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Jianyun Liu, Richard M Gallo, Masood A Khan, Abhirami K Iyer, Ian M Kratzke, Randy R Brutkiewicz
Invariant Natural Killer T (iNKT) cells play critical roles in autoimmune, anti-tumor and anti-microbial immune responses, and are activated by glycolipids presented by the MHC class I-like molecule, CD1d. How the activation of signaling pathways impacts antigen (Ag)-dependent iNKT cell activation is not well-known. In the current study, we found that the MAPK JNK2 not only negatively regulates CD1d-mediated Ag presentation in APCs, but also contributes to CD1d-independent iNKT cell activation. A deficiency in the JNK2 (but not JNK1) isoform enhanced Ag presentation by CD1d...
November 22, 2018: European Journal of Immunology
Florian Kuehn, Fatemeh Adiliaghdam, Sulaiman R Hamarneh, Robin Vasan, Enyu Liu, Yang Liu, Juan M Ramirez, Raza S Hoda, Alexander R Munoz, Frank C Ko, Michael Armanini, Daniel J Brooks, Mary L Bouxsein, Marie B Demay, Richard A Hodin
BACKGROUND: The gut is becoming increasingly recognized as the source of various systemic diseases, and recently, it has been linked to bone metabolism via the so-called gut-bone axis. The microbiome and gut-derived mediators are thought to impact upon bone metabolism, and administration of probiotics has been shown to have beneficial effects in bone. The gut brush border enzyme intestinal alkaline phosphatase (IAP) plays an important role in controlling calcium absorption, inhibiting lipopolysaccharides, and other inflammatory mediators responsible for endotoxemia and appears to preserve the normal gut microbiota...
December 2018: Journal of Surgical Research
Barbara L Parry, Charles J Meliska, Ana M Lopez, Diane L Sorenson, L Fernando Martinez, Henry J Orff, Richard L Hauger, Daniel F Kripke
BACKGROUND: Peripartum major depression (MD) disables mothers and impairs emotional and neurocognitive development of offspring. We tested the hypothesis that critically-timed wake therapy (WT) relieves peripartum MD by altering melatonin and sleep timing, differentially, in antepartum vs. postpartum depressed patients (DP). METHODS: In a university clinical research center, we initially randomized 50 women - 26 antepartum (17 healthy comparison-HC, 9 DP) and 24 postpartum (8 HC, 16 DP) - to a cross-over trial of one night of early-night wake therapy (EWT: sleep 3:00-7:00 am) vs...
November 5, 2018: Journal of Affective Disorders
Melissa A Cunningham, Mara Lennard Richard, Jena R Wirth, Jennifer L Scott, Jackie Eudaly, Phil Ruiz, Gary S Gilkeson
Female sex is a risk factor for lupus. Sex hormones, sex chromosomes and hormone receptors are implicated in the pathogenic pathways in lupus. Estrogen receptor alpha (ERα) knockout (KO) mice are used for defining hormone receptor effects in lupus. Prior studies of ERα KO in lupus have conflicting results, likely due to sex hormone levels, different lupus strains and different ERα KO constructs. Our objective was to compare a complete KO of ERα vs. the original functional KO of ERα (expressing a short ERα) on disease expression and immune phenotype, while controlling sex hormone levels...
November 8, 2018: Journal of Autoimmunity
Jeeyeon Kim, Miesha Farahmand, Colleen Dunn, Carlos E Milla, Rina I Horii, Ewart A C Thomas, Richard B Moss, Jeffrey J Wine
To determine if ivacaftor (Kalydeco) influences non-CF human CFTR function in vivo, we measured CFTR-dependent (C-sweat) and CFTR-independent (M-sweat) rates from multiple identified sweat glands in 8 non-CF adults. The two types of sweating were stimulated sequentially with intradermal injections of appropriate reagents; each gland served as its own control via alternating off-on drug tests on both arms, given at weekly intervals with 3 off and 3 on tests per subject. We compared drug effects on C-sweating stimulated by either high or low concentrations of β-adrenergic cocktail, and on methacholine-stimulated M-sweating...
November 2, 2018: Scientific Reports
Elaine Pirie, Shayoni Ray, Calvin Pan, Wuxia Fu, Andrew F Powers, Danielle Polikoff, Colton M Miller, Katrina M Kudrna, Edward N Harris, Aldons J Lusis, Rosanne M Crooke, Richard G Lee
Antisense oligonucleotides (ASOs) have demonstrated variation of efficacy in patient populations. This has prompted our investigation into the contribution of genetic architecture to ASO pharmacokinetics (PK) and pharmacodynamics (PD). Genome wide association (GWA) and transcriptomic analysis in a hybrid mouse diversity panel (HMDP) were used to identify and validate novel genes involved in the uptake and efficacy of a single dose of a Malat1 constrained ethyl (cEt) modified ASO. The GWA of the HMDP identified two significant associations on chromosomes 4 and 10 with hepatic Malat1 ASO concentrations...
October 2018: PLoS Genetics
Stephanie B Syc-Mazurek, Rebecca L Rausch, Kimberly A Fernandes, Michael P Wilson, Richard T Libby
The mitogen-activated protein kinase (MAPK) pathway has been shown to be involved in both neurodevelopment and neurodegeneration. c-Jun N-terminal kinase (JNK), a MAPK important in retinal development and after optic nerve crush injury, is regulated by two upstream kinases: MKK4 and MKK7. The specific requirements of MKK4 and MKK7 in retinal development and retinal ganglion cell (RGC) death after axonal injury, however, are currently undefined. Optic nerve injury is an important insult in many neurologic conditions including traumatic, ischemic, inflammatory, and glaucomatous optic neuropathies...
October 26, 2018: Cell Death & Disease
Robyn A Grant, Aimee A Wong, Emre Fertan, Richard E Brown
Active whisking in mice and rats is one of the fastest behaviours known in mammals and is used to guide complex behaviours such as exploration and navigation. During object contact, whisker movements are actively controlled and undergo robust changes in timing, speed and position. This study quantifies whisker movements in 6-7 month old male and female 5xFAD mice, and their C57/SJL F1 wildtype (WT) controls. As well as genotype, we examined sex differences and the effects of retinal degeneration (rd). Mice were filmed using a high-speed video camera at 500fps, under infrared light while behaving freely in three tasks: object exploration, sequential object exploration and tunnel running...
October 23, 2018: Genes, Brain, and Behavior
Lin Lin, Adam H Metherel, Alex P Kitson, Shoug M Alashmali, Kathryn E Hopperton, Marc-Olivier Trépanier, Peter J Jones, Richard P Bazinet
N-acylethanolamines (NAEs) are lipid signaling mediators, which can be synthesized from dietary fatty acids via n-acylphosphatidylethanolamine-phospholipase D (NAPE-PLD) and in turn influence physiological outcomes; however, the roles of NAPE-PLD upon dietary fatty acid modulation are not fully understood. Presently, we examine if NAPE-PLD is necessary to increase NAEs in response to dietary fatty acid manipulation. Post-weaning male wild-type (C57Bl/6), NAPE-PLD (-/+) and NAPE-PLD (-/-) mice received isocaloric fat diets containing either beef tallow, corn oil, canola oil or fish oil (10% wt/wt from fat) for 9 weeks...
September 5, 2018: Journal of Nutritional Biochemistry
Renee M Potera, Mou Cao, Lin F Jordan, Richard T Hogg, Jessica S Hook, Jessica G Moreland
Acute lung injury (ALI), developing as a component of the systemic inflammatory response syndrome (SIRS), leads to significant morbidity and mortality. Reactive oxygen species (ROS), produced in part by the neutrophil NADPH oxidase 2 (Nox2), have been implicated in the pathogenesis of ALI. Previous studies in our laboratory demonstrated the development of pulmonary inflammation in Nox2-deficient (gp91phox-/y ) mice that was absent in WT mice in a murine model of SIRS. Given this finding, we hypothesized that Nox2 in a resident cell in the lung, specifically the alveolar macrophage, has an essential anti-inflammatory role...
October 4, 2018: Inflammation
Alexander Dank, Eddy J Smid, Richard A Notebaart
OBJECTIVE: Saccharomyces cerevisiae is used worldwide for the production of ale-type beers. This yeast is responsible for the production of the characteristic fruity aroma compounds. Esters constitute an important group of aroma active secondary metabolites produced by S. cerevisiae. Previous work suggests that esterase activity, which results in ester degradation, may be the key factor determining the abundance of fruity aroma compounds. Here, we test this hypothesis by deletion of two S...
September 27, 2018: BMC Research Notes
Chantal Donovan, Malcolm R Starkey, Richard Y Kim, Batika M J Rana, Jillian L Barlow, Bernadette Jones, Tatt Jhong Haw, Prema Mono Nair, Kurtis Budden, Guy J M Cameron, Jay C Horvat, Peter A Wark, Paul S Foster, Andrew N J McKenzie, Philip M Hansbro
Pulmonary inflammation in chronic obstructive pulmonary disease (COPD) is characterized by both innate and adaptive immune responses; however, their specific roles in the pathogenesis of COPD are unclear. Therefore, we investigated the roles of T and B lymphocytes and group 2 innate lymphoid cells (ILC2s) in airway inflammation and remodelling, and lung function in an experimental model of COPD using mice that specifically lack these cells (Rag1-/- and Rorafl/fl Il7rCre [ILC2-deficient] mice). Wild-type (WT) C57BL/6 mice, Rag1-/- , and Rorafl/fl Il7rCre mice were exposed to cigarette smoke (CS; 12 cigarettes twice a day, 5 days a week) for up to 12 weeks, and airway inflammation, airway remodelling (collagen deposition and alveolar enlargement), and lung function were assessed...
September 27, 2018: Journal of Leukocyte Biology
Raphael G Ferreira, Lilian C Rodrigues, Daniele C Nascimento, Alexandre Kanashiro, Paulo H Melo, Vanessa F Borges, Aline Gozzi, Douglas da Silva Prado, Marcos C Borges, Fernando S Ramalho, Sean R Stowell, Richard D Cummings, Marcelo Dias-Baruffi, Fernando Q Cunha, Jose C Alves-Filho
Sepsis is an overwhelming systemic inflammation resulting from an uncontrolled infection that causes extensive tissue damage, organ dysfunction and eventually death. A growing body of evidence indicates that impaired neutrophil migration to the site of infection is associated with poor outcome in sepsis. Here we show that galectin-3 (Gal-3), an endogenous glycan-binding protein, plays a critical role in sepsis outcome. We found that serum Gal-3 concentration increased in patients with septic shock and mice undergoing sepsis induced by cecal ligation and puncture (CLP)...
November 2018: Journal of Infection
Daniela A Braun, Svjetlana Lovric, David Schapiro, Ronen Schneider, Jonathan Marquez, Maria Asif, Muhammad Sajid Hussain, Ankana Daga, Eugen Widmeier, Jia Rao, Shazia Ashraf, Weizhen Tan, C Patrick Lusk, Amy Kolb, Tilman Jobst-Schwan, Johanna Magdalena Schmidt, Charlotte A Hoogstraten, Kaitlyn Eddy, Thomas M Kitzler, Shirlee Shril, Abubakar Moawia, Kathrin Schrage, Arwa Ishaq A Khayyat, Jennifer A Lawson, Heon Yung Gee, Jillian K Warejko, Tobias Hermle, Amar J Majmundar, Hannah Hugo, Birgit Budde, Susanne Motameny, Janine Altmüller, Angelika Anna Noegel, Hanan M Fathy, Daniel P Gale, Syeda Seema Waseem, Ayaz Khan, Larissa Kerecuk, Seema Hashmi, Nilufar Mohebbi, Robert Ettenger, Erkin Serdaroğlu, Khalid A Alhasan, Mais Hashem, Sara Goncalves, Gema Ariceta, Mercedes Ubetagoyena, Wolfram Antonin, Shahid Mahmood Baig, Fowzan S Alkuraya, Qian Shen, Hong Xu, Corinne Antignac, Richard P Lifton, Shrikant Mane, Peter Nürnberg, Mustafa K Khokha, Friedhelm Hildebrandt
Steroid-resistant nephrotic syndrome (SRNS) almost invariably progresses to end-stage renal disease. Although more than 50 monogenic causes of SRNS have been described, a large proportion of SRNS remains unexplained. Recently, it was discovered that mutations of NUP93 and NUP205, encoding 2 proteins of the inner ring subunit of the nuclear pore complex (NPC), cause SRNS. Here, we describe mutations in genes encoding 4 components of the outer rings of the NPC, namely NUP107, NUP85, NUP133, and NUP160, in 13 families with SRNS...
October 1, 2018: Journal of Clinical Investigation
Maria Kupreeva, Abdoulaye Diane, Richard Lehner, Watts Russell, Mahua Ghosh, Spencer D Proctor, Donna F Vine
Polycystic Ovary Syndrome (PCOS) is a highly associated with cardiometabolic risk and the metabolic syndrome (MetS), predisposing women to increased risk of developing Type 2 Diabetes and Cardiovascular Disease (CVD). Metformin is commonly used to treat insulin resistance-glucose intolerance, and flutamide, an androgen receptor antagonist, is used to target hyperandrogenemia and dyslipidemia. Currently, the physiological mechanism of action of these treatments on androgen, lipidogenic and insulin signaling pathways remains unclear in the PCOS...
August 28, 2018: American Journal of Physiology. Endocrinology and Metabolism
Shuai Li, Paul G Lucey, Ralph E Milliken, Paul O Hayne, Elizabeth Fisher, Jean-Pierre Williams, Dana M Hurley, Richard C Elphic
Water ice may be allowed to accumulate in permanently shaded regions on airless bodies in the inner solar system such as Mercury, the Moon, and Ceres [Watson K, et al. (1961) J Geophys Res 66:3033-3045]. Unlike Mercury and Ceres, direct evidence for water ice exposed at the lunar surface has remained elusive. We utilize indirect lighting in regions of permanent shadow to report the detection of diagnostic near-infrared absorption features of water ice in reflectance spectra acquired by the Moon Mineralogy Mapper [M (3)] instrument...
September 4, 2018: Proceedings of the National Academy of Sciences of the United States of America
Hesham M Shehata, Shahzada Khan, Elise Chen, Patrick E Fields, Richard A Flavell, Shomyseh Sanjabi
Identifying novel pathways that promote robust function and longevity of cytotoxic T cells has promising potential for immunotherapeutic strategies to combat cancer and chronic infections. We show that sprouty 1 and 2 (Spry1/2) molecules regulate the survival and function of memory CD8+ T cells. Spry1/2 double-knockout (DKO) ovalbumin (OVA)-specific CD8+ T cells (OT-I cells) mounted more vigorous autoimmune diabetes than WT OT-I cells when transferred to mice expressing OVA in their pancreatic β-islets. To determine the consequence of Spry1/2 deletion on effector and memory CD8+ T cell development and function, we used systemic infection with lymphocytic choriomeningitis virus (LCMV) Armstrong...
September 18, 2018: Proceedings of the National Academy of Sciences of the United States of America
Xuhui Bao, Ya Hua, Richard F Keep, Guohua Xi
Our previous studies have found that pretreatment with a low dose of thrombin (thrombin preconditioning, TPC) reduces infarct volume and attenuates brain edema after focal cerebral ischemia in vivo and protects against the neuronal death induced by oxygen glucose deprivation (OGD) in vitro . In this study, we found that TPC (24 hours exposure to 0.5 or 1 U/ml thrombin) protects against OGD-induced astrocyte death, and that such protection is through protease activated receptor-1 (Par-1) and the p44/42 mitogen activated protein kinase (MAPK)/p90 ribosomal S6 kinase (p90RSK)/heat shock protein 25 (HSP25) pathway...
February 2018: Conditioning medicine
Michelle Yen, Richard S Lewis
The binding of STIM1 to Orai1 controls the opening of store-operated CRAC channels as well as their extremely high Ca2+ selectivity. Although STIM1 dimers are known to bind directly to the cytosolic C termini of the six Orai1 subunits (SUs) that form the channel hexamer, the dependence of channel activation and selectivity on the number of occupied binding sites is not well understood. Here we address these questions using dimeric and hexameric Orai1 concatemers in which L273D mutations were introduced to inhibit STIM1 binding to specific Orai1 SUs...
October 1, 2018: Journal of General Physiology
Jessy J Alexander, Jeyantt S Sankaran, Kenneth L Seldeen, Ramkumar Thiyagarajan, Alexander Jacob, Richard J Quigg, Bruce R Troen, Stefan Judex
Complement system is an important arm of the immune system that promotes inflammation. Complement Factor H (FH) is a critical regulator of the alternative complement pathway. Its absence causes pathology in different organs resulting in diseases such as age related macular degeneration and dense deposit disease. Recent studies suggest that the complement system plays a role in bone development and homeostasis. To determine the role of FH in bone architecture, we studied the FH knockout (fh-/-) mice. 3D reconstructions of femur from 16 week old fh-/- mice reveal significant changes, such as decreased BV/TV (4...
August 1, 2018: Immunobiology
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