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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)...
July 4, 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
Kelly A Jenkins, Martin J Fossat, Siwen Zhang, Durgesh K Rai, Sean Klein, Richard Gillilan, Zackary White, Grayson Gerlich, Scott A McCallum, Roland Winter, Sol M Gruner, Doug Barrick, Catherine A Royer
The effect of introducing internal cavities on protein native structure and global stability has been well documented, but the consequences of these packing defects on folding free-energy landscapes have received less attention. We investigated the effects of cavity creation on the folding landscape of the leucine-rich repeat protein pp32 by high-pressure (HP) and urea-dependent NMR and high-pressure small-angle X-ray scattering (HPSAXS). Despite a modest global energetic perturbation, cavity creation in the N-terminal capping motif (N-cap) resulted in very strong deviation from two-state unfolding behavior...
August 28, 2018: Proceedings of the National Academy of Sciences of the United States of America
Goran Tomic, Edward Morrissey, Sarah Kozar, Shani Ben-Moshe, Alice Hoyle, Roberta Azzarelli, Richard Kemp, Chandra Sekhar Reddy Chilamakuri, Shalev Itzkovitz, Anna Philpott, Douglas J Winton
The intestinal epithelium is largely maintained by self-renewing stem cells but with apparently committed progenitors also contributing, particularly following tissue damage. However, the mechanism of, and requirement for, progenitor plasticity in mediating pathological response remain unknown. Here we show that phosphorylation of the transcription factor Atoh1 is required for both the contribution of secretory progenitors to the stem cell pool and for a robust regenerative response. As confirmed by lineage tracing, Atoh1+ cells (Atoh1(WT)CreERT2 mice) give rise to multilineage intestinal clones both in the steady state and after tissue damage...
September 6, 2018: Cell Stem Cell
Vasila A Sulaymonova, Margret C Fuchs, Richard Gloaguen, Robert Möckel, Silke Merchel, Martin Rudolph, Matthias R Krbetschek
Cosmogenic nuclide (CN) dating relies on specific target minerals such as quartz as markers to identify geologic events, including the timing of landscape evolution. The presence of feldspar in sediment samples poses a challenge to the separation of quartz and affects the chemical procedures for extracting the radioactive CNs 10 Be and 26 Al. Additionally, feldspar contamination reduces the 26 Al/27 Al ratio, thus hinders the accurate determination of 26 Al by accelerator mass spectrometry (AMS). Using fluvial sediment samples from Central Asia, which contain 16-50 weight percent (wt...
2018: MethodsX
Edward B Garon, Jill M Siegfried, Laura P Stabile, Patricia A Young, Diana C Marquez-Garban, David J Park, Ravi Patel, Eddie H Hu, Saeed Sadeghi, Rupesh J Parikh, Karen L Reckamp, Brad Adams, Robert M Elashoff, David Elashoff, Tristan Grogan, He-Jing Wang, Sanja Dacic, Meghan Brennan, Yacgley Valdes, Simon Davenport, Steven M Dubinett, Michael F Press, Dennis J Slamon, Richard J Pietras
OBJECTIVES: This open-label, randomized phase II trial evaluated antitumor efficacy of an antiestrogen, fulvestrant, in combination with human epidermal growth factor receptor (EGFR) inhibitor, erlotinib, in advanced non-small cell lung cancer (NSCLC) patients. MATERIALS AND METHODS: Patients with advanced or metastatic NSCLC, ECOG 0-2, previous chemotherapy unless patient refusal, and no prior EGFR-directed therapy were randomized 2:1 to erlotinib 150 mg oral daily plus 500 mg intramuscular fulvestrant on day 1, 15, 29 and every 28 days thereafter or erlotinib alone 150 mg oral daily...
September 2018: Lung Cancer: Journal of the International Association for the Study of Lung Cancer
Magda Bahcall, Mark M Awad, Lynette M Sholl, Frederick H Wilson, Man Xu, Stephen Wang, Sangeetha Palakurthi, Jihyun Choi, Elena V Ivanova, Giulia C Leonardi, Bryan C Ulrich, Cloud P Paweletz, Paul T Kirschmeier, Masayuki Watanabe, Hideo Baba, Mizuki Nishino, Rebecca J Nagy, Richard B Lanman, Marzia Capelletti, Emily S Chambers, Amanda J Redig, Paul A VanderLaan, Daniel B Costa, Yu Imamura, Pasi A Jänne
Purpose: MET inhibitors can be effective therapies in patients with MET exon 14 ( MET ex14) mutant non-small cell lung cancer (NSCLC). However, long-term efficacy is limited by the development of drug resistance. In this study, we characterize acquired amplification of wild-type (WT) KRAS as a molecular mechanism behind crizotinib resistance in three cases of MET ex14-mutant NSCLC and propose a combination therapy to target it. Experimental Design: The patient-derived cell line and xenograft (PDX) DFCI358 were established from a crizotinib-resistant MET ex14-mutant patient tumor with massive focal amplification of WT KRAS To characterize the mechanism of KRAS-mediated resistance, molecular signaling was analyzed in the parental cell line and its KRAS siRNA-transfected derivative...
August 2, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Jessica L Kostick-Dunn, Jerilyn R Izac, John C Freedman, Lee T Szkotnicki, Lee D Oliver, Richard T Marconi
Cyclic-di-GMP (c-di-GMP) contributes to the regulation of processes required by the Lyme disease (LD) spirochetes to complete the tick-mammal enzootic cycle. Our understanding of the effector mechanisms of c-di-GMP in the Borrelia is evolving. While most LD spirochete isolates encode a single PilZ domain containing c-di-GMP receptor designated as PlzA, genome analyses have revealed that a subset encode a second PilZ domain protein (PlzB). The c-di-GMP binding potential of PlzB, and its role in LD spirochete biology, have not been investigated...
2018: Frontiers in Cellular and Infection Microbiology
Seok-Ho Yu, Peng Zhao, Pradeep K Prabhakar, Tiantian Sun, Aaron Beedle, Geert-Jan Boons, Kelley W Moremen, Lance Wells, Richard Steet
Deficiency in subunits of the conserved oligomeric Golgi (COG) complex results in pleiotropic defects in glycosylation and causes congenital disorders in humans. Insight regarding the functional consequences of this defective glycosylation and the identity of specific glycoproteins affected is lacking. A chemical glycobiology strategy was adopted to identify the surface glycoproteins most sensitive to altered glycosylation in COG-deficient Chinese hamster ovary (CHO) cells. Following metabolic labeling, an unexpected increase in GalNAz incorporation into several glycoproteins, including α-dystroglycan (α-DG), was noted in cog1 -deficient ldlB cells...
September 14, 2018: Journal of Biological Chemistry
Bharadwaja S T Peddinti, Frank Scholle, Reza A Ghiladi, Richard J Spontak
To combat the global threat posed by surface-adhering pathogens that are becoming increasingly drug-resistant, we explore the anti-infective efficacy of bulk thermoplastic elastomer films containing ∼1 wt % zinc-tetra(4- N-methylpyridyl)porphine (ZnTMPyP4+ ), a photoactive antimicrobial that utilizes visible light to generate singlet oxygen. This photodynamic polymer is capable of inactivating five bacterial strains and two viruses with at least 99.89% and 99.95% success, respectively, after exposure to noncoherent light for 60 min...
August 8, 2018: ACS Applied Materials & Interfaces
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