss of junctophilin-2 (JPH2), a structural protein critical in forming junctional membrane complexes in which excitation-contraction takes place. Several mechanisms have been proposed to mediate the loss of JPH2, one being cleavage by the calcium-dependent protease calpain. The downstream mechanisms underlying HF progression after JPH2 cleavage are presently poorly understood. In this study, we used Labcas to bioinformatically predict putative calpain cleavage sites on JPH2. We identified a cleavage site that produces a novel C-terminal JPH2 peptide (JPH2-CTP) using several domain-specific antibodies. Western …

Effects Of A Postnatal Atrx Conditional Knockout In Neurons On Autism-Like Behaviours In Male And Female Mice., Nicole Martin-Kenny, Nathalie G Bérubé

Paediatrics Publications

BACKGROUND: Alpha-thalassemia/mental retardation, X-linked, or ATRX, is an autism susceptibility gene that encodes a chromatin remodeler. Mutations of ATRX result in the ATR-X intellectual disability syndrome and have been identified in autism spectrum disorder (ASD) patients. The mechanisms by which ATRX mutations lead to autism and autistic-like behaviours are not yet known. To address this question, we generated mice with postnatal Atrx inactivation in excitatory neurons of the forebrain and performed a battery of behavioural assays that assess autistic-like behaviours.

METHODS: Male and female mice with a postnatal conditional ablation of ATRX were generated using the Cre/lox system under the …