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101. Analysis of the Trichuris suis excretory/secretory proteins as a function of life cycle stage and their immunomodulatory properties

Author: Rajesh M. Valanparambil, Armando Jardim, Elizabeth Siciliani, Dante S. Zarlenga, Timothy G. Geary, Louis-Philippe Leroux, Maritza Jaramillo, Mifong Tam, Dolores E. Hill, Makedonka Mitreva, Mohamad Nasr, Joel V. Weinstock, Joseph F. Urban, Mary M. Stevenson, Bruce A. Rosa, Institut Armand Frappier (INRS-IAF), Réseau International des Instituts Pasteur (RIIP)-Institut National de la Recherche Scientifique [Québec] (INRS), Centre for Host-Parasite Interaction [Montreal] (CHPI), Institute of Parasitology [Sainte-Anne-de-Bellevue], McGill University = Université McGill [Montréal, Canada], The McDonnell Genome Institute (MGI), Washington University in Saint Louis (WUSTL), USDA Agricultural Research Service [Maricopa, AZ] (USDA), United States Department of Agriculture (USDA), Tufts Medical Center [Boston], Research was supported in part from a grant from Natural Sciences and Engineering Research Council of Canada Discovery Grant #238249, (A.J.) and Canadian Institutes of Health Research grants to (A.J., M.M.S.). The work at Washington University was supported by NIH grants AI081803 and GM097435 to M.M. The work at the USDA was supported by ARS Research Project 1265-32000-094-00D., and We wish to acknowledge Daniel Defoy at the Proteomics Platform of the Quebec Genomics Center part of the Centre de Recherche du Centre Hospitalier de l’Université Laval (CRCHUL) (Quebec City, QC, Canada) for performing the LC-MS/MS analyses.
Subjects: 0301 basic medicine, Swine, medicine.medical_treatment, T cell, lcsh:Medicine, Nitric Oxide, T-Lymphocytes, Regulatory, Article, 03 medical and health sciences, 0302 clinical medicine, Immune system, medicine, Animals, Secretion, IL-2 receptor, lcsh:Science, Life Cycle Stages, Multidisciplinary, Arginase, biology, Chemistry, Macrophages, lcsh:R, Trichuris suis, FOXP3, Dendritic Cells, Helminth Proteins, biology.organism_classification, Cell biology, Trichuris, 030104 developmental biology, Cytokine, medicine.anatomical_structure, Cytokines, [SDV.IMM]Life Sciences [q-bio]/Immunology, Tumor necrosis factor alpha, lcsh:Q, 030215 immunology
Abstract: Parasitic worms have a remarkable ability to modulate host immune responses through several mechanisms including excreted/secreted proteins (ESP), yet the exact nature of these proteins and their targets often remains elusive. Here, we performed mass spectrometry analyses of ESP (TsESP) from larval and adult stages of the pig whipworm Trichuris suis (Ts) and identified ~350 proteins. Transcriptomic analyses revealed large subsets of differentially expressed genes in the various life cycle stages of the parasite. Exposure of bone marrow-derived macrophages and dendritic cells to TsESP markedly diminished secretion of the pro-inflammatory cytokines TNFα and IL-12p70. Conversely, TsESP exposure strongly induced release of the anti-inflammatory cytokine IL-10, and also induced high levels of nitric oxide (NO) and upregulated arginase activity in macrophages. Interestingly, TsESP failed to directly induce CD4+ CD25+ FoxP3+ regulatory T cells (Treg cells), while OVA-pulsed TsESP-treated dendritic cells suppressed antigen-specific OT-II CD4+ T cell proliferation. Fractionation of TsESP identified a subset of proteins that promoted anti-inflammatory functions, an activity that was recapitulated using recombinant T. suis triosephosphate isomerase (TPI) and nucleoside diphosphate kinase (NDK). Our study helps illuminate the intricate balance that is characteristic of parasite-host interactions at the immunological interface, and further establishes the principle that specific parasite-derived proteins can modulate immune cell functions.
Published: 2018
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102. Screening of rare-earth-lean intermetallic 1-11 and 1-11-X compounds of YNi9In2-type for hard-magnetic applications

Author: Christian Elsässer, Daniel F. Urban, Georg Krugel, and Wolfgang Körner
Subjects: 010302 applied physics, Materials science, Condensed matter physics, Mechanical Engineering, Rare earth, Metals and Alloys, Intermetallic, 02 engineering and technology, Type (model theory), 021001 nanoscience & nanotechnology, Condensed Matter Physics, Magnetocrystalline anisotropy, 01 natural sciences, Crystallography, Magnetization, Ferromagnetism, Mechanics of Materials, Magnet, 0103 physical sciences, General Materials Science, Density functional theory, 0210 nano-technology
Abstract: We report on theoretical investigations of ferromagnetic rare-earth-transition-metal phases with the structure of YNi9In2 and with additional atoms X at two interstitial positions. By a high-throughput-screening (HTS) approach based on density functional theory the intrinsic key properties of hard magnets, namely the magnetization M, energy product (BH)max and uniaxial magnetocrystalline anisotropy constant K1 are estimated. The HTS identifies several promising phases NdFe10AX with A = Ti, V, Cr, Mn, Fe, Co, Ni, Cu, Zn, Al, Si, P, and X = B, C, N. These phases partially outperform Nd2Fe14B in terms of (BH)max and K1 values, and they contain about 35% less rare-earth atoms.
Published: 2018
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103. Bacillus thuringiensis Cry5B protein as a new pan-hookworm cure

Author: Jason B. Noon, Joseph F. Urban, Dwight D. Bowman, Raffi V. Aroian, Bin Zhan, Gary R. Ostroff, Alice C.Y. Lee, Melanie M. Miller, Thanh-Thanh Nguyen, David Koch, Ambily Abraham, Yan Hu, and Ricardo Toshio Fujiwara
Subjects: Ancylostomatoidea, 0301 basic medicine, Hookworm, Veterinary medicine, Ancylostoma, Necator americanus, 030231 tropical medicine, Bacillus thuringiensis, Article, Ancylostomiasis, lcsh:Infectious and parasitic diseases, Necatoriasis, Hemolysin Proteins, Hookworm Infections, 03 medical and health sciences, Dogs, 0302 clinical medicine, Bacterial Proteins, Cricetinae, parasitic diseases, Anthelmintic, medicine, Animals, Pharmacology (medical), lcsh:RC109-216, Intestinal Diseases, Parasitic, Cry5B, Ancylostoma ceylanicum, Anthelmintics, Pharmacology, Bacillus thuringiensis Toxins, biology, Necator, medicine.disease, biology.organism_classification, 3. Good health, Endotoxins, 030104 developmental biology, Infectious Diseases, Parasitology, Ancylostoma caninum, medicine.drug
Abstract: Hookworms are intestinal nematode parasites that infect nearly half a billion people and are globally one of the most important contributors to iron-deficiency anemia. These parasites have significant impacts in developing children, pregnant women and working adults. Of all the soil-transmitted helminths or nematodes (STNs), hookworms are by far the most important, with disease burdens conservatively estimated at four million DALYs (Disability-Adjusted Life Years) and with productivity losses of up to US$139 billion annually. To date, mainly one drug, albendazole is used for hookworm therapy in mass drug administration, which has on average ∼80% cure rate that is lower (, Graphical abstract Image 1, Highlights • Bacillus thuringiensis (Bt) Cry5B is a new pan-hookworm cure. • Bt Cry5B is highly active against Ancylostoma caninum hookworm infections in dogs. • Bt Cry5B is highly active against Necator americanus. • Cry5B acts independent of the host immune system and directly on hookworms. • Cry5B retains full bioactivity after repeated dosing.
Published: 2018

104. Recirculating Immunocompetent Cells in Colitic Mice Intensify Their Lung Response to Bacterial Endotoxin

Author: Peter S. Thorne, M. Nedim Ince, Jamie Truscott, Sarah Winckler, Sonay Beyatli, Nervana Metwali, David E. Elliott, Xiaoqun Guan, Ahmed Metwali, and Joseph F. Urban
Subjects: 0301 basic medicine, Effector and regulatory cells, Physiology, Lymphocyte recirculation, Population, Inflammation, Inflammatory bowel disease, Proinflammatory cytokine, 03 medical and health sciences, Airway hyperresponsiveness, Antigen, Cell Movement, Helminths, Respiratory Hypersensitivity, medicine, Animals, Lymphocytes, Colitis, education, Lung, education.field_of_study, business.industry, Bacterial endotoxin, Gastroenterology, Innate and adaptive immune responses, FOXP3, Forkhead Transcription Factors, Intercellular Adhesion Molecule-1, medicine.disease, 3. Good health, Endotoxins, Mice, Inbred C57BL, Toll-Like Receptor 4, 030104 developmental biology, medicine.anatomical_structure, Inflammatory bowel disease (IBD), Immunology, Cytokines, Female, Original Article, medicine.symptom, business
Abstract: Background Patients with inflammatory bowel disease have higher incidence of airway hyperresponsiveness compared to the general population. Lung inflammation leading to airway hyperresponsiveness causes illnesses for more than ten percent of the population in USA. Aims We investigated the lung response to bacterial endotoxin in colitic mice. Methods Rag-1 mice were transplanted with negatively selected splenic T cells. Some mice groups were treated with NSAID to develop colitis. All mice were treated with bacterial endotoxin and necropsied 3 weeks later. Results Colitic mice developed intensified lung inflammation on day 21 of treatment with bacterial endotoxin. Pulmonary lymphocytes from colitic mice displayed a proinflammatory cytokine profile, expressed high ICAM1 and low FoxP3. CD11c+, CD8+ cells bound and responded to non-systemic antigens from gut-localized microbiota and had higher expression of TLR4. Conclusions Colitic mice developed exacerbated lung inflammation in response to bacterial endotoxin compared to non-colitic mice. Proinflammatory cytokines from pulmonary lymphocytes induced high expression of ICAM1 and suppressed FoxP3 on CD4+ cells. CD11c+, CD8+ cells binding and responding to gut-localized antigens as well as high expression of TLR4 indicate innate and adaptive lung response to bacterial endotoxin. Inflammatory cells from colons of colitic mice homed in the lungs as well as the intestine suggesting recirculation of sensitized immunocompetent cells. These data support our hypothesis that colitis intensifies lung inflammation.
Published: 2018
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105. Effect of Charge Delivery on Thromboembolism During Radiofrequency Ablation in Canines

Author: David A. Igel, Samuel J. Asirvatham, Bernard Lim, James P. Kent, K.L. Venkatachalam, Daniel C. Sigg, and Jon F. Urban
Subjects: 0301 basic medicine, Radiofrequency ablation, medicine.medical_treatment, Catheter ablation, Femoral artery, 030204 cardiovascular system & hematology, Article, Extracorporeal, law.invention, 03 medical and health sciences, Dogs, 0302 clinical medicine, law, Thromboembolism, medicine.artery, medicine, Animals, business.industry, Arrhythmias, Cardiac, Atrial fibrillation, medicine.disease, Ablation, Catheter, 030104 developmental biology, Embolism, Catheter Ablation, business, Nuclear medicine
Abstract: Objectives This study investigated whether delivering negative charge to catheter tips reduces thromboembolism during catheter ablation. Background Radiofrequency (RF) ablation prevents atrial fibrillation that can cause stroke or death. However, ablation itself can cause stroke (2%) or silent ischemia (2% to 41%), possibly via particulate debris that embolizes after coagulum adherence to catheter surfaces. Coagulum formation on RF catheters can be prevented by applying negative charge, but it is unknown if charge reduces peripheral thromboembolism. Methods Paired (Charge ON vs. OFF) endocardial RF ablations were performed in 9 canines using nonirrigated RF catheters. Continuous negative charge was delivered via −100 μA of DC current applied to ablation catheter electrodes. Intracardiac echocardiography was used to navigate the catheter and to monitor coagulum formation. In a subset of 5 canines, microemboli flowing through polyester tubing between the femoral artery and vein (extracorporeal loop) were monitored with bubble counters and inline filter fabric. After each ablation, catheter-tip coagulum and blood particles deposited on the filters were quantified using photography and imaging software (ImageJ, U.S. National Institutes of Health, Bethesda, Maryland). Results Negative charge significantly decreased the extracorporeal loop median filter area covered by particles (n = 19 pairs) by 10.2 mm 2 (p = 0.03), and decreased median filter particles by 349 (p = 0.03). Negative charge also decreased the percentage of the catheter tip surface area covered by coagulum (n = 39 pairs) by 7.2% (p = 0.03). Conclusions Negative charge delivery to ablation catheter tips during RF ablation can reduce particulate embolization material in an extracorporeal loop, and potentially reduce thromboembolic risk associated with RF ablation.
Published: 2018
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106. Bifidobacterium animalis subspecies lactis modulates the local immune response and glucose uptake in the small intestine of juvenile pigs infected with the parasitic nematode Ascaris suum

Author: Joseph F. Urban, Kathleen B. Madden, Gloria Solano-Aguilar, Alejandro Quinoñes, Sukla Lakshman, Harry D. Dawson, Yue Xie, Terez Shea-Donohue, and Ethiopia Beshah
Subjects: 0301 basic medicine, Microbiology (medical), Male, Swine, Biology, Probiotic, Microbiology, Type 2 immune response, Jejunum, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Immune system, Th2 Cells, Bifidobacterium animalis, Intestine, Small, medicine, nematode infection, Animals, Intestinal Mucosa, Ascaris suum, Swine Diseases, Ascariasis, immune modulation, Ascaris, Probiotics, Gastroenterology, Th1 Cells, medicine.disease, biology.organism_classification, eosinophil infiltration, Small intestine, intestinal function, 030104 developmental biology, Infectious Diseases, medicine.anatomical_structure, Glucose, chemistry, Nematode infection, 030211 gastroenterology & hepatology, Female, Th2 cytokines, Histamine, Research Paper
Abstract: An evaluation of a localized intestinal allergic type-2 response concomitant with consumption of probiotic bacteria is not well documented. This study investigated the effect of feeding probiotic Bifidobacterium animalis subspecies lactis (Bb12) or a placebo in weaned pigs that were also inoculated with Ascaris suum (A. suum) eggs to induce a strong Th2-dependent allergic type 2 immune response. Sections of jejunal mucosa were mounted in Ussing chambers to determine changes in permeability and glucose absorption, intestine and liver samples were collected for analysis of type-2 related gene expression, jejunum examined histologically, and sera and intestinal fluid were assayed for parasite antigen specific antibody. The prototypical parasite-induced secretory response to histamine and reduced absorption of glucose in the jejunum were attenuated by feeding Bb12 without a change in mucosal resistance. Parasite antigen-specific IgA response in the serum and IgG1 and IgG2 response in the ileal fluid were significantly increased in A. suum-infected pigs treated with Bb12 compared to infected pigs given the placebo. Ascaris suum-induced eosinophilia in the small intestinal mucosa was inhibited by Bb12 treatment without affecting the normal expulsion of A. suum 4th stage larvae (L4) or the morphometry of the intestine. Expression of genes associated with Th1/Th2 cells, Treg cells, mast cells, and physiological function in the intestine were modulated in A. suum infected-pigs treated with Bb12. These results suggested that Bb12 can alter local immune responses and improve intestinal function during a nematode infection by reducing components of a strong allergenic type-2 response in the pig without compromising normal parasite expulsion.
Published: 2018

107. Activation of intestinal tuft cell-expressed Sucnr1 triggers type 2 immunity in the mouse small intestine

Author: Wenwen Ren, Weiwei Lei, Robert F. Margolskee, Ichiro Matsumoto, Peihua Jiang, Makoto Ohmoto, and Joseph F. Urban
Subjects: Male, 0301 basic medicine, Succinic Acid, Biology, urologic and male genital diseases, Receptors, G-Protein-Coupled, Mice, 03 medical and health sciences, Immune system, Intestine, Small, medicine, Succinate receptor 1, Animals, Tuft, TRPM5, Nippostrongylus brasiliensis, Immunity, Mucosal, Cells, Cultured, Cell Proliferation, Strongylida Infections, Mice, Knockout, Goblet cell, Multidisciplinary, urogenital system, Microbiota, Epithelial Cells, Biological Sciences, Gustducin, biology.organism_classification, female genital diseases and pregnancy complications, Cell biology, Mice, Inbred C57BL, 030104 developmental biology, medicine.anatomical_structure, Female, Goblet Cells, Nippostrongylus, Tuft cell
Abstract: The hallmark features of type 2 mucosal immunity include intestinal tuft and goblet cell expansion initiated by tuft cell activation. How infectious agents that induce type 2 mucosal immunity are detected by tuft cells is unknown. Published microarray analysis suggested that succinate receptor 1 (Sucnr1) is specifically expressed in tuft cells. Thus, we hypothesized that the succinate–Sucnr1 axis may be utilized by tuft cells to detect certain infectious agents. Here we confirmed that Sucnr1 is specifically expressed in intestinal tuft cells but not in other types of intestinal epithelial cells, and demonstrated that dietary succinate induces tuft and goblet cell hyperplasia via Sucnr1 and the tuft cell-expressed chemosensory signaling elements gustducin and Trpm5. Conventional mice with a genetic Sucnr1 deficiency (Sucnr1−/−) showed diminished immune responses to treatment with polyethylene glycol and streptomycin, which are known to enhance microbiota-derived succinate, but responded normally to inoculation with the parasitic worm Nippostrongylus brasiliensis that also produces succinate. Thus, Sucnr1 is required for microbiota-induced but not for a generalized worm-induced type 2 immunity.
Published: 2018
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108. Toxoplasma gondii tissue cyst formation and density of tissue cysts in shoulders of pigs 7 and 14 days after feeding infected mice tissues

Author: Dolores E. Hill, Oliver C.H. Kwok, Surabhi Rani, Fernando H.A. Murata, Abani K. Pradhan, Camila K. Cerqueira-Cézar, Joseph F. Urban, Jitender P. Dubey, and M. Sadler
Subjects: Male, 0301 basic medicine, Shoulder, Veterinary medicine, Swine, 030231 tropical medicine, Antibodies, Protozoan, Excretion, Feces, Mice, 03 medical and health sciences, 0302 clinical medicine, Direct agglutination test, parasitic diseases, medicine, Animals, Muscle, Skeletal, Swine Diseases, Infectivity, CATS, General Veterinary, biology, Oocysts, Toxoplasma gondii, General Medicine, 030108 mycology & parasitology, medicine.disease, biology.organism_classification, Toxoplasmosis, Red Meat, Toxoplasmosis, Animal, Cats, Female, Parasitology, Digestion, Toxoplasma
Abstract: Among the meat sources of Toxoplasma gondii, pork is considered important in the epidemiology of toxoplasmosis in the USA. How soon after infection T. gondii forms tissue cysts in pork is unknown. In the present study, eight serologically negative ˜3 months old pigs were fed mouse tissues infected with VEG (Type III) strain of T. gondii and euthanized 7 (4 pigs) and 14 days (4 pigs) post-inoculation (p.i.). Meat from the right shoulder of each pig was bioassayed in mice for T. gondii tissue cysts by peptic digestion. From each pig, the shoulder muscle was cut at random spots into 5 g, 10 g and 50 g portions. Extreme care was taken to use different scalpels and forceps to minimize cross contamination among 17 samples (6 replicates of each 5 g and 10 g portions and 5 replicates of 50 g). From the four pigs euthanized at 7 days p.i., a composite of ˜200 g of leftover meat from each shoulder was bioassayed in cats and their feces were tested for oocyst excretion. All eight pigs developed T. gondii antibodies (modified agglutination test, MAT, 1: 80 or higher) and viable T. gondii was isolated from shoulder meat of each pig. All four cats fed pork from excreted T. gondii oocysts. The density of T. gondii, based on mouse infectivity, varied within 5–50 g samples each pig, and between pigs within the same group, day 7 versus day 14 p.i. There were no significant differences in mouse bioassay results obtained with day 7 versus day 14 infected pigs. Overall, the rate of isolation of T. gondii increased with sample size of meat bioassayed. Results demonstrate that tissue cysts are formed early in infection and they are unevenly distributed.
Published: 2019
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109. Role of NADPH oxidase versus neutrophil proteases in antimicrobial host defense.

Author: R Robert Vethanayagam, Nikolaos G Almyroudis, Melissa J Grimm, David C Lewandowski, Christine T N Pham, Timothy S Blackwell, Ruta Petraitiene, Vidmantas Petraitis, Thomas J Walsh, Constantin F Urban, and Brahm H Segal
Subjects: Medicine, Science
Abstract: NADPH oxidase is a crucial enzyme in mediating antimicrobial host defense and in regulating inflammation. Patients with chronic granulomatous disease, an inherited disorder of NADPH oxidase in which phagocytes are defective in generation of reactive oxidant intermediates (ROIs), suffer from life-threatening bacterial and fungal infections. The mechanisms by which NADPH oxidase mediate host defense are unclear. In addition to ROI generation, neutrophil NADPH oxidase activation is linked to the release of sequestered proteases that are posited to be critical effectors of host defense. To definitively determine the contribution of NADPH oxidase versus neutrophil serine proteases, we evaluated susceptibility to fungal and bacterial infection in mice with engineered disruptions of these pathways. NADPH oxidase-deficient mice (p47(phox-/-)) were highly susceptible to pulmonary infection with Aspergillus fumigatus. In contrast, double knockout neutrophil elastase (NE)(-/-)×cathepsin G (CG)(-/-) mice and lysosomal cysteine protease cathepsin C/dipeptidyl peptidase I (DPPI)-deficient mice that are defective in neutrophil serine protease activation demonstrated no impairment in antifungal host defense. In separate studies of systemic Burkholderia cepacia infection, uniform fatality occurred in p47(phox-/-) mice, whereas NE(-/-)×CG(-/-) mice cleared infection. Together, these results show a critical role for NADPH oxidase in antimicrobial host defense against A. fumigatus and B. cepacia, whereas the proteases we evaluated were dispensable. Our results indicate that NADPH oxidase dependent pathways separate from neutrophil serine protease activation are required for host defense against specific pathogens.
Published: 2011
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110. Bilateral periventricular nodular heterotopia – neonatal cranial ultrasound.

Author: A R Horn, A Nel, and M F Urban
Subjects: Ultrasound, Heterotopia, Infant, Medical physics. Medical radiology. Nuclear medicine, R895-920
Abstract: A female neonate was delivered at 30 weeks’ gestation to a mother with suspected bilateral periventricular nodular heterotopia (PNH) on computed tomography brain scan. Antenatal ultrasound (US) performed at 28 weeks’ gestation showed mild lateral cerebral ventricle dilatation, but no other fetal anomalies. Clinical examination revealed mild dysmorphic features: facial and skull asymmetry, square-shaped ears, and long tapering fingers. Chromosomal analysis showed a 46XX karyotype.
Published: 2010
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111. Neutrophil extracellular traps contain calprotectin, a cytosolic protein complex involved in host defense against Candida albicans.

Author: Constantin F Urban, David Ermert, Monika Schmid, Ulrike Abu-Abed, Christian Goosmann, Wolfgang Nacken, Volker Brinkmann, Peter R Jungblut, and Arturo Zychlinsky
Subjects: Immunologic diseases. Allergy, RC581-607, Biology (General), QH301-705.5
Abstract: Neutrophils are the first line of defense at the site of an infection. They encounter and kill microbes intracellularly upon phagocytosis or extracellularly by degranulation of antimicrobial proteins and the release of Neutrophil Extracellular Traps (NETs). NETs were shown to ensnare and kill microbes. However, their complete protein composition and the antimicrobial mechanism are not well understood. Using a proteomic approach, we identified 24 NET-associated proteins. Quantitative analysis of these proteins and high resolution electron microscopy showed that NETs consist of modified nucleosomes and a stringent selection of other proteins. In contrast to previous results, we found several NET proteins that are cytoplasmic in unstimulated neutrophils. We demonstrated that of those proteins, the antimicrobial heterodimer calprotectin is released in NETs as the major antifungal component. Absence of calprotectin in NETs resulted in complete loss of antifungal activity in vitro. Analysis of three different Candida albicans in vivo infection models indicated that NET formation is a hitherto unrecognized route of calprotectin release. By comparing wild-type and calprotectin-deficient animals we found that calprotectin is crucial for the clearance of infection. Taken together, the present investigations confirmed the antifungal activity of calprotectin in vitro and, moreover, demonstrated that it contributes to effective host defense against C. albicans in vivo. We showed for the first time that a proportion of calprotectin is bound to NETs in vitro and in vivo.
Published: 2009
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112. Retnla (relmalpha/fizz1) suppresses helminth-induced Th2-type immunity.

Author: John T Pesce, Thirumalai R Ramalingam, Mark S Wilson, Margaret M Mentink-Kane, Robert W Thompson, Allen W Cheever, Joseph F Urban, and Thomas A Wynn
Subjects: Immunologic diseases. Allergy, RC581-607, Biology (General), QH301-705.5
Abstract: Retnla (Resistin-like molecule alpha/FIZZ1) is induced during Th2 cytokine immune responses. However, the role of Retnla in Th2-type immunity is unknown. Here, using Retnla(-/-) mice and three distinct helminth models, we show that Retnla functions as a negative regulator of Th2 responses. Pulmonary granuloma formation induced by the eggs of the helminth parasite Schistosoma mansoni is dependent on IL-4 and IL-13 and associated with marked increases in Retnla expression. We found that both primary and secondary pulmonary granuloma formation were exacerbated in the absence of Retlna. The number of granuloma-associated eosinophils and serum IgE titers were also enhanced. Moreover, when chronically infected with S. mansoni cercariae, Retnla(-/-) mice displayed significant increases in granulomatous inflammation in the liver and the development of fibrosis and progression to hepatosplenic disease was markedly augmented. Finally, Retnla(-/-) mice infected with the gastrointestinal (GI) parasite Nippostrongylus brasiliensis had intensified lung pathology to migrating larvae, reduced fecundity, and accelerated expulsion of adult worms from the intestine, suggesting Th2 immunity was enhanced. When their immune responses were compared, helminth infected Retnla(-/-) mice developed stronger Th2 responses, which could be reversed by exogenous rRelmalpha treatment. Studies with several cytokine knockout mice showed that expression of Retnla was dependent on IL-4 and IL-13 and inhibited by IFN-gamma, while tissue localization and cell isolation experiments indicated that eosinophils and epithelial cells were the primary producers of Retnla in the liver and lung, respectively. Thus, the Th2-inducible gene Retnla suppresses resistance to GI nematode infection, pulmonary granulomatous inflammation, and fibrosis by negatively regulating Th2-dependent responses.
Published: 2009
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113. Impact of Micronutrients on the Immune Response of Animals

Author: Joseph F. Urban, Harry D. Dawson, Kiran S. Panickar, and Allen Smith
Subjects: 0301 basic medicine, Inflammation, Biology, 03 medical and health sciences, Immune system, Genetics, medicine, Animals, Humans, Microbiome, Phagocytic Cell, Mammals, 030109 nutrition & dietetics, Innate immune system, General Veterinary, Innate lymphoid cell, Avitaminosis, Vitamins, Acquired immune system, Micronutrient, Trace Elements, 030104 developmental biology, Immune System, Immunology, Animal Science and Zoology, medicine.symptom, Biotechnology
Abstract: Vitamins and minerals (micronutrients) play an important role in regulating and shaping an immune response. Deficiencies generally result in inadequate or dysregulated cellular activity and cytokine expression, thereby affecting the immune response. Decreased levels of natural killer, granulocyte, and phagocytic cell activity and T and B cell proliferation and trafficking are associated with inadequate levels of micronutrients, as well as increased susceptibility to various adverse health conditions, including inflammatory disorders, infection, and altered vaccine efficacy. In addition, most studies of micronutrient modulation of immune responses have been done in rodents and humans, thus limiting application to the health and well-being of livestock and companion animals. This exploratory review elucidates the role of vitamins and minerals on immune function and inflammatory responses in animals (pigs, dogs, cats, horses, goats, sheep, and cattle), with reference to rodents and humans.
Published: 2018
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114. Heavier and darker

Author: F. Urban
Subjects: Physics, 010308 nuclear & particles physics, Space and Planetary Science, 0103 physical sciences, Dark matter, Astronomy and Astrophysics, Astrophysics, 010306 general physics, 01 natural sciences
Published: 2017
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115. IL-4 up-regulates cyclooxygenase-1 expression in macrophages

Author: Ashley E. Shay, Joseph F. Urban, Bo-Jhih Guan, Vivek Narayan, K. Sandeep Prabhu, and Bastihalli T. Diwakar
Subjects: Male, 0301 basic medicine, Immunology, Macrophage polarization, Bone Marrow Cells, AMP-Activated Protein Kinases, Ligands, Biochemistry, Immunomodulation, 03 medical and health sciences, Animals, Humans, Enzyme Inhibitors, Receptor, Protein kinase A, Molecular Biology, Mechanistic target of rapamycin, Cells, Cultured, Interleukin 4, Tissue homeostasis, Strongylida Infections, biology, Prostaglandin D2, Macrophages, Models, Immunological, Membrane Proteins, Interleukin, AMPK, Cell Biology, Macrophage Activation, Metformin, Recombinant Proteins, Cell biology, Enzyme Activation, Mice, Inbred C57BL, Luminescent Proteins, HEK293 Cells, 030104 developmental biology, Enzyme Induction, Cyclooxygenase 1, biology.protein, Interleukin-4, Nippostrongylus
Abstract: Macrophages use various cell-surface receptors to sense their environment and undergo polarized responses. The cytokines, interleukin (IL)-4 and IL-13, released from T-helper type 2 (Th2) cells, drive macrophage polarization toward an alternatively activated phenotype (M2). This phenotype is associated with the expression of potent pro-resolving mediators, such as the prostaglandin (PG) D2-derived cyclopentenone metabolite, 15d-PGJ2, produced by the cyclooxygenase (Ptgs; Cox) pathway. Interestingly, IL-4 treatment of bone marrow-derived macrophages (BMDMs) significantly down-regulates Cox-2 protein expression, whereas Cox-1 levels are significantly increased. This phenomenon not only challenges the dogma that Cox-1 is only developmentally regulated, but also demonstrates a novel mechanism in which IL-4-dependent regulation of Cox-1 involves the activation of the mechanistic target of rapamycin complex (mTORC). Using specific chemical inhibitors, we demonstrate here that IL-4-dependent Cox-1 up-regulation occurs at the post-transcriptional level via the Fes-Akt-mTORC axis. Activation of AMP-activated protein kinase (AMPK) by metformin, inhibition of mTORC by torin 1, or CRISPR/Cas9-mediated genetic knock-out of tuberous sclerosis complex-2 (Tsc2) blocked the IL-4-dependent expression of Cox-1 and the ability of macrophages to polarize to M2. However, use of 15d-PGJ2 partially rescued the effects of AMPK activation, suggesting the importance of Cox-1 in macrophage polarization as also observed in a model of gastrointestinal helminth clearance. In summary, these findings suggest a new paradigm where IL-4-dependent up-regulation of Cox-1 expression may play a key role in tissue homeostasis and wound healing during Th2-mediated immune responses, such as parasitic infections.
Published: 2017
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116. Macroscopic Modeling of the Linear Viscoelastic Vibration Behavior of Short Fiber Reinforced Plastics

Author: P. Middendorf and F. Urban
Published: 2020
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117. Determination of formation energies and phase diagrams of transition metal oxides with DFT+U

Author: Christian Elsässer, Daniel F. Urban, Daniel Mutter, and Publica
Subjects: Work (thermodynamics), Materials science, general_materials_science, materials modeling, Iron oxide, Oxide, Thermodynamics, transition metal oxide, lcsh:Technology, Article, chemistry.chemical_compound, Atomic orbital, Transition metal, Molecule, transition metal oxides, materials modelling, lcsh:Microscopy, density functional theory, lcsh:QC120-168.85, Phase diagram, lcsh:QH201-278.5, lcsh:T, phase diagram, chemistry, lcsh:TA1-2040, lcsh:Descriptive and experimental mechanics, Density functional theory, lcsh:Electrical engineering. Electronics. Nuclear engineering, lcsh:Engineering (General). Civil engineering (General), lcsh:TK1-9971, phase diagrams, DFT+U
Abstract: Knowledge about the formation energies of compounds is essential to derive phase diagrams of multicomponent phases with respect to elemental reservoirs. The determination of formation energies using common (semi-)local exchange-correlation approximations of the density functional theory (DFT) exhibits well-known systematic errors if applied to oxide compounds containing transition metal elements. In this work, we generalize, reevaluate, and discuss a set of approaches proposed and widely applied in the literature to correct for errors arising from the over-binding of the O2 molecule and from correlation effects of electrons in localized transition-metal orbitals. The DFT+U method is exemplarily applied to iron oxide compounds, and a procedure is presented to obtain the U values, which lead to formation energies and electronic band gaps comparable to the experimental values. Using such corrected formation energies, we derive the phase diagrams for LaFeO3, Li5FeO4, and NaFeO2, which are promising materials for energy conversion and storage devices. A scheme is presented to transform the variables of the phase diagrams from the chemical potentials of elemental phases to those of precursor compounds of a solid-state reaction, which represents the experimental synthesis process more appropriately. The discussed workflow of the methods can directly be applied to other transition metal oxides.
Published: 2020

118. First-principles calculation of electroacoustic properties of wurtzite (Al,Sc)N

Author: Christian Elsässer, Oliver Ambacher, Daniel F. Urban, and Publica
Subjects: piezoelectrics, Materials science, chemistry.chemical_element, FOS: Physical sciences, 02 engineering and technology, 01 natural sciences, Condensed Matter::Materials Science, Metastability, 0103 physical sciences, calculations, Scandium, 010306 general physics, Wurtzite crystal structure, Condensed Matter - Materials Science, piezoelectricity, Condensed matter physics, Materials Science (cond-mat.mtrl-sci), first-principles, density functional calculation, 021001 nanoscience & nanotechnology, disordered alloys, Piezoelectricity, Bond length, Molecular geometry, chemistry, Content (measure theory), elasticity, Density functional theory, 0210 nano-technology, Wurtzite
Abstract: We study the electroacoustic properties of aluminum scandium nitride crystals Al$_{1-x}$Sc$_x$N with the metastable wurtzite structure by means of first-principles calculations based on density functional theory. We extract the material property data relevant for electroacoustic device design, namely the full tensors of elastic and piezoelectric constants. Atomistic models were constructed and analyzed for a variety of Sc concentrations $0\le x\le50$ %. The functional dependence of the material properties on the scandium concentration was extracted by fitting the data obtained from an averaging procedure for different disordered atomic configurations. We give an explanation of the observed elastic softening and the extraordinary increase in piezoelectric response as function of Sc content in terms of an element specific analysis of bond lengths and bond angles., Comment: 14 pages, 13 figures
Published: 2020
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119. Eradicating, retaining, balancing, swarming, shuttling and dumping : a myriad of tasks for neutrophils during fungal infection

Author: Emelie Backman and Constantin F. Urban
Subjects: Microbiology (medical), Chemokine, Neutrophils, Phagocytosis, Swarming (honey bee), Biology, Extracellular Traps, Microbiology, 03 medical and health sciences, Immune system, Animals, Humans, 030304 developmental biology, 0303 health sciences, 030306 microbiology, Fungi, Degranulation, Immunology in the medical area, Neutrophil extracellular traps, Antimicrobial, Infectious Diseases, Mycoses, Immunologi inom det medicinska området, Immunology, biology.protein, Cytokines, Intracellular
Abstract: Opportunistic, invasive mycoses in immunocompromised patients remain challenging for health care with unacceptably high levels of morbidity and mortality. Neutrophils are essential in host protection against invasive mycoses. Upon development of acute infection, neutrophils are recruited from circulation to the infected tissue, where they exert a considerable variety of effector functions with the ultimate task to eradicate invading microbes. Effector functions include recognition, phagocytosis and intracellular killing of microorganisms via oxidative and non-oxidative mechanisms, excretion of antimicrobial factors from intracellular storages (degranulation), release of neutrophil extracellular traps (NETs) and of extracellular vesicles (EVs), as well as generation of cytokines and chemokines to modulate immune responses. Herein, we describe recent findings which further our understanding of the roles of neutrophils during opportunistic fungal infections which could serve as starting point for the development of immune-targeted interventions to improve clinical management of affected individuals.
Published: 2020

120. Production and Characterization of ZFP36L1 Antiserum against Recombinant Protein from Escherichia coli

Author: Cao, Heping, Lin, Rui, Ghosh, Sanjukta, Anderson, Richard A., and F. Urban, Joseph, Jr.
Published: 2008
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121. 5-(Hydroxyphenyl)-γ-Valerolactone-Sulfate, a Key Microbial Metabolite of Flavan-3-ols, Is Able to Reach the Brain: Evidence from Different in Silico, In Vitro and In Vivo Experimental Models

Author: Cláudia N. Santos, Nicoletta Brindani, Monia Savi, Claudio Curti, Gloria Solano-Aguilar, Cindy D. Davis, Joseph F. Urban, Inês Figueira, Saebyeol Jang, Maria Alexandra Brito, Donatella Stilli, Cristina Domenech-Coca, Josep M. del Bas, Pedro Mena, Daniele Del Rio, Donato Angelino, Kwang S. Kim, Aleksey Molokin, Furio Brighenti, Cinta Bladé, Diogo Carregosa, and Sukla Lakshman
Subjects: 0301 basic medicine, valerolactone, Swine, In silico, blood brain barrier, lcsh:TX341-641, Blood–brain barrier, Article, Lactones, 03 medical and health sciences, chemistry.chemical_compound, neurodegenerative disease, catechin, In vivo, Flavan, medicine, Animals, Humans, Vitis, Pentanoic Acids, proanthocyanidin, flavan-3-ol, metabolites, polyphenols, Blood brain barrier, Catechin, Flavan-3-ol, Gut, Metabolites, Neurodegenerative disease, Permeability, Polyphenols, Proanthocyanidin, Valerolactone, Flavonoids, Cacao, 030109 nutrition & dietetics, Nutrition and Dietetics, Plant Extracts, Sulfates, Cocoa Extract, Brain, Endothelial Cells, Models, Theoretical, In vitro, Rats, 030104 developmental biology, medicine.anatomical_structure, chemistry, Biochemistry, Blood-Brain Barrier, Polyphenol, gut, permeability, lcsh:Nutrition. Foods and food supply, Food Science
Abstract: Phenolic compounds have been recognized as promising compounds for the prevention of chronic diseases, including neurodegenerative ones. However, phenolics like flavan-3-ols (F3O) are poorly absorbed along the gastrointestinal tract and structurally rearranged by gut microbiota, yielding smaller and more polar metabolites like phenyl-&gamma, valerolactones, phenylvaleric acids and their conjugates. The present work investigated the ability of F3O-derived metabolites to cross the blood-brain barrier (BBB), by linking five experimental models with increasing realism. First, an in silico study examined the physical-chemical characteristics of F3O metabolites to predict those most likely to cross the BBB. Some of these metabolites were then tested at physiological concentrations to cross the luminal and abluminal membranes of brain microvascular endothelial cells, cultured in vitro. Finally, three different in vivo studies in rats injected with pure 5-(3&prime, 4&prime, dihydroxyphenyl)-&gamma, valerolactone, and rats and pigs fed grapes or a F3O-rich cocoa extract, respectively, confirmed the presence of 5-(hydroxyphenyl)-&gamma, valerolactone-sulfate (3&prime, isomer) in the brain. This work highlighted, with different experimental models, the BBB permeability of one of the main F3O-derived metabolites. It may support the neuroprotective effects of phenolic-rich foods in the frame of the &ldquo, gut-brain axis&rdquo
Published: 2019

122. Finite Element Analysis of SAW Propagation Characteristics in c-plane (0001) and a-plane (11-20) AlScN Thin Films

Author: Nicolas Kurz, Agne Zukauskaite, Daniel F. Urban, Bjoern Christian, Niclas M. Feil, Oliver Ambacher, Abdullah Altayara, and Anli Ding
Subjects: 010302 applied physics, Electromechanical coupling coefficient, Coupling, Materials science, Condensed matter physics, Plane (geometry), Surface acoustic wave, 02 engineering and technology, 021001 nanoscience & nanotechnology, 01 natural sciences, Piezoelectricity, Finite element method, 0103 physical sciences, Radio frequency, Phase velocity, 0210 nano-technology
Abstract: Al 1−x Sc x N (AlScN) is known for its large elastic and piezoelectric constants and thus is a favorable material for applications in novel radio frequency (RF) components. We investigated a-plane AlScN on r-plane Al 2 O 3 (AlScN(11-20)/Al 2 O 3 (1-102)). The surface acoustic wave (SAW) propagation properties of AlScN(11-20)/Al 2 O 3 (1-102) and AlScN(11-20)/Al 2 O 3 (1-102) were analyzed using finite element method (FEM) simulations and the results were compared. Rayleigh-type and Sezawa-type wave modes were identified and the acoustic parameters such as phase velocity, electromechanical coupling coefficient, and reflectivity were evaluated. An increased effective coupling of 5.5 % was detected for Rayleigh-type waves on AlScN(11-20)/Al 2 O 3 (1-102). The Sezawa-type modes show an even higher coupling up to 6.2 %. Furthermore, we detected increased reflectivity of AlScN(11-20) films compared to c-plane AlScN(0001). Our results reveal the potential of using a-plane AlScN for increasing the electromechanical coupling, which is needed for the upcoming piezo-acoustic filter requirements.
Published: 2019
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123. BHLHE40 Promotes T

Author: Nicholas N, Jarjour, Tara R, Bradstreet, Elizabeth A, Schwarzkopf, Melissa E, Cook, Chin-Wen, Lai, Stanley Ching-Cheng, Huang, Reshma, Taneja, Thaddeus S, Stappenbeck, Steven J, Van Dyken, Joseph F, Urban, and Brian T, Edelson
Subjects: Homeodomain Proteins, Mice, Knockout, Immunity, Cellular, Nematospiroides dubius, Mucous Membrane, Transcription, Genetic, Granulocyte-Macrophage Colony-Stimulating Factor, Article, Cytokine Receptor Common beta Subunit, Disease Models, Animal, Mice, Th2 Cells, parasitic diseases, Basic Helix-Loop-Helix Transcription Factors, Animals, Female, Interleukin-5, Strongylida Infections
Abstract: The transcription factor BHLHE40 is an emerging regulator of the immune system. Recent studies suggest that BHLHE40 regulates type 2 immunity, but this has not been demonstrated in vivo. We found that BHLHE40 is required in T cells for a protective T(H)2 cell response in mice infected with the helminth Heligmosomoides polygyrus bakeri (H. polygyrus). H. polygyrus elicited changes in gene and cytokine expression by lamina propria CD4(+) T cells, many of which were BHLHE40-dependent, including production of the common beta (β(C), CSF2RB) chain family cytokines GM-CSF and IL-5. In contrast to deficiency in GM-CSF or IL-5 alone, loss of both GM-CSF and IL-5 signaling impaired protection against H. polygyrus. Overall, we show that BHLHE40 regulates the T(H)2 cell transcriptional program during helminth infection to support normal expression of Csf2, Il5, and other genes required for protection and reveal unexpected redundancy of β(C) chain-dependent cytokines previously thought to possess substantially divergent functions.
Published: 2019

124. Visualizing Hypoxia in a Murine Model of Candida albicans Infection Using in vivo Biofluorencence

Author: José Pedro Lopes and Constantin F. Urban
Subjects: Candida albicans infection, Systemic disease, biology, Strategy and Management, Mechanical Engineering, Metals and Alloys, Fungal pathogen, Hypoxia (medical), biology.organism_classification, medicine.disease, Industrial and Manufacturing Engineering, Microbiology, Immune system, In vivo, Murine model, medicine, Methods Article, medicine.symptom, Candida albicans
Abstract: Candida albicans is a leading human fungal pathogen that uses several metabolic adaptations to escape immune cells and causes systemic disease. Here, we describe a protocol for measuring one of these adaptations, the ability to thrive in hypoxic niches. Hypoxia was generated after successful subdermal infection with C. albicans in a murine infection model. Hypoxia was measured using a fluorescent dye for carbonic anhydrase 9, a host enzyme active under hypoxic conditions. Emitted fluorescence was subsequently quantified using an IVIS system. This protocol was optimized for the use in subdermal infection in mice but has the potential to be adapted to other models of fungal infection.
Published: 2019

125. Neuropeptide CGRP limits group 2 innate lymphoid cell responses and constrains type 2 inflammation

Author: Yuefeng Huang, Yasmine Belkaid, David Artis, Fred P. Davis, Françoise Meylan, Oliver J. Harrison, Hiroyuki Nagashima, Yuka Kanno, Chen Yao, Kathleen M. Caron, John J. O'Shea, Joseph F. Urban, Han-Yu Shih, Yohei Mikami, and Tanel Mahlakõiv
Subjects: 0301 basic medicine, Innate immune system, Lymphocyte, Immunology, Innate lymphoid cell, Interleukin, Inflammation, Calcitonin gene-related peptide, Biology, Article, Interleukin 33, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Infectious Diseases, medicine.anatomical_structure, 030220 oncology & carcinogenesis, medicine, Immunology and Allergy, medicine.symptom, Tissue homeostasis
Abstract: Innate lymphocytes maintain tissue homeostasis at mucosal barriers, with group 2 innate lymphoid cells (ILC2s) producing type 2 cytokines and controlling helminth infection. While the molecular understanding of ILC2 responses has advanced, the complexity of microenvironmental factors impacting ILC2s is becoming increasingly apparent. Herein, we used single-cell analysis to explore the diversity of gene expression among lung lymphocytes during helminth infection. Following infection, we identified a subset of ILC2s that preferentially expressed Il5-encoding interleukin (IL)-5, together with Calca-encoding calcitonin gene-related peptide (CGRP) and its cognate receptor components. CGRP in concert with IL-33 and neuromedin U (NMU) supported IL-5 but constrained IL-13 expression and ILC2 proliferation. Without CGRP signaling, ILC2 responses and worm expulsion were enhanced. Collectively, these data point to CGRP as a context-dependent negative regulatory factor that shapes innate lymphocyte responses to alarmins and neuropeptides during type 2 innate immune responses.
Published: 2019

126. Comparison of Fragmentation Functions for Jets Dominated by Light Quarks and Gluons from pp and Pb+Pb Collisions in ATLAS

Author: Tadamitsu Kishimoto, T. Kuhl, Siarhei Harkusha, Mario Sannino, Eric Hayato Takasugi, Philipp Stolte, Flavia De Almeida Dias, Iacopo Vivarelli, Reda Tafirout, Klaus Kurt Desch, Richard Nickerson, Julia Hrdinka, Jemal Khubua, Francisco Alonso, Arnaud Lucotte, Y. A. Kurochkin, Liza Mijović, E. Torrence, Stephen Watts, Ben Smart, Katsuo Tokushuku, Augusto Santiago Cerqueira, Dmytro Hohov, Alexander Kupco, Edoardo Gorini, F. A. Jimenez Morales, Daniel Turgeman, Magnar Kopangen Bugge, Antonio Giannini, D. Chakraborty, Michael Schernau, Claus Gössling, Benedetto Gorini, Giorgi Arabidze, P. Giromini, Koji Sato, Nedaa Asbah, Janusz Chwastowski, Sharka Todorova-Nova, Fumiya Yamane, Erich Varnes, D. Álvarez Piqueras, S. Yu. Sivoklokov, H. Duran Yildiz, Christian Grefe, Robert Johannes Langenberg, L. Di Ciaccio, Mohammad Jawad Kareem, Stewart Patrick Swift, David Lynn, J. Montejo Berlingen, Pierre-Francois Giraud, A. De Benedetti, M. De Beurs, Huacheng Cai, Ingo Burmeister, Ian Dawson, Alessandra Forti, Vincent Pascuzzi, Xiangyang Ju, Yuta Okazaki, Reiner Hauser, R. J. Sobie, Hasko Stenzel, Kirill Grevtsov, Yann Coadou, Faig Ahmadov, Priscilla Pani, Stephen Maxfield, Bruce Gallop, Diallo Boye, Manuel Neumann, Serhat Istin, Michaela Queitsch-Maitland, Karishma Sekhon, Aaron Angerami, Alejandro Alonso, Gabriele Sabato, Francesco Giuli, Antonios Leisos, Joost Vossebeld, Monica Dobre, Felix Fidelio Klitzner, Rachel Rosten, R. Madar, Gianluca Introzzi, Markus Elsing, T. M. H. Wolf, Camilla Vittori, Pa. Malecki, Lee Sawyer, Arnaud Duperrin, Heather Gray, Katharina Maria Ecker, Atanu Pathak, John Myers, Claude Leroy, Efstathios Karentzos, Ivan Sykora, Chihiro Kozakai, Steven Williams, J. D. Hansen, J. E. Salazar Loyola, Abraham Seiden, Adam Jackson Parker, Andrey Karyukhin, M. Reale, Rafal Staszewski, Jakub Andrzej Kremer, Andreas Hoecker, Atsushi Mizukami, Benjamin Henry Hooberman, Fairouz Malek, Andrew Mehta, Riccardo Vari, Anna Shcherbakova, I. M. Gregor, Tetsuro Mashimo, Luka Kanjir, Peter Charles Mcnamara, Jong-Sung Yu, Maria Pilar Casado, Peter Johannes Falke, Dennis Perepelitsa, Anum Qureshi, Emma Tolley, Jeffrey Rogers Dandoy, Harald Joerg Stelzer, Roman Lysak, Massimo Antonelli, M. Della Pietra, Naim Bora Atlay, Benjamin Jacque Gutelman, H. Zhang, Mats Joakim Robert Olsson, Tomas Sykora, Valery Schegelsky, Sabrina Groh, Jorge Andres Lopez Lopez, Konrad Kleinknecht, S. Farrell, Hiroyuki Iwasaki, John-Bjarne Hansen, E. Le Guirriec, Clement Helsens, Martin Spangenberg, Giuseppe Avolio, Dengfeng Zhang, Masahiro Yamatani, Victor Sorin Martoiu, Bmm Allbrooke, Petr Balek, Timothy Brooks, Massimo Lazzaroni, Simen Hellesund, Teresa Barillari, Oldrich Kepka, Alessandra Baas, Armin Michael Nairz, Marzieh Bahmani, Philipp Jonathan Lösel, Sebastian Heer, Ondrej Hladik, Marine Kuna, Tomas Jakoubek, Krisztian Peters, Valentinos Christodoulou, T. R. V. Billoud, Fumiaki Ito, Philip Sommer, Andrey Ryzhov, Masaki Ishitsuka, N. Benekos, Christoph Eckardt, Kun Liu, Vladimir Zhulanov, P. S. Wells, M. A. Pleier, Qiang Li, Eitan Gozani, Fabrizio Petrucci, Fabrizio Miano, P. Gadow, Michael Hance, A. J. Barr, Sergey Karpov, Halina Abramowicz, Dmitry Golubkov, Katharina Schleicher, W. D. Breaden Madden, Fabian Alexander Förster, J. A. Aparisi Pozo, Laura Jean Bergsten, Gabriella Gaudio, Cecilia Tosciri, Denis Salihagic, M. Shimojima, Kristin Lohwasser, J. G. Panduro Vazquez, Giovanna Cottin, Ksenia Gasnikova, Federico Scutti, Dirk Sammel, Roberto Spighi, Bartlomiej Zabinski, Krzysztof Korcyl, Jihyun Jeong, Christopher Meyer, Sylvain Tisserant, Wolfgang Walkowiak, Jennet Dickinson, E. J. W. Moyse, Stewart Martin-Haugh, H. Bahrasemani, Daniel Whiteson, Masao Saito, Stan Bentvelsen, J. C. Vermeulen, V. Dao, Carlos Escobar, E. D. Mendes Gouveia, Geoffrey Mullier, Terry Richard Wyatt, Fabrice Balli, Douglas Davis, Toshi Sumida, Takuto Kunigo, Haifeng Li, J. Van Nieuwkoop, N. C. Mc Fadden, A. T. Watson, R. Bartoldus, Victor Kukhtin, Petr Hamal, Stefan Richter, Chen Zhou, D. M. Strom, Nurcan Ozturk, Carlos Sandoval, Lydia Beresford, Andreas Warburton, C. A. Marin Tobon, Rosanna Ignazzi, C. Bohm, Haiping Peng, V. V. Lyubushkin, David Rousseau, Serban Protopopescu, Igor Boyko, Jerome Samarati, Kelsey O'Connor, Craig Wiglesworth, Andy Haas, Laser Seymour Kaplan, Bradley Cox, Vladimir Peshekhonov, Ryne Michael Carbone, Xuan Zhang, Yuta Sano, Jiancong Zeng, Gabriele Bertoli, Antonio Zoccoli, Nicholas Adam Styles, Federico Meloni, V. Izzo, A. Rodriguez Perez, G. Calderini, Carmen García, Kerry Ann Parker, M. Villaplana Perez, Iro Koletsou, Yiming Abulaiti, M. Cano Bret, Thomas Trefzger, Elliot Hughes, Daniel Scheirich, D. P. J. Lack, S. Calvente Lopez, Gordon Watts, Nikolaos Tsirintanis, Y. Kulchitsky, Artur Cardoso Coimbra, A. Kobayashi, Joe Taenzer, Kate Shaw, Lorne Levinson, Jahred Adelman, Alain Bellerive, Andrzej Olszewski, Pierfrancesco Butti, Salvatore Bruno, Cheng-Chieh Peng, George Redlinger, Christian Johann Riegel, Anatoly Borisov, A. De Maria, J. Boudreau, Eirik Gramstad, Nils Krumnack, Vojtech Pleskot, Trevor Vickey, Takashi Mitani, Christian Ohm, Alice Polyxeni Morris, Sarah Kate Boutle, T. Dias Do Vale, Xi Chen, Theodoros Alexopoulos, Phillip Gutierrez, Matthew Thomas Anthony, Ruo-yu Shang, Martin Tripiana, Steffen Schmitt, D. Zhang, James Pinfold, Carsten Dulsen, Chikuma Kato, Song-Ming Wang, Andrea Catinaccio, S. Li, Djamel Eddine Boumediene, Kalliopi Iordanidou, Xiaoguang Yue, Tomas Dado, Paul Hanke, Shunichi Akatsuka, Attila Krasznahorkay, Jana Schaarschmidt, Dennis Sperlich, James Shank, Christian Weiser, Jeffrey Wayne Hetherly, Gregor Kramberger, M. U. F Martensson, Seyed Ruhollah Shojaii, Fabio Cardillo, Julius Hrivnac, Petter Nilsson, Rachel Maria Avramidou, Andrew D. Hamilton, Barbara Liberti, G. Carlino, Peter Berta, Despoina Sampsonidou, Peter Steinberg, Wei Guo, Anatoli Romaniouk, Horst Severini, Andrea Messina, Aidan Robson, Giulio Tiziano Forcolin, Andrew Stuart Bell, D. P. Benjamin, Joachim Heinrich, Grazia Cabras, Arthur James Horton, T. Cuhadar Donszelmann, R. S. Orr, Noam Hod, Thu Pham, Gabija Zemaityte, Kouta Onogi, Pawel Klimek, Igor Gavrilenko, Matteo Bauce, Adam Jinaru, H. S. Chen, Antonio Limosani, Raymond Brock, G. Mikenberg, Giovanni Crosetti, Stefania Antonia Stucci, Giovanna Bruni, Klaus Mönig, Filomena Sopkova, William Joseph Johnson, Lewis Joseph Wilkins, Ph. Schune, W-M. Yao, Yong’an Liu, Paolo Massarotti, P. A. Delsart, Nicoletta Garelli, Todd Seiss, Dj. Sijacki, Michael R. Wessels, German D Carrillo-Montoya, Rachael Ann Creager, Paul Jackson, Ozan Arslan, Jared Gregory Vasquez, Anthony Keith Morley, Peter Wagner, Wladyslaw Dabrowski, S. R. Paredes Saenz, Oliver Ricken, Elvedin Tahirovic, Wendy Taylor, Y. Huang, Tsz Yu Ng, T. Ženiš, Pavel Tsiareshka, C. Dallapiccola, Emily McDonald, Ph. Schwemling, Mahmoud Alstaty, Shih-Chang Lee, Patrick Bryant, Flera Rizatdinova, John Derek Chapman, Xanthe Hoad, W. Kozanecki, Andreas Sogaard, Marcella Capua, Katharina Becker, Wasikul Islam, Felix Mueller, Arno Straessner, Jozsef Toth, Elena Korolkova, Wen-Xu Wang, Susumu Terada, Vladimir Smakhtin, Andreas Kugel, J. O. Nielsen, Luis March, Jeannine Wagner-kuhr, F. Khalil-zada, J. Chen, G. Lehmann Miotto, C. M. Vergel Infante, Kerim Suruliz, Monika Wielers, C. F. Feng, Adam Edward Barton, Li Zhou, Eric Lancon, Mohamed Ouchrif, Christopher Willis, Silvia Franchino, A. De Santo, Tobias Bisanz, Tadej Novak, Remco Castelijn, D. P. C. Sankey, Bojan Hiti, Ilaria Luise, Jason Lea Oliver, Katherine Pachal, James Monk, Yao Ming, K. Kordas, James Ferrando, Stephan Hageböck, Alexander Fenyuk, Yuji Enari, T. Javůrek, Maria Roberta Devesa, Igor Potrap, Antonio Policicchio, Markus Atkinson, Graham Richard Lee, Y. Guo, Philipp Horn, Eric Drechsler, Leigh Schaefer, Thilo Pauly, Hideki Okawa, Soumya Mohapatra, M. Silva, M. H. Klein, Stephen Burke, Stéphane Viel, Ana Cueto, Ralf Hertenberger, Ilya Tsukerman, L. Barranco Navarro, A. J. Beddall, Junjie Zhu, Gabriel Alexandru Popeneciu, Marcel Vos, Stephen Hillier, M.A. Haleem, Luis Hervas, D. Boscherini, Thomas Philippe Calvet, O. Le Dortz, Liang Li, Francois Vazeille, Pedro Urrejola, S. H. Robertson, W. Buttinger, C. J. S. Young, M. J. Kobel, Miroslav Myska, Blake Burghgrave, P. Morettini, Gerhard Brandt, Brian Edward Lindquist, Leonid Serkin, Hubert Kroha, Stephen Kam-wah Chan, Werner Spolidoro Freund, Tina Sfiligoj, Saverio D'Auria, Hong Ma, Lara Katharina Schildgen, Cheng Guang Zhu, Azzah Aziz Alshehri, Zuzana Barnovska-Blenessy, Thomas Daubney, Evgeniya Cheremushkina, Carla Sbarra, Paris Moschovakos, P. Mättig, A. Di Girolamo, Ludovic Michel Scyboz, Vakhtang Tsulaia, Michal Suk, Shoji Asai, Claire Malone, Oliver Stelzer-Chilton, Oliver James Winston, Yongsun Kim, Elisabeth Schopf, Olga Igonkina, Sarah Jones, Calliope Louisa Sotiropoulou, Monica D'Onofrio, A. Bruni, Markus Wobisch, Masahiro Ikeno, Robert Kehoe, Renat Sadykov, P. J. Clark, Edmund Dawe, Stefano Zambito, Andrea Dell'Acqua, Masato Aoki, James Walder, Robert Leone, Petar Bokan, Silvia Resconi, Mazuza Ghneimat, Tim Adye, Grigore Tarna, Loan Truong, Marcel Vreeswijk, Verena Maria Walbrecht, R. D. Kass, Zdenek Hubacek, Frederic Derue, T. Moa, Giorgio Chiarelli, Mario Campanelli, K. K. Gan, Andrej Filipcic, Lingshan Xu, Pavel Podberezko, Alexandra Tudorache, Brian Petersen, Namig Javadov, Siegfried Bethke, Caterina Doglioni, Stanislav Tokár, J. Ocariz, Tamar Djobava, Petr Andreevich Gorbounov, Irakli Minashvili, Louis Guillaume Gagnon, Sinan Kuday, Zachary Alden Meadows, Richard Polifka, Miaoran Lu, Luca Colasurdo, R. Camacho Toro, Mariyan Petrov, L. F. Oleiro Seabra, Alexander Zaitsev, Adrian Chitan, Zeno Dixon Greenwood, Jason Tyler Colt Barkeloo, Sebastian Wahrmund, Jeroen Schouwenberg, Lidija Živković, Benjamin Wynne, A. De Salvo, Radek Novotny, Andrew Buckley, Koji Terashi, Takahiro Fusayasu, Marumi Kado, Martin White, Eric Feng, Sahal Yacoob, Oleg Solovyanov, Ulrike Schnoor, Kristof Schmieden, Danuta Kisielewska, Margherita Spalla, Marie Christine Lanfermann, Nils Flaschel, C. N. P. Gee, Artem Basalaev, Kamil Augsten, A. M. Henriques Correia, Joseph Stanford Ennis, Karel Smolek, Werner Wiedenmann, Craig Buttar, M-S. Barisits, Jyoti Prakash Biswal, Henrik Oppen, Jing Wang, Fred Wickens, Juraj Bracinik, Yoichi Ninomiya, J. Del Peso, Tim Jones, Giuseppe Mornacchi, David Martin Bjergaard, Manuel Patrice Geisler, A. Tarek Abouelfadl Mohamed, Borut Paul Kerševan, Michele Livan, Q. J. Li, Thomas Lohse, Annick Lleres, Lydia Roos, Yi-Tao Wang, Gino Marceca, Kazuya Mochizuki, D. V. Dedovich, Jean-Francois Grivaz, Jiri Hejbal, Vadim Bednyakov, Kotaro Wakamiya, K. Potamianos, T. Vazquez Schroeder, Michaela Mlynarikova, Trine Poulsen, P. de Jong, Christopher Samuel Pollard, Claudio Luci, Patrawan Pasuwan, Driss Benchekroun, M. Pedersen, Timothy Barklow, Daria Zieminska, C. A. Chavez Barajas, Sebastian Liem, Mutsuto Hagihara, Marco Vanadia, P. C. F. Glaysher, Andrei Snesarev, Joao Saraiva, Otilia Anamaria Ducu, S. L. Lloyd, Ahmimed Ouraou, S.-C. Hsu, Koichi Nagai, Marcin Wladyslaw Wolter, O. Bessidskaia Bylund, Heberth Torres, Kunihiro Nagano, Maddalena Giulini, Chikara Fukunaga, Alessandra Betti, David Richard Shope, Alan Litke, Mieczyslaw Witold Krasny, Friedrich Hoenig, J. S. Lange, Giancarlo Panizzo, Fares Djama, Torsten Paul Ake Åkesson, Mateusz Dyndal, Adrian Buzatu, Ewelina Lobodzinska, Carlo Schiavi, Anna Macchiolo, Stanley Lai, Samuel Webb, L. K. Gladilin, Eram Rizvi, John Rutherfoord, Florian Urs Bernlochner, Dwayne Patrick Spiteri, Philipp Mogg, Z. Xi, Guido Gagliardi, Fabian-Phillipp Tepel, Laurelle Maria Veloce, Cristina Galea, H. F-W. 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Benhar Noccioli, Ariel Schwartzman, Chung-Yau Lo, Yousuke Kataoka, Vladimir Nikolaenko, E. B. F. G. Knoops, Francesco Guescini, Paolo Mastrandrea, Maarten Boonekamp, Andrey Kiryunin, Peter Nemethy, M. D. M. Capeans Garrido, Elizaveta Shabalina, Harry James Moss, Sanmay Ganguly, Antonio Sbrizzi, Pierre Petroff, Nansi Andari, Lianyou Shan, Richard Nisius, Fridolin Dittus, Ehud Duchovni, Sergey Denisov, Fabian Thiele, Timothy Andeen, Viviana Cavaliere, William James Fawcett, Melissa Ridel, Deshan Kavishka Abhayasinghe, Sebastien Rettie, Amal Vaidya, J. Barreiro Guimarães da Costa, Michela Paganini, Michael Bender, Sergey Burdin, Dmitry Emeliyanov, Yasuhiro Makida, M. Vicente Barreto Pinto, Daniele Madaffari, Francesco Lanni, Daniel Tovey, Nikolai Fomin, Riccardo Poggi, Steve McMahon, Robert Gardner, Joaquin Hoya, Ilias Panagoulias, Andrey Minaenko, Daniel Marley, Calin Alexa, Andrey Soukharev, Claire Antel, Martina Laura Ojeda, Nacim Haddad, Michael Dührssen, Emre Celebi, Nan Lu, S. 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McCarn Deiana, Chiara Roda, Robert Reed, Michael Düren, Tobias Golling, Adam Bailey, Callum Robert Kilby, Eleni Myrto Asimakopoulou, Mark Andrew Pickering, Anton Wolf, D. Berge, Simon Feigl, Carlos Lacasta, Masaya Ishino, Paolo Bagnaia, Evgeny Shulga, Benjamin Weinert, G. Eigen, Mirta Dumancic, F. Bührer, F. Safai Tehrani, Anne-luise Poley, Dimitris Varouchas, Tobias Kupfer, Georgios Zacharis, Alexander Gavrilyuk, Lucian Stefan Ancu, David Delgove, Dorothee Schaile, Frank Fiedler, Giovanni Maccarrone, Vaclav Vrba, Marino Romano, Claudia Bertella, Bartosz Mindur, Antonio Baroncelli, Ulrich Landgraf, Adriana Milic, Antonio Boveia, Gabriel Palacino, Francois Touchard, R. Goncalves Gama, D. Gillberg, Rupert Leitner, Didier Ferrere, Chloe Gray, Luigi Vigani, Edward Diehl, Odette Benary, Marcus Morgenstern, Mihai Caprini, Trisha Farooque, Alexander Paramonov, Peter Sherwood, Pavel Starovoitov, Bernhard Meirose, William Axel Leight, Vadim Gratchev, Xuai Zhuang, Samira Hassani, A. T. 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A. M. Wiik-Fuchs, Nathan Rogers Bernard, Driss Goujdami, Giulio Usai, Pepijn Johannes Bakker, M. Miñano Moya, Claudia Merlassino, Balazs Konya, Henry Lubatti, Marta Maria Perego, E. Yu. Soldatov, Raquel Pezoa, Louis D'eramo, Niklaus Lehmann, Marco Fraternali, Peyton Rose, Baptiste Abeloos, Thibault Guillemin, Umar Gul, Ian Brock, Jan Schaeffer, Peter Tornambe, Trygve Buanes, S. P. Y. Yuen, D. Paredes Hernandez, K. O. H. Vadla, Olaf Nackenhorst, R. Kowalewski, Chiara Debenedetti, S. González de la Hoz, Bernard Brickwedde, M. Beretta, J. Tanaka, Y. Hernández Jiménez, Apostolos Tsirigotis, Lukasz Zwalinski, Andreas Reiss, Peter Hansen, Masahiro Morinaga, Xiao-yan Li, Sheena Schier, Peter Kodys, D. Levin, Karsten Köneke, E. von Toerne, Sergey Senkin, Julien Caudron, Rachid Mazini, Joyful Elma Mdhluli, Bo Liu, Veysi Erkcan Ozcan, Juan Pedro Ochoa-Ricoux, Venugopal Ellajosyula, M. Mikuž, Andrea Sciandra, Peter Jenni, V. S. Bobrovnikov, Akanksha Vishwakarma, Silvia Biondi, Alessia Murrone, Peter Buchholz, Arka Santra, K. F. Di Petrillo, J. L. La Rosa Navarro, Zdenek Dolezal, Mark Sutton, D. Pohl, Lorenz Hauswald, Simon Berlendis, Thomas Naumann, Abdeslam Hoummada, M. C. N. Fiolhais, Georges Aad, Laura Jeanty, Evgeniy Khramov, Alberto Mengarelli, P. D. Thompson, Jonathan Long, Efe Yigitbasi, S. A. Olivares Pino, Saminder Dhaliwal, Riccardo-Maria Bianchi, M. Rescigno, Joseph Izen, Ruslan Mashinistov, Quentin Buat, Alessandra Ciocio, K. Sliwa, Will Davey, Maria Giulia Ratti, J. Kroll, A. Pacheco Pages, Nguyen Phuong Dang, Hidetoshi Otono, Tasneem Rashid, Carmen Maidantchik, L. Manhaes de Andrade Filho, A. P. Pereira Peixoto, Hiroshi Sakamoto, T. S. Lau, Farida Fassi, Uladzimir Kruchonak, R. W. L. Jones, Cristian Stanescu, Ovsat Abdinov, Ismet Siral, Dimitrios Iliadis, Antoine Laudrain, Christopher Grud, Savannah Jennifer Thais, A. G. Clark, Nora Emilia Pettersson, Margaret Susan Lutz, A. Korn, Oliver Majersky, Robert Hankache, Josh Mcfayden, Andrew Pilkington, Sabine Crépé-Renaudin, Vitaliano Chiarella, Bobby Samir Acharya, H. A. Neal, Atsuhiko Ochi, Sune Jakobsen, Giacomo Artoni, Jessica Metcalfe, Kurt Keys Hill, Stephanie Zimmermann, Chris Hays, Dilip Jana, Barbara Wosiek, A. Soloshenko, Thomas Dennis Powell, Reinhard Schwienhorst, Marc Geisen, Roland Jansky, Sophie Trincaz-Duvoid, Kazuhiko Hara, Martin Florian Bessner, Guillaume Unal, A. Artamonov, Daniela Bortoletto, E. Fullana Torregrosa, Nello Bruscino, James Howarth, M. E. Pozo Astigarraga, Robert Adam Vallance, Irina Antonela Cioara, Matthew Peter Heath, Daniela Salvatore, Tord Ekelof, Monica Verducci, J. Beringer, E. Sideras Haddad, Wade Cameron Fisher, Lj Simic, Osamu Sasaki, S. George, Yongsheng Gao, Mark Kruse, Giacinto Piacquadio, Stephen Haywood, Sotirios Vlachos, Evgeny Starchenko, C. Padilla Aranda, J. Griffiths, Kosuke Takeda, Darren Price, Fedor Prokoshin, Pierre Savard, L. L. Ma, Alison Lister, G. Zhang, Aaron Liblong, Nadezda Proklova, Yun Sang Chow, Paul Fraser Harrison, Takuya Honda, Walter Lampl, D. Oliveira Damazio, Matthew Craig Mondragon, David Cameron, Giulia Ripellino, Julian Constantin Schmoeckel, Mathieu Benoit, Jason Dhia Mansour, Yuji Yamazaki, Lewis James Armitage, Tomasz Bold, R. M. Barnett, Andrea Negri, Alberto Valero, F. Parodi, S. Y. Suzuki, Zinonas Zinonos, Paul Tipton, Allen Mincer, Anatoly Kozhin, S. J. Chen, Ryan Justin Atkin, David Francis, Marcello Fanti, Veronika Magerl, Albert Francis Casha, Robert Stanek, J. Huston, Souad Batlamous, Vanja Morisbak, T. R. Van Daalen, Chrysostomos Valderanis, Stefano Giagu, Alexander Undrus, T. M. Megy, Calum Michael Macdonald, Steven Patrick Alkire, Yohei Yamaguchi, David Miller, Vladimir Vinogradov, Simon Henry Connell, Tatsuya Masubuchi, Oliver Keith Baker, Jiri Kvita, Lucas Macrorie Flores, Filipe Veloso, Nenad Vranjes, Ece Akilli, Nikiforos Nikiforou, Francesca Ungaro, Christopher Potter, Francesco Crescioli, Victoria Jane Martin, Francesco Cirotto, Cecile Deterre, John Alison, Sara Valentinetti, Nicola Semprini-Cesari, S. Chen, Alexey Anisenkov, Nikita Belyaev, Ann Miao Wang, G. Duckeck, Vaclav Vacek, V. Andrei, Federica Legger, Stanislav Pospisil, Clara Troncon, Masaharu Nomachi, Markus Zinser, Robert Keyes, Gabriel Stoicea, David DeMarco, Massimiliano Bellomo, Chris Sander, Grigori Rybkin, Evelin Meoni, J. A. Parsons, Jan Jongmanns, Ester Ricci, Aranzazu Ruiz-Martinez, Stefan Koperny, Julie Kirk, Craig Sawyer, Susanne Kersten, Lorenzo Rossini, James Lacey, D. Di Valentino, Ivan Angelozzi, Stefan Stonjek, Xuanhong Lou, Mark Hodgkinson, Kathryn Grimm, Nikolai Marcel Hartmann, M. Morii, Frank Winklmeier, L. R. Flores Castillo, Emily Charlotte Graham, V. Castillo Gimenez, Jonathan Shlomi, Fabian Kuger, W. Fedorko, Sergey Kuleshov, Revital Kopeliansky, Harshna Jivan, D. M. Portillo Quintero, Alan Peyaud, Magda Anna Chelstowska, Yang Gao, Elliott Cheu, F. Lasagni Manghi, Christine Kourkoumelis, Alexander Mann, Qipeng Hu, Pedro Jorge, Simone Sottocornola, Enrico Junior Schioppa, Henso Abreu, John Huth, Gvantsa Mchedlidze, Shuyang Hu, H. J. Cheng, Mauro Iodice, Lingxin Meng, Aidan Grummer, Sebastian Grinstein, Wolfgang Mader, H. Zhu, Soo Ryu, R. E. Long, Q. Ouyang, Pierre Marc Luzi, Sascha Mehlhase, Sergii Raspopov, Cyril Becot, Michael Huebner, Felix Cormier, H. Kagan, Yanyan Du, Ruggero Turra, Yang Qin, Aviv Ruben Cukierman, Yasushi Nagasaka, Boris Lemmer, R. J. Hawkings, Dave Lewis, Domizia Orestano, Semen Turchikhin, Christopher Anelli, Ian Connelly, L. Pacheco Rodriguez, Ph Gris, Richard Bates, Matt Zhang, P. Johansson, William Trischuk, Maia Mosidze, K. H. Hiller, Theodora Papadopoulou, Raimund Ströhmer, Audrey Ducourthial, Ossama AbouZeid, Helge Christoph Beck, Oxana Smirnova, Konstantinos Bachas, Birgit Sylvia Stapf, Carsten Bittrich, Steffen Maeland, R. D. Schamberger, Pascal Pralavorio, Lamberto Luminari, R. C. W. Henderson, Martin Rybar, Alison Elliot, Maciej Trzebinski, Kyungeon Choi, Laurent Vacavant, Giancarlo Spigo, Kathleen Whalen, Athina Kourkoumeli-Charalampidi, Paul Laycock, Emmanuel Sauvan, Stuart Derek Walker, Gabriella Sciolla, S. De Castro, Thomas Meideck, Hans Peter Beck, Chao Wang, M. J. Shochet, Aimilianos Koulouris, Alexandre Rozanov, Johann Collot, Stephen Albert Weber, Magdalena Slawinska, Shaojun Sun, Louis Fayard, Benoit Lefebvre, Thorwald Klapdor-kleingrothaus, Savanna Marie Shaw, A. Mirto, Michele Pinamonti, Sabine Lammers, T. Kobayashi, Claudio Santoni, Volker Büscher, Stephen Jiggins, J. A. Wilson, Garabed Halladjian, Klaus Hamacher, A. S. Thompson, C. A. Solans Sanchez, Tomas Slavicek, Markus Nordberg, Tatiana Klioutchnikova, Arnaud Dubreuil, Giordon Stark, J. C. Rivera Vergara, P. H. Sales De Bruin, Vakhtang Tsiskaridze, Per Olov Joakim Gradin, J. Jimenez Pena, Jean-Francois Laporte, Andrew Blue, Lidia Dell'Asta, Luca Ambroz, A. T. Goshaw, Smita Darmora, Hernan Wahlberg, Pavel Shatalov, Jochen Dingfelder, Alex Kastanas, Alaettin Serhan Mete, Chaowaroj Wanotayaroj, Fabrice Hubaut, Matthew Berg Epland, Giulia Gonella, J. N. Butler, Anyes Taffard, You Zhou, Heather Lynn Russell, H. De la Torre, F. Rauscher, P. Skubic, Janet Dietrich, Lesya Anna Horyn, Simone Amoroso, John Morris, D. E. Ferreira de Lima, Andrey Kamenshchikov, S. Prell, M. Del Gaudio, Maosen Zhou, Rohin Narayan, Dominik Derendarz, Tom McCarthy, Nima Sherafati, Y. L. Liu, David Calvet, David Sosa, Nicolas Ellis, Stefan Simion, Johan Sebastian Bonilla, Y. S. Ng, S. V. Zeißner, Alexander Melzer, Alan James Taylor, Philip Phillips, Samuel Silverstein, Chav Chhiv Chau, Hajime Nanjo, Matthew Smith, Gregory David Hallewell, Pavol Strizenec, J. Salt, Siegfried Wenig, Yoav Afik, Jiri Dolejsi, P. T. E. Taylor, Alastair Dewhurst, Heinz Pernegger, Alexander Oh, H. H. Williams, Giada Mancini, Archil Durglishvili, Corentin Allaire, Michal Simon, Steinar Stapnes, Ludovico Pontecorvo, Ralf P. Richter, Hok Chuen Cheng, P. K. Teng, Jie Zhang, James H Cochran, Marcela Mikestikova, Matthew Feickert, Sven Menke, Mogens Dam, Hisaya Kurashige, Snezana Nektarijevic, R. El Kosseifi, Harish Potti, Heiko Lacker, Yee Chinn Yap, Josh Moss, H. L. Zhu, Cesare Bini, James Black, Alberto Annovi, Zhen Yan, Michael Kagan, Rodney Walker, David Robert Wardrope, R. K. Keeler, Steffen Schaepe, Enrique Kajomovitz, M. V. Silva Oliveira, Evgenii Baldin, Louis Helary, M. Faucci Giannelli, Jonathan Crane, Karol Krizka, Stefan Gadatsch, Takahiko Kondo, Nicolas Scharmberg, Jun Gao, Mathis Kolb, Eftychia Tzovara, Stephen Sekula, Arthur Schaffer, Xifeng Ruan, Christopher Hayes, Anna Mastroberardino, Bruno Lenzi, David Kirchmeier, Sara Alderweireldt, K. J. C. Leney, D. De Pedis, Alberto Stabile, Iwona Grabowska-Bold, R. Caminal Armadans, A. M. Cooper-Sarkar, R. Di Sipio, T. Lari, Johannes Frederic Damp, C. Zeitnitz, Paolo Sabatini, Maximilian Hils, Alexey Buzykaev, Stefano Camarda, Jennifer Kathryn Roloff, Rinat Fakhrutdinov, A. Juste Rozas, Arnulf Quadt, Jiangyong Jia, Stefano Terzo, Kevin Kroeninger, Helen Hayward, Frederick Dallaire, Nicolo Vladi Biesuz, Alexander Law, Miha Zgubic, Cherifa Sabrina Amrouche, Antonio Ereditato, Elena Rocco, S. Campana, Annabelle Julia Chuinard, Silvia Fressard-Batraneanu, Takashi Yamanaka, P. M. Watkins, Elemer Nagy, Shunsuke Honda, Adam Kaluza, Veronique Boisvert, Colleen Jennifer Treado, Harinder Singh Bawa, Oliver Kortner, Hrachya Hakobyan, Christophe Clement, Rosy Nicolaidou, Katharina Bierwagen, Brigitte Vachon, Arthur Eugen Bolz, Vincenzo Canale, Benjamin William Allen, Stefanie Todt, Kenneth Wraight, Yu-Ting Shen, S. Yu. Smirnov, T. Yamazaki, Janna Katharina Behr, Yury Smirnov, Charles William Kalderon, Sebastian Artz, J. Proudfoot, James Andrew Kendrick, Johannes Donatus Mellenthin, Jakub Cúth, Matej Melo, Lorenzo Feligioni, Irinel Caprini, Alexander Cheplakov, S. R. Hou, S. Errede, Valerio Vercesi, Ellis Kay, Kazuki Todome, Mossadek Talby, Lucrezia Stella Bruni, W. J. Murray, Nico Madysa, Kevin Thomas Bauer, Aaron Michael Soffa, Jean-Pierre Meyer, John Andrew Raine, Philipp Fleischmann, Tatyana Kharlamova, Benedict Tobias Winter, C. Young, Kilian Rosbach, Gabriela Navarro, Veronica Fabiani, M. El Kacimi, Akira Yamamoto, Giovanni Siragusa, Balthasar Maria Schachtner, Tulin Varol, Lukas Heinrich, H. Ten Kate, Simona Serena Bocchetta, A. Ventura, Petr Sicho, R. S. P. Mueller, Jianqiao Ye, Marco Lavorgna, Frederic Deliot, David Salek, Jacob Henry Rawling, C. Di Donato, Francesco Spanò, O. M. Kind, Giuseppe Salamanna, Ines Ochoa, K. J. Anderson, S. Yang, Zuzana Rurikova, V. Araujo Ferraz, F. J. Munoz Sanchez, Emma Sian Kuwertz, Joseph Haley, F. Wang, Y. Amaral Coutinho, Laurent Schoeffel, Y. W. Liu, Andrea Sansoni, Wei Wang, Martine Bosman, Sergio Gonzalez-Sevilla, Michael Pitt, Jovan Mitrevski, Murrough Landon, Hongfang Liu, Margherita Primavera, Daniel Lawrence Briglin, Dave Charlton, Rachel Hyneman, Hulin Wang, Monique A. M. Gignac, Hansdieter Schweiger, Corinne Goy, Victor Maleev, Karl Jakobs, James Boyd, Carlo Enrico Pandini, Nicolas Morange, Joseph Reichert, Markus Schumacher, D. Shoaleh Saadi, Anjishnu Bandyopadhyay, G. A. Chelkov, Shogo Kido, Michael David Werner, Ioannis Nomidis, Gideon Bella, D. Fassouliotis, Konstantin Toms, Jacqueline Batley, Manuela Venturi, Babar Ali, Kerstin Tackmann, Olga Novgorodova, D. Su, Vincent Hedberg, Andrea Favareto, Yang Yang, A. Ferrer, Bengt Lund-Jensen, Valerio Bortolotto, Susumu Oda, J. S. Keller, Aaron Foley Webb, Alexi Gongadze, Giovanni Darbo, Marianna Testa, Holly Ann Pacey, Graeme Stewart, Mattias Ellert, M. Losada, P. M. Tuts, Lene Bryngemark, Gianluca Alimonti, Rainer Stamen, Franziska Iltzsche, Jacob Julian Kempster, Christos Anastopoulos, Bianca Osculati, Stanislav Suchek, James Frost, Pier-Olivier Deviveiros, Jonas Strandberg, David Malon, and Anna Kaczmarska
Subjects: Physics, Large Hadron Collider, Photon, Astrophysics::High Energy Astrophysical Phenomena, General Physics and Astronomy, Parton, 01 natural sciences, Charged particle, Nuclear physics, Fragmentation (mass spectrometry), 0103 physical sciences, Quark–gluon plasma, High Energy Physics::Experiment, Nuclear Experiment, 010306 general physics, Nucleon, Jet quenching
Abstract: Charged-particle fragmentation functions for jets azimuthally balanced by a high-transverse-momentum, prompt, isolated photon are measured in 25 pb^{-1} of pp and 0.49 nb^{-1} of Pb+Pb collision data at 5.02 TeV per nucleon pair recorded with the ATLAS detector at the Large Hadron Collider. The measurements are compared to predictions of Monte Carlo generators and to measurements of inclusively selected jets. In pp collisions, a different jet fragmentation function in photon-tagged events from that in inclusive jet events arises from the difference in fragmentation between light quarks and gluons. The ratios of the fragmentation functions in Pb+Pb events to that in pp events are used to explore the parton color-charge dependence of jet quenching in the hot medium. In relatively peripheral collisions, fragmentation functions exhibit a similar modification pattern for photon-tagged and inclusive jets. However, photon-tagged jets are observed to have larger modifications than inclusive jets in central Pb+Pb events.
Published: 2019
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127. Deficiency in Bhlhe40 impairs resistance toH. polygyrus bakeriand reveals novel Csf2rb-dependent regulation of anti-helminth immunity

Author: Stanley Ching-Cheng Huang, Elizabeth A. Schwarzkopf, Tara R. Bradstreet, Reshma Taneja, Brian T. Edelson, Thaddeus S. Stappenbeck, Joseph F. Urban, Steven J. Van Dyken, Chin-Wen Lai, Nicholas N. Jarjour, and Melissa E. Cook
Subjects: 0303 health sciences, Lamina propria, medicine.medical_treatment, Regulator, Biology, biology.organism_classification, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, medicine.anatomical_structure, Cytokine, Immunity, Immunology, parasitic diseases, medicine, Heligmosomoides polygyrus, Beta (finance), Gene, Transcription factor, 030304 developmental biology, 030215 immunology
Abstract: The cytokines GM-CSF and IL-5 are thought to possess largely divergent functions despite a shared dependence on the common beta (βC) chain to initiate signaling. Although IL-5 is part of the core type 2 cytokine signature and is required for protection against some helminths, it is dispensable for immunity to others, such asHeligmosomoides polygyrus bakeri(H. polygyrus). Whether this is due to compensatory mechanisms is unclear. The transcription factor Bhlhe40 has been shown to control GM-CSF production and is proposed to be a novel regulator of T helper type 2 cells. We have found that Bhlhe40 is required in T cells for a protective memory response to secondaryH. polygyrusinfection.H. polygyrusrechallenge elicited dramatic Bhlhe40-dependent changes in gene and cytokine expression by lamina propria CD4+T cells andin vitro-polarized TH2 cells, including induction of GM-CSF and maximal production of type 2 cytokines including IL-5. βCchain-deficient, but not GM-CSF-deficient, mice rechallenged withH. polygyrushad severely impaired protective immunity. Our results demonstrate that Bhlhe40 is an essential regulator of TH2 cell immunity during helminth infection and reveal unexpected redundancy of βCchain-dependent cytokines.
Published: 2019
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128. Dietary Patterns Differentially Affect Microbiome Composition and Function in a Porcine Model of Obesity-related Metabolic Disorder (OR23-04-19)

Author: R. Gupta, Michael S. Humphrys, Masoumeh Sikaroodi, Monika Proszkowiec-Weglarz, Ethiopia Beshah, Bryan T. Vinyard, Maura E Walker, Patrick M. Gillevet, Gloria Solano-Aguilar, Victoria Lozano, Jonathan Shao, Aleksey Molokin, Alice H. Lichtenstein, Nirupa R Matthan, Joseph F. Urban, Sukla Lakshman, Saebyeol Jang, and Stefania Lamon-Fava
Subjects: Genetics, Nutrition and Dietetics, Diet therapy, Metabolic disorder, Medicine (miscellaneous), Unsaturated Dietary Fats, Biology, Affect (psychology), medicine.disease, Obesity, Nutritional Microbiology, medicine, Intestinal bacteria, Microbiome, Function (biology), Food Science
Abstract: OBJECTIVES: To determine the impact of two isocaloric diets containing (38% ,15% and 47% energy from fat, protein and carbohydrate, respectively): Western diet (WD) rich in saturated fat, refined carbohydrate, low in fiber and high in cholesterol, and a heart healthy diet (HHD) rich in unsaturated fat, unrefined carbohydrate, fruits/vegetables, high in fiber and low in cholesterol, on the composition and function of the gut microbiome METHODS: Thirty-Ossabaw pigs were fed WD or HHD diets with half within each group therapeutically treated with statin (atorvastatin [Lipitor]). The fecal microbiome was analyzed one and six months after dietary intervention by 16S rRNA sequencing and metagenomic function was empirically inferred RESULTS: Genus diversity was transiently affected with a reduced Shannon Diversity index one month after feeding the WD or HHD (FDR P
Published: 2019

129. Comparative Nutrigenomics Analysis of the Pig, Mouse and Human (P15-004-19)

Author: Harry D. Dawson, Joseph F. Urban, Thomas T.Y. Wang, and Celine Chen
Subjects: Genetics, Comparative genomics, Cell type, Nutrition and Dietetics, Medicine (miscellaneous), Genomics, Nutrient sensing, Biology, Genome, Nutrigenomics, Nutrient-Gene Interactions, Gene, Transcription factor, Food Science
Abstract: OBJECTIVES: The seminal work of Miller and Ullrey examined the suitability of the pig as a model for human nutrition concluded “With the possible exception of nonhuman primates, it is apparent that the omnivorous pig is one of the best models for study of nutrition issues in the omnivorous human.” To date, a cross-species, large-scale analysis of genes related to nutrition and metabolism has not been reported. Our goal was to systematically review similarities and differences in nutrition-related physiology, and where different, to explore possible etiologies behind each phenomena using comparative genomics. METHODS: A broad literature and laboratory-based analysis was conducted comparing 1532 genes associated with porcine, murine, and human macro and micronutrient metabolism, including metalloproteins. Four questions were addressed. Are genes in specific pathways conserved? Are the genes/proteins structurally and functionally similar? Are the genes expressed in similar cell types? Are the genes regulated in a similar manner to stimuli? RESULTS: Pigs have roughly 4-fold fewer unique genes (66) than the mouse (240) and human (209). The great majority of these unique genes were zinc-containing members of the KRAB-A box Transcription Factor Superfamily. Analysis of 142 non-orthologous genes revealed that these genes were 10 times more likely to be present in only pigs and humans (120) than only in mice and humans (17). Genes involved in vitamin A and lipid metabolism were more highly conserved between pigs and humans. Notable, differences were found between humans and pigs in regard to genes encoding digestive enzymes and nutrient sensing genes. In some cases, mechanistic data were obtained to explain for previously described differences in physiology. For example, the lack of porcine salivary lipase and amylase activities is likely related to the absence of these genes in the pig. Analysis of 888 orthologous genes indicated a greater pig-human protein similarity for almost every gene examined. CONCLUSIONS: Overall, the genomic and physiological parameters examined were more similar between pigs and humans than mice and humans. This supports the proposition that evaluating nutrition in pigs provides data that is more physiologically relevant to humans. FUNDING SOURCES: Supported by USDA/ARS Project Plan 1235-51,000-055-00D.
Published: 2019

130. A Western-Type Dietary Pattern Induces an Atherogenic Gene Expression Profile in the Coronary Arteries of the Ossabaw Pig

Author: Sukla Lakshman, Saebyeol Jang, Joseph F. Urban, Gloria Solano-Aguilar, Aleksey Molokin, Nirupa R Matthan, Alice H. Lichtenstein, Stefania Lamon-Fava, Maura E Walker, W. Evan Johnson, and Tyler Faits
Subjects: medicine.medical_specialty, Atorvastatin, Saturated fat, dietary patterns, Medicine (miscellaneous), 030204 cardiovascular system & hematology, Anterior Descending Coronary Artery, Transcriptome, Coronary artery disease, 03 medical and health sciences, chemistry.chemical_compound, transcriptomics, 0302 clinical medicine, Internal medicine, Ossabaw pig, medicine, Genomics, Proteomics, and Metabolomics, 030304 developmental biology, Original Research, 2. Zero hunger, 0303 health sciences, Nutrition and Dietetics, business.industry, Cholesterol, Unsaturated fat, atorvastatin, medicine.disease, Coronary arteries, medicine.anatomical_structure, Endocrinology, chemistry, atherosclerosis, business, coronary artery disease, Food Science, medicine.drug
Abstract: Background Current cardiovascular risk reduction guidance focuses on shifts in dietary patterns, rather than single foods or nutrients. Experimental studies are needed to identify the mechanisms by which food-based diets affect the development and progression of atherosclerosis. Objectives The aim of this study was to investigate the effect of 2 food-based dietary patterns and statin therapy on the transcriptome of the left anterior descending coronary artery of the Ossabaw pig. Methods Pigs were randomly assigned to 1 of 4 groups and fed isocaloric diets for 6 mo; Heart Healthy–style diet (HHD) (high in unsaturated fat, unrefined grain, fruits/vegetables) or Western-style diet (WD) (high in saturated fat, cholesterol, refined grain), with or without atorvastatin. A 2-factor edge R analysis was used to determine differential gene expression in the left anterior descending coronary artery. Results Relative to the HHD, the WD resulted in the differential expression of 143 genes, of which 139 genes were upregulated and 4 genes were downregulated (all log fold change ≥0.6, false discovery rate
Published: 2019

131. Low salt exposure results in inactivation of Toxoplasma gondii bradyzoites during formulation of dry cured ready-to-eat pork sausage

Author: H.R. Gamble, Jitender P. Dubey, R. Holley, D.S. Hawkins-Cooper, Joseph F. Urban, Dolores E. Hill, V.M. Fournet, A. Porto-Fett, J. Fredericks, and John B. Luchansky
Subjects: 0301 basic medicine, Curing (food preservation), Food industry, Epidemiology, Microorganism, 030231 tropical medicine, Toxoplasma gondii, Dry cured sausage, Article, lcsh:Infectious and parasitic diseases, 03 medical and health sciences, 0302 clinical medicine, parasitic diseases, lcsh:RC109-216, Food science, Ready to eat meat, Dry cured, biology, business.industry, Outbreak, food and beverages, 030108 mycology & parasitology, biology.organism_classification, Pepperoni, Parasitology, Fermentation, business, Bacteria
Abstract: The production of safe and healthy food products represents one of the main objectives of the food industry. The presence of microorganisms in meat and products containing meat can result in a range of human health problems, as well as economic losses to producers of these products. However, contaminated meat products continue to initiate serious and large-scale outbreaks of disease in consumers. In addition to outbreaks of diseases caused by bacteria and viruses, parasitic organisms, such as Toxoplasma gondii, are responsible for foodborne infections worldwide, and in the case of T. gondii, is considered the 2nd leading cause of death from foodborne illness in the U.S. Transmission of Toxoplasma gondii has historically been linked to the consumption of raw or undercooked meat products, including pork. Specific concerns with respect to pork products are ready-to-eat (RTE) pork meals. These are pork or products containing pork that are prepared by curing or drying, and are not intended to be cooked before being consumed. Previous studies have demonstrated that T. gondii is inactivated during dry cured sausage preparation, apparently in the batter during fermentation. In this study, we have analyzed timing of inactivation of T. gondii in freshly prepared pepperoni batter to confirm our previous findings, to determine how quickly inactivation occurs during fermentation, and to confirm what parameters of the sausage preparation are involved in inactivation of the parasite. Results from the current and previous study indicate that rapid inactivation of T. gondii bradyzoites occurs in low salt batter for dry cured sausage within 4 h of initiation of fermentation., Highlights • Pork containing Toxoplasma bradyzoites was used to prepare dry cured pepperoni sausage. • A low salt (1.3%) formulation was used to prepare the pepperoni batter. • T. gondii was inactivated in pepperoni batter in
Published: 2019

132. Rapid cell cycling of both circulating and resident memory CD8+ T cells driven by common gamma chain-dependent cytokines

Author: Nicholas N Jarjour, Kelsey M Wanhainen, Henrique Borges da Silva, Changwei Peng, Ryan J Martinez, Matthew A Huggins, Joseph F Urban, Sara E Hamilton, and Stephen C Jameson
Subjects: Immunology, Immunology and Allergy
Abstract: Diverse populations of resident leukocytes live and self-renew within the tissues of the body, but the mechanisms controlling their proliferation are poorly understood. Among these populations are many memory CD8+ T cells, which are found throughout the body and can locally control reinfection. A poor ability of vaccines to elicit stable and appropriate tissue-resident CD8+ T cell populations has likely contributed to long-standing challenges in vaccinating against several important pathogens. The factors required to support TRM proliferation in homeostasis are not well understood. We propose that proliferating TRMs flexibly use the available members of the common gamma chain-(γC)-dependent cytokine family to persist as bystanders during other immune responses. We have found that many γC-dependent cytokines can mediate cell-intrinsic signaling to drive proliferation of both circulating and resident memory CD8+ T cells of known antigen specificities without cognate antigen. Via transcriptional analysis of resting and in vivo cytokine-stimulated TRMs, we are elucidating downstream signaling and the gene expression signature of cytokine-driven TRM proliferation. We have also found that memory CD8+ T cells proliferate similarly in response to exogenous cytokines or unrelated pathogens, consistent with pathogen-elicited γC-dependent cytokine signals driving memory CD8+ T cell proliferation. These data support the concept that TRMs use γC-dependent cytokines produced during infections to support enhanced proliferation, likely to promote their maintenance. Our findings may lead to novel methods to therapeutically enhance TRM immunity.
Published: 2021
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133. Systematic Search for Lithium Ion Conducting Compounds by Screening of Compositions Combined with Atomistic Simulation

Author: Daniel F. Urban, Daniel Mutter, and Christian Elsässer
Subjects: Work (thermodynamics), Materials science, Mechanical Engineering, Analytical chemistry, chemistry.chemical_element, Thermodynamics, 02 engineering and technology, Solid state electrolyte, 010402 general chemistry, 021001 nanoscience & nanotechnology, Condensed Matter Physics, 01 natural sciences, Structural framework, 0104 chemical sciences, Ion, chemistry, Mechanics of Materials, Ionic conductivity, General Materials Science, Lithium, 0210 nano-technology, Systematic search
Abstract: Replacing liquid by solid state electrolytes has the potential to significantly improve current Li ion batteries concerning performance and safety. The material class NZP, based on the compound NaZr2(PO4)3, exhibits a structural framework suitable for ionic conduction. In this work, a systematic compositional screening and simulation approach, combining classical molecular-dynamics, first-principles calculations, and structural analysis was applied, with which a set of new Li ion conducting NZP compounds could be identified.
Published: 2017
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134. Microfluidic platform for electrophysiological recordings from host-stage hookworm and Ascaris suum larvae: A new tool for anthelmintic research

Author: Kristin J. Robinson, Shawn R. Lockery, William M. Roberts, Janis C. Weeks, Jon J. Vermeire, Melissa Keaney, Joseph F. Urban, and John M. Hawdon
Subjects: 0301 basic medicine, Pathology, medicine.medical_specialty, Hookworm, Serotonin, Ancylostoma, Pharyngeal pumping, Microfluidics, Drug Evaluation, Preclinical, Electropharyngeogram, lcsh:Infectious and parasitic diseases, 03 medical and health sciences, Ivermectin, parasitic diseases, medicine, Anthelmintic, Animals, Pharmacology (medical), lcsh:RC109-216, Ascaris suum, Ancylostoma ceylanicum, Pharmacology, Anthelmintics, biology, Ascaris, ScreenChip, biology.organism_classification, Cell biology, Electrophysiological Phenomena, Electrophysiology, 030104 developmental biology, Infectious Diseases, Nematode, Microfluidic, Invited Article, Larva, Parasitology, medicine.drug
Abstract: The screening of candidate compounds and natural products for anthelmintic activity is important for discovering new drugs against human and animal parasites. We previously validated in Caenorhabditis elegans a microfluidic device (‘chip’) that records non-invasively the tiny electrophysiological signals generated by rhythmic contraction (pumping) of the worm's pharynx. These electropharyngeograms (EPGs) are recorded simultaneously from multiple worms per chip, providing a medium-throughput readout of muscular and neural activity that is especially useful for compounds targeting neurotransmitter receptors and ion channels. Microfluidic technologies have transformed C. elegans research and the goal of the current study was to validate hookworm and Ascaris suum host-stage larvae in the microfluidic EPG platform. Ancylostoma ceylanicum and A. caninum infective L3s (iL3s) that had been activated in vitro generally produced erratic EPG activity under the conditions tested. In contrast, A. ceylanicum L4s recovered from hamsters exhibited robust, sustained EPG activity, consisting of three waveforms: (1) conventional pumps as seen in other nematodes; (2) rapid voltage deflections, associated with irregular contractions of the esophagus and openings of the esophogeal-intestinal valve (termed a ‘flutter’); and (3) hybrid waveforms, which we classified as pumps. For data analysis, pumps and flutters were combined and termed EPG ‘events.’ EPG waveform identification and analysis were performed semi-automatically using custom-designed software. The neuromodulator serotonin (5-hydroxytryptamine; 5HT) increased EPG event frequency in A. ceylanicum L4s at an optimal concentration of 0.5 mM. The anthelmintic drug ivermectin (IVM) inhibited EPG activity in a concentration-dependent manner. EPGs from A. suum L3s recovered from pig lungs exhibited robust pharyngeal pumping in 1 mM 5HT, which was inhibited by IVM. These experiments validate the use of A. ceylanicum L4s and A. suum L3s with the microfluidic EPG platform, providing a new tool for screening anthelmintic candidates or investigating parasitic nematode feeding behavior., Graphical abstract Image 1, Highlights • Pharyngeal pumping in nematodes generates an electropharyngeogram (EPG). • The EPG provides a readout of the electrical activity of neurons and muscles. • A microfluidic platform for recording EPGs was validated in parasitic nematodes. • EPG activity and drug responses were characterized in host-stage larvae. • Microfluidic EPG recordings provide a powerful new tool for anthelmintic research.
Published: 2016

135. Critical Role for Interleukin-25 in Host Protective Th2 Memory Response against Heligmosomoides polygyrus bakeri

Author: Viktoriya Grinchuk, Zhonghan Yang, Allen Smith, Chenlin Pei, An-Jiang Wang, Rex Sun, Aiping Zhao, Joseph F. Urban, Chao Zhao, Anya X. Fan, Nonghua Lu, Yue Xie, and Terez Shea-Donohue
Subjects: 0301 basic medicine, medicine.medical_treatment, Secondary infection, Immunology, Biology, Microbiology, Mice, 03 medical and health sciences, Th2 Cells, Downregulation and upregulation, Interleukin 25, parasitic diseases, medicine, Animals, IL17RB, Strongylida Infections, Mice, Knockout, Nematospiroides dubius, Receptors, Interleukin-17, Cellular Microbiology: Pathogen-Host Cell Molecular Interactions, Arginase, Host (biology), Interleukins, medicine.disease, biology.organism_classification, Up-Regulation, Mice, Inbred C57BL, 030104 developmental biology, Infectious Diseases, Cytokine, Gene Expression Regulation, Nematode infection, Hormones, Ectopic, Intercellular Signaling Peptides and Proteins, Parasitology, Heligmosomoides polygyrus, Immunologic Memory
Abstract: Infection with parasitic nematodes, especially gastrointestinal geohelminths, affects hundreds of millions of people worldwide and thus poses a major risk to global health. The host mechanism of defense against enteric nematode infection remains to be fully understood, but it involves a polarized type 2 immunity leading to alterations in intestinal function that facilitate worm expulsion. We investigated the role of interleukin-25 (IL-25) in host protection against Heligmosomoides polygyrus bakeri infection in mice. Our results showed that Il25 and its receptor subunit, Il17rb , were upregulated during a primary infection and a secondary challenge infection with H. polygyrus bakeri . Genetic deletion of IL-25 (IL-25 −/− ) led to an attenuated type 2 cytokine response and increased worm fecundity in mice with a primary H. polygyrus bakeri infection. In addition, the full spectrum of the host memory response against a secondary infection with H. polygyrus bakeri was severely impaired in IL-25 −/− mice, including delayed type 2 cytokine responses, an attenuated functional response of the intestinal smooth muscle and epithelium, diminished intestinal smooth muscle hypertrophy/hyperplasia, and impaired worm expulsion. Furthermore, exogenous administration of IL-25 restored the host protective memory response against H. polygyrus bakeri infection in IL-25 −/− mice. These data demonstrate that IL-25 is critical for host protective immunity against H. polygyrus bakeri infection, highlighting its potential application as a therapeutic agent against parasitic nematode infection worldwide.
Published: 2016
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136. Downregulation of the Syk Signaling Pathway in Intestinal Dendritic Cells Is Sufficient To Induce Dendritic Cells That Inhibit Colitis

Author: Timothy G. Geary, Joseph F. Urban, Arthur M. Blum, Makedonka Mitreva, Long Hang, Mary M. Stevenson, Sangeeta Kumar, Armando Jardim, Joel V. Weinstock, and Clifford A. Lowell
Subjects: 0301 basic medicine, Messenger, Syk, Inbred C57BL, Oral and gastrointestinal, Mice, 0302 clinical medicine, 2.1 Biological and endogenous factors, Immunology and Allergy, Aetiology, Receptor, Mice, Knockout, Nematospiroides dubius, CLEC7A, hemic and immune systems, Colitis, Cell biology, Intestines, Phosphorylation, Signal transduction, Signal Transduction, Knockout, 1.1 Normal biological development and functioning, Immunology, chemical and pharmacologic phenomena, Biology, Autoimmune Disease, Article, 03 medical and health sciences, Downregulation and upregulation, Underpinning research, parasitic diseases, medicine, Animals, Syk Kinase, RNA, Messenger, Strongylida Infections, Animal, Inflammatory and immune system, Inflammatory Bowel Disease, Dendritic Cells, medicine.disease, biology.organism_classification, Mice, Inbred C57BL, Disease Models, Animal, 030104 developmental biology, Disease Models, RNA, Heligmosomoides polygyrus, Digestive Diseases, 030215 immunology
Abstract: Helminthic infections modulate host immunity and may protect people in less-developed countries from developing immunological diseases. In a murine colitis model, the helminth Heligmosomoides polygyrus bakeri prevents colitis via induction of regulatory dendritic cells (DCs). The mechanism driving the development of these regulatory DCs is unexplored. There is decreased expression of the intracellular signaling pathway spleen tyrosine kinase (Syk) in intestinal DCs from H. polygyrus bakeri–infected mice. To explore the importance of this observation, it was shown that intestinal DCs from DC-specific Syk−/− mice were powerful inhibitors of murine colitis, suggesting that loss of Syk was sufficient to convert these cells into their regulatory phenotype. DCs sense gut flora and damaged epithelium via expression of C-type lectin receptors, many of which signal through the Syk signaling pathway. It was observed that gut DCs express mRNA encoding for C-type lectin (CLEC) 7A, CLEC9A, CLEC12A, and CLEC4N. H. polygyrus bakeri infection downmodulated CLEC mRNA expression in these cells. Focusing on CLEC7A, which encodes for the dectin-1 receptor, flow analysis showed that H. polygyrus bakeri decreases dectin-1 expression on the intestinal DC subsets that drive Th1/Th17 development. DCs become unresponsive to the dectin-1 agonist curdlan and fail to phosphorylate Syk after agonist stimulation. Soluble worm products can block CLEC7A and Syk mRNA expression in gut DCs from uninfected mice after a brief in vitro exposure. Thus, downmodulation of Syk expression and phosphorylation in intestinal DCs could be important mechanisms through which helminths induce regulatory DCs that limit colitis.
Published: 2016
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137. Type 3 muscarinic receptors contribute to intestinal mucosal homeostasis and clearance of Nippostrongylus brasiliensis through induction of TH2 cytokines

Author: Aiping Zhao, Leon P. McLean, Rex Sun, Jean-Pierre Raufman, Joseph F. Urban, Neemesh Desai, Allen Smith, Viktoriya Grinchuk, Lumei Cheung, and Terez Shea-Donohue
Subjects: 0301 basic medicine, Mice, 129 Strain, Time Factors, Physiology, Inflammation, 03 medical and health sciences, Th2 Cells, Intestinal mucosa, Physiology (medical), Intestine, Small, Muscarinic acetylcholine receptor, medicine, Animals, Homeostasis, Genetic Predisposition to Disease, Nippostrongylus, Nippostrongylus brasiliensis, Intestinal Mucosa, Mucosal homeostasis, Immunity, Mucosal, Cells, Cultured, Strongylida Infections, Mice, Knockout, Receptor, Muscarinic M3, Hepatology, biology, Macrophages, Gastroenterology, Epithelial Biology and Secretion, Macrophage Activation, biology.organism_classification, Phenotype, Mice, Inbred C57BL, Disease Models, Animal, 030104 developmental biology, Host-Pathogen Interactions, Immunology, Cytokines, medicine.symptom
Abstract: Despite increased appreciation for the role of nicotinic receptors in the modulation of and response to inflammation, the contribution of muscarinic receptors to mucosal homeostasis, clearance of enteric pathogens, and modulation of immune cell function remains relatively undefined. Uninfected and Nippostrongylus brasiliensis-infected wild-type and type 3 muscarinic receptor (M3R)-deficient ( Chrm3 −/−) mice were studied to determine the contribution of M3R to mucosal homeostasis as well as host defense against the TH2-eliciting enteric nematode N. brasiliensis. Intestinal permeability and expression of TH1/TH17 cytokines were increased in uninfected Chrm3 −/− small intestine. Notably, in Chrm3 −/− mice infected with N. brasiliensis, small intestinal upregulation of TH2 cytokines was attenuated and nematode clearance was delayed. In Chrm3 −/− mice, TH2-dependent changes in small intestinal function including smooth muscle hypercontractility, increased epithelial permeability, decreased epithelial secretion and absorption, and goblet cell expansion were absent despite N. brasiliensis infection. These findings identify an important role for M3R in host defense and clearance of N. brasiliensis, and support the expanding role of cholinergic muscarinic receptors in maintaining mucosal homeostasis.
Published: 2016
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138. Developmental Acquisition of Regulomes Underlies Innate Lymphoid Cell Functionality

Author: Yohei Mikami, Liying Guo, Yuka Kanno, Fred P. Davis, Han-Yu Shih, Hong-Wei Sun, John J. O'Shea, Joseph F. Urban, Stephen R. Brooks, and Giuseppe Sciumè
Subjects: Genetics and Molecular Biology (all), 0301 basic medicine, Cellular differentiation, Gene regulatory network, Biology, Inbred C57BL, Biochemistry, Article, General Biochemistry, Genetics and Molecular Biology, Chromatin remodeling, Mice, 03 medical and health sciences, 0302 clinical medicine, Immune system, Animals, Cell Lineage, Gene Regulatory Networks, Lymphocytes, Transcription factor, Female, Gene Expression Regulation, Mice, Inbred C57BL, Transcriptome, Biochemistry, Genetics and Molecular Biology (all), Effector, Innate lymphoid cell, Chromatin, Cell biology, 030104 developmental biology, 030215 immunology
Abstract: Summary Innate lymphoid cells (ILCs) play key roles in host defense, barrier integrity, and homeostasis and mirror adaptive CD4 + T helper (Th) cell subtypes in both usage of effector molecules and transcription factors. To better understand the relationship between ILC subsets and their Th cell counterparts, we measured genome-wide chromatin accessibility. We find that chromatin in proximity to effector genes is selectively accessible in ILCs prior to high-level transcription upon activation. Accessibility of these regions is acquired in a stepwise manner during development and changes little after in vitro or in vivo activation. Conversely, dramatic chromatin remodeling occurs in naive CD4 + T cells during Th cell differentiation using a type-2-infection model. This alteration results in a substantial convergence of Th2 cells toward ILC2 regulomes. Our data indicate extensive sharing of regulatory circuitry across the innate and adaptive compartments of the immune system, in spite of their divergent developing pathways.
Published: 2016
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139. Acidic chitinase primes the protective immune response to gastrointestinal nematodes

Author: Luke Barron, Allen Smith, Kevin W. Bock, Ian N. Moore, Robert W. Thompson, Lori Fitz, Thomas A. Wynn, Rafael de Queiroz Prado, Sandra White, Lee A. Borthwick, Kevin M. Vannella, Allen W. Cheever, Kevin M. Hart, Margaret M. Mentink-Kane, Thirumalai R. Ramalingam, Joshua Sciurba, and Joseph F. Urban
Subjects: 0301 basic medicine, Immunology, Gene Expression, Inflammation, Article, Host-Parasite Interactions, 03 medical and health sciences, Immune system, Chloride Channels, Lectins, parasitic diseases, Hypersensitivity, medicine, Animals, Immunology and Allergy, Helminths, Nippostrongylus, Lung, Strongylida Infections, Mice, Knockout, Nematospiroides dubius, Physiological function, Interleukin-13, biology, Reverse Transcriptase Polymerase Chain Reaction, Chitinases, Immunity, Flow Cytometry, Acquired immune system, beta-N-Acetylhexosaminidases, Gastrointestinal Tract, Mice, Inbred C57BL, 030104 developmental biology, medicine.anatomical_structure, Microscopy, Fluorescence, Hormones, Ectopic, Chitinase, biology.protein, Intercellular Signaling Peptides and Proteins, medicine.symptom
Abstract: Acidic mammalian chitinase (AMCase) is known to be induced by allergens and helminths, yet its role in immunity is unclear. Using AMCase-deficient mice, we show that AMCase deficiency reduced the number of group 2 innate lymphoid cells during allergen challenge but was not required for establishment of type 2 inflammation in the lung in response to allergens or helminths. In contrast, AMCase-deficient mice showed a profound defect in type 2 immunity following infection with the chitin-containing gastrointestinal nematodes Nippostrongylus brasiliensis and Heligmosomoides polygyrus bakeri. The impaired immunity was associated with reduced mucus production and decreased intestinal expression of the signature type 2 response genes Il13, Chil3, Retnlb, and Clca1. CD103(+) dendritic cells, which regulate T cell homing, were also reduced in mesenteric lymph nodes of infected AMCase-deficient mice. Thus, AMCase functions as a critical initiator of protective type 2 responses to intestinal nematodes but is largely dispensable for allergic responses in the lung.
Published: 2016
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140. Interleukin-13 Receptor α1-Dependent Responses in the Intestine Are Critical to Parasite Clearance

Author: Thomas A. Wynn, Luigi Notari, Joseph F. Urban, Thirumalai R. Ramalingam, Rex Sun, Terez Shea-Donohue, Kathleen B. Madden, Tim Vanuytsel, Aiping Zhao, and Jennifer A. Bohl
Subjects: 0301 basic medicine, Immunology, Biology, Microbiology, Mice, 03 medical and health sciences, 0302 clinical medicine, Immune system, Downregulation and upregulation, medicine, Animals, Parasite hosting, Intestinal Diseases, Parasitic, Intestinal Mucosa, Receptor, Beta (finance), Strongylida Infections, Mice, Knockout, Mice, Inbred BALB C, Host Response and Inflammation, Goblet cell, Interleukin-13 receptor, medicine.disease, Interleukin-13 Receptor alpha1 Subunit, Intestines, 030104 developmental biology, Infectious Diseases, medicine.anatomical_structure, Nematode infection, Female, Parasitology, Heligmosomatoidea, 030215 immunology
Abstract: Nematode infection upregulates interleukin-4 (IL-4) and IL-13 and induces STAT6-dependent changes in gut function that promote worm clearance. IL-4 and IL-13 activate the type 2 IL-4 receptor (IL-4R), which contains the IL-13Rα1 and IL-4Rα chains. We used mice deficient in IL-13Rα1 (IL-13Rα1 −/− ) to examine the contribution of IL-13 acting at the type 2 IL-4R to immune and functional responses to primary (Hb1) and secondary (Hb2) infections with the gastrointestinal nematode parasite Heligmosomoides bakeri . There were differences between strains in the IL-4 and IL-13 expression responses to Hb1 but not Hb2 infection. Following Hb2 infection, deficient mice had impaired worm expulsion and higher worm fecundity despite normal production of Th2-derived cytokines. The upregulation of IL-25 and IL-13Rα2 in Hb1- and Hb2-infected wild-type (WT) mice was absent in IL-13Rα1 −/− mice. Goblet cell numbers and resistin-like molecule beta (RELM-β) expression were attenuated significantly in IL-13Rα1 −/− mice following Hb2 infections. IL-13Rα1 contributes to the development of alternatively activated macrophages, but the type 1 IL-4R is also important. Hb1 infection had no effects on smooth muscle function or epithelial permeability in either strain, while the enhanced mucosal permeability and changes in smooth muscle function and morphology observed in response to Hb2 infection in WT mice were absent in IL-13Rα1 −/− mice. Notably, the contribution of claudin-2, which has been linked to IL-13, does not mediate the increased mucosal permeability following Hb2 infection. These results show that activation of IL-13Rα1 is critical for key aspects of the immune and functional responses to Hb2 infection that facilitate expulsion.
Published: 2016
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141. Interleukin-33 Promotes Serotonin Release from Enterochromaffin Cells for Intestinal Homeostasis

Author: Shan Chen, Jian Li, Zuojia Chen, Andy Stewart, Yuefeng Huang, Girak Kim, Giorgio Trinchieri, Alexander T. Chesler, Chuan Wu, Joseph F. Urban, Ling-Gang Wu, Jialie Luo, and Wei Li
Subjects: 0301 basic medicine, Serotonin, Neuroimmunomodulation, medicine.medical_treatment, Immunology, Trichuris muris, Mice, 03 medical and health sciences, 0302 clinical medicine, Immune system, Enterochromaffin Cells, medicine, Animals, Homeostasis, Immunology and Allergy, Secretion, Calcium Signaling, Trichuriasis, Mice, Knockout, Neurons, biology, Interleukin-33, biology.organism_classification, Cell biology, Gut Epithelium, Intestines, Mice, Inbred C57BL, Interleukin 33, Trichuris, 030104 developmental biology, Infectious Diseases, Cytokine, 030220 oncology & carcinogenesis, Enterochromaffin cell, Peristalsis
Abstract: Summary The gastrointestinal tract is known as the largest endocrine organ that encounters and integrates various immune stimulations and neuronal responses due to constant environmental challenges. Enterochromaffin (EC) cells, which function as chemosensors on the gut epithelium, are known to translate environmental cues into serotonin (5-HT) production, contributing to intestinal physiology. However, how immune signals participate in gut sensation and neuroendocrine response remains unclear. Interleukin-33 (IL-33) acts as an alarmin cytokine by alerting the system of potential environmental stresses. We here demonstrate that IL-33 induced instantaneous peristaltic movement and facilitated Trichuris muris expulsion. We found that IL-33 could be sensed by EC cells, inducing release of 5-HT. IL-33-mediated 5-HT release activated enteric neurons, subsequently promoting gut motility. Mechanistically, IL-33 triggered calcium influx via a non-canonical signaling pathway specifically in EC cells to induce 5-HT secretion. Our data establish an immune-neuroendocrine axis in calibrating rapid 5-HT release for intestinal homeostasis.
Published: 2021
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142. Atomistic analysis of Li migration in Li1+AlTi2−(PO4)3 (LATP) solid electrolytes

Author: Daniel F. Urban, Daniel Mutter, and Daniel Pfalzgraf
Subjects: Materials science, Diffusion, Ionic bonding, Energy landscape, Thermodynamics, 02 engineering and technology, General Chemistry, 010402 general chemistry, 021001 nanoscience & nanotechnology, Condensed Matter Physics, 01 natural sciences, 0104 chemical sciences, Ion, Energy profile, Fast ion conductor, Ionic conductivity, General Materials Science, Density functional theory, 0210 nano-technology
Abstract: We examine the ionic migration of Li in LATP [Li1+xAlxTi2−x(PO4)3] solid electrolytes from an atomistic viewpoint by means of density functional theory calculations. We vary the Al content and investigate its effects on the crystal structure of LATP and on the migration energy landscape of interstitial Li ions. The energy profiles governing the Li diffusion are found to be systematically influenced by the position of Al ions in direct vicinity of the migration path, and we derive a simplified classification scheme of three universal energy profile shapes. The overall influence of the Al/Ti-ratio on the Li migration is analyzed by a separation into chemical and geometrical aspects. This work provides a solid basis for a resource-efficient computational examination of the ionic conductivity of Li in LATP with varying Al/Ti concentrations.
Published: 2021
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143. Evidence for a Supergalactic Structure of Magnetic Deflection Multiplets of Ultra-high-energy Cosmic Rays

Author: R. U. Abbasi, M. Abe, T. Abu-Zayyad, M. Allen, R. Azuma, E. Barcikowski, J. W. Belz, D. R. Bergman, S. A. Blake, R. Cady, B. G. Cheon, J. Chiba, M. Chikawa, A. di Matteo, T. Fujii, K. Fujisue, K. Fujita, R. Fujiwara, M. Fukushima, G. Furlich, W. Hanlon, M. Hayashi, N. Hayashida, K. Hibino, R. Higuchi, K. Honda, D. Ikeda, T. Inadomi, N. Inoue, T. Ishii, R. Ishimori, H. Ito, D. Ivanov, H. Iwakura, H. M. Jeong, S. Jeong, C. C. H. Jui, K. Kadota, F. Kakimoto, O. Kalashev, K. Kasahara, S. Kasami, H. Kawai, S. Kawakami, S. Kawana, K. Kawata, E. Kido, H. B. Kim, J. H. Kim, M. H. Kim, S. W. Kim, S. Kishigami, V. Kuzmin, M. Kuznetsov, Y. J. Kwon, K. H. Lee, B. Lubsandorzhiev, J. P. Lundquist, K. Machida, H. Matsumiya, T. Matsuyama, J. N. Matthews, R. Mayta, M. Minamino, K. Mukai, I. Myers, S. Nagataki, K. Nakai, R. Nakamura, T. Nakamura, Y. Nakamura, T. Nonaka, H. Oda, S. Ogio, M. Ohnishi, H. Ohoka, Y. Oku, T. Okuda, Y. Omura, M. Ono, R. Onogi, A. Oshima, S. Ozawa, I. H. Park, M. S. Pshirkov, J. Remington, D. C. Rodriguez, G. Rubtsov, D. Ryu, H. Sagawa, R. Sahara, Y. Saito, N. Sakaki, T. Sako, N. Sakurai, K. Sano, T. Seki, K. Sekino, P. D. Shah, F. Shibata, T. Shibata, H. Shimodaira, B. K. Shin, H. S. Shin, J. D. Smith, P. Sokolsky, N. Sone, B. T. Stokes, T. A. Stroman, T. Suzawa, Y. Takagi, Y. Takahashi, M. Takamura, R. Takeishi, A. Taketa, M. Takita, Y. Tameda, H. Tanaka, K. Tanaka, M. Tanaka, Y. Tanoue, S. B. Thomas, G. B. Thomson, P. Tinyakov, I. Tkachev, H. Tokuno, T. Tomida, S. Troitsky, Y. Tsunesada, Y. Uchihori, S. Udo, T. Uehama, F. Urban, T. Wong, K. Yada, M. Yamamoto, K. Yamazaki, J. Yang, K. Yashiro, M. Yosei, Y. Zhezher, and Z. Zundel
Subjects: Physics, 010504 meteorology & atmospheric sciences, High-energy astronomy, Astrophysics::High Energy Astrophysical Phenomena, media_common.quotation_subject, Astronomy and Astrophysics, Cosmic ray, Astrophysics, 01 natural sciences, Galaxy, Spectral line, Magnetic field, Space and Planetary Science, Sky, 0103 physical sciences, Ultra-high-energy cosmic ray, Anisotropy, 010303 astronomy & astrophysics, 0105 earth and related environmental sciences, media_common
Abstract: Evidence for a large-scale supergalactic cosmic-ray multiplet (arrival directions correlated with energy) structure is reported for ultra-high-energy cosmic-ray (UHECR) energies above 1019 eV using 7 years of data from the Telescope Array (TA) surface detector and updated to 10 years. Previous energy–position correlation studies have made assumptions regarding magnetic field shapes and strength, and UHECR composition. Here the assumption tested is that, because the supergalactic plane is a fit to the average matter density of the local large-scale structure, UHECR sources and intervening extragalactic magnetic fields are correlated with this plane. This supergalactic deflection hypothesis is tested by the entire field-of-view (FOV) behavior of the strength of intermediate-scale energy–angle correlations. These multiplets are measured in spherical cap section bins (wedges) of the FOV to account for coherent and random magnetic fields. The structure found is consistent with supergalactic deflection, the previously published energy spectrum anisotropy results of the TA (the Hotspot and Coldspot), and toy-model simulations of a supergalactic magnetic sheet. The seven year data posttrial significance of this supergalactic structure of multiplets appearing by chance, on an isotropic sky, is found by Monte Carlo simulation to be 4.2σ. The 10 years of data posttrial significance is 4.1σ. Furthermore, the starburst galaxy M82 is shown to be a possible source of the TA Hotspot, and an estimate of the supergalactic magnetic field using UHECR measurements is presented.
Published: 2020
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144. Western Versus Heart Healthy Dietary Pattern Alters Genes Expression Associated with Lipid Metabolism, Interferon Signaling and Inflammation in Jejunum of Ossabaw Pigs

Author: Sukla Lakshman, Gloria Solano-Aguilar, Jerrold R. Turner, Nirupa R Matthan, Stefania Lamon-Fava, Zhi Chai, Maura E Walker, Xiang-Dong Wang, Alice H. Lichtenstein, Shumao Ye, and Joseph F. Urban
Subjects: medicine.medical_specialty, Nutrition and Dietetics, Cholesterol, Dietary Patterns, Medicine (miscellaneous), Inflammation, Lipid metabolism, Biology, biology.organism_classification, Jejunum, chemistry.chemical_compound, medicine.anatomical_structure, Endocrinology, chemistry, Interferon, Suidae, Internal medicine, Gene expression, medicine, medicine.symptom, Signal transduction, Food Science, medicine.drug
Abstract: OBJECTIVES: A gastrointestinal tract (GI) that allows for bacterial translocation has been associated with enhanced systemic inflammation and may play a critical role in the development of coronary artery disease (CAD). Diet quality and statin therapy are established modulators of CAD, but their effect in GI health is relatively unexplored. Jejunal mucosa gene expression was compared in Ossabaw pigs fed a heart healthy-type diet (HHD) and Western-type diet (WD), with and without statin therapy. METHODS: Pigs (N = 32) were randomized into 4 groups and fed isocalorically for 6 months: WD (high in saturated fat, refined carbohydrate, cholesterol, and low in fiber) or HHD (high in unsaturated fat, whole grains, fruits and vegetables, fiber, supplemented with fish oil, and low in cholesterol), with or without statin therapy. RNA sequencing was conducted in isolated jejunal mucosa at the end of the study. Principal component analysis, hierarchical clustering and xCell analysis were used to cross-check and ensure consistent sampling. Two-factor edgeR analysis and Ingenuity Pathway Analysis were used to identify genes, pathways, and biological functions altered by diet and/or statin. Independent of groups, Spearman's correlation coefficients were calculated to identify associations between genes of interest and atherosclerotic lesion severity in the coronary arteries or cardiometabolic risk factors (serum triglyceride, LDL, HDL, TNF-α, hsCRP). RESULTS: HHD and WD resulted in differential expression of genes related to lipid metabolism (SCD, FADS1, SQLE) in the jejunal mucosa. The expression of these genes was associated with atherosclerotic lesion severity and serum lipoprotein concentrations. Higher interferon signaling and inflammation were observed in pigs fed WD versus HHD. In the jejunal mucosa, 7 genes related to inflammation were significantly associated with serum TNF-α and/or hsCRP concentrations. There was no significant effect of statin on gene expression, nor diet x statin interaction. Expression of genes related to jejunum permeability was unaffected by diet or statin. CONCLUSIONS: Gene expression in the jejunum of Ossabaw pigs was altered by dietary patterns, but not statin, and linked to atherosclerotic lesion severity associated with lipid metabolism and inflammatory markers. FUNDING SOURCES: USDA-ARS-NEA, JM-USDA-HNRCA, and Tufts University.
Published: 2020
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145. Method: Isolation of Epithelial Cell RNA from Frozen Jejunum Segments While Minimizing Smooth Muscle Cell RNA Contamination

Author: Sukla Lakshman, Gloria Solano-Aguilar, Stefania Lamon-Fava, Zhi Chai, Joseph F. Urban, Alice H. Lichtenstein, Shumao Ye, Jerrold R. Turner, Nirupa R Matthan, Maura E Walker, and Xiang-Dong Wang
Subjects: Nutrition and Dietetics, Chemistry, Cell, Medicine (miscellaneous), RNA, Contamination, Isolation (microbiology), Epithelium, Cell biology, Jejunum, medicine.anatomical_structure, Smooth muscle, Methods, medicine, Gene, Food Science
Abstract: OBJECTIVES: High RNA quality is a prerequisite for accurate PCR and sequencing results. Dissecting a specific tissue fraction from frozen samples while maintaining RNA quality is challenging. Starting with frozen pig jejunum segments, we describe a novel method to isolate epithelial cell RNA while minimizing contamination with smooth muscle cell RNA. METHODS: Jejunum tissue segments from Ossabaw pigs (N = 30) were snap-frozen in liquid nitrogen upon harvest from a diet-statin study and stored at −80°C. At the time of RNA isolation samples were incubated in prechilled RNAlater-ICE at −20°C for 24 hours, opened longitudinally, and epithelium cleanly separated from the muscle layer using a scalpel and tweezers. Total RNA was extracted from the epithelium using TRI-reagent. RNA Quality Indicator (RQI) of total RNA was measured using Experion RNA StdSens Analysis kit. RNA-sequencing was performed on Illumina NextSeq 500 platform. Raw sequencing data were aligned to the domestic pig (sus scrofa 11.1) reference genome and applied to subsequent analyses. xCell, a gene signature-based tool trained by thousands of single cell types from various sources, was used to estimate enrichment of epithelial cells (target) and smooth muscle cells (contamination) across samples. A Student t-test was used to compare the enrichment scores of these two cell types between the current method and a traditional method (small jejunal pieces collected at necropsy and stored frozen until RNA isolation). RESULTS: RQI ranged from 8.6 to 9.7, above the standard for RNA sequencing (RQI > 8). The enrichment score of epithelial cells was significantly higher in the current method (mean = 0.030, SD = 0.006) compared to the traditional method (mean = 0.016, SD = 0.013) (P
Published: 2020
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146. The Chemoattractant Receptor Ebi2 Drives Intranodal Naive CD4

Author: Antonio P, Baptista, Anita, Gola, Yuefeng, Huang, Pedro, Milanez-Almeida, Parizad, Torabi-Parizi, Joseph F, Urban, Virginia S, Shapiro, Michael Y, Gerner, and Ronald N, Germain
Subjects: CD4-Positive T-Lymphocytes, Mice, Knockout, Antigen Presentation, Mice, Inbred BALB C, Histocompatibility Antigens Class II, Cell Differentiation, Dendritic Cells, Adaptive Immunity, CD8-Positive T-Lymphocytes, Receptors, G-Protein-Coupled, Mice, Inbred C57BL, Mice, Animals, Lymph Nodes, Antigens
Abstract: Lymph nodes (LNs) play critical roles in adaptive immunity by concentrating in one location the antigens, antigen-presenting cells, and antigen-responsive lymphocytes involved in such responses. Recent studies have revealed nonrandom localization of innate and adaptive immune cells within these organs, suggesting that microanatomical positioning optimizes responses involving sparse cooperating cells. Here, we report that the peripheral localization of LN cDC2 dendritic cells specialized for MHC-II antigen presentation is matched by a similarly biased paracortical distribution of CD4
Published: 2019

147. Dietary patterns influence epicardial adipose tissue fatty acid composition and inflammatory gene expression in the Ossabaw pig

Author: Gloria Solano-Aguilar, Saebyeol Jang, Sukla Lakshman, Alice H. Lichtenstein, Nirupa R Matthan, Stefania Lamon-Fava, Joseph F. Urban, Aleksey Molokin, Maura E Walker, Audrey Goldbaum, and Huicui Meng
Subjects: 0301 basic medicine, Male, Swine, Endocrinology, Diabetes and Metabolism, Saturated fat, Clinical Biochemistry, Adipose tissue, Coronary Artery Disease, 030204 cardiovascular system & hematology, Biochemistry, Receptors, G-Protein-Coupled, chemistry.chemical_compound, 0302 clinical medicine, Atorvastatin, chemistry.chemical_classification, Nutrition and Dietetics, Chemistry, Fatty Acids, Lipids, Adipose Tissue, Fatty Acids, Unsaturated, lipids (amino acids, peptides, and proteins), Female, Adiponectin, medicine.symptom, Pericardium, Polyunsaturated fatty acid, Signal Transduction, medicine.medical_specialty, Peroxisome proliferator-activated receptor gamma, Inflammation, Article, 03 medical and health sciences, Internal medicine, medicine, Animals, Molecular Biology, Arachidonate 5-Lipoxygenase, Unsaturated fat, Fatty acid, Lipid signaling, Dietary Fats, Toll-Like Receptor 2, Diet, PPAR gamma, 030104 developmental biology, Endocrinology, Gene Expression Regulation, Cyclooxygenase 2
Abstract: Epicardial adipose tissue (EAT) inflammation is implicated in the development and progression of coronary atherosclerosis. Dietary saturated and polyunsaturated fatty acids (SFAs and PUFA) can influence adipose tissue inflammation. We investigated the influence of dietary patterns, with emphasis on dietary fat type, and statin therapy, on EAT fatty acid (FA) composition and inflammatory gene expression. Thirty-two Ossabaw pigs were fed isocaloric amounts of a Heart Healthy (high in unsaturated fat) or Western (high in saturated fat) diets +/- atorvastatin for 6 months. EAT FA composition reflected dietary fat composition. There was no significant effect of atorvastatin on EAT FA composition. Total and long-chain SFAs were positively associated with inflammatory signaling (TLR2) and a gene involved in lipid mediator biosynthesis (PTGS2) (P
Published: 2019

148. A Western-type dietary pattern and atorvastatin induce epicardial adipose tissue interferon signaling in the Ossabaw pig

Author: Tyler Faits, Alice H. Lichtenstein, Aleksey Molokin, Joseph F. Urban, Sukla Lakshman, W. Evan Johnson, Maura E Walker, Gloria Solano-Aguilar, Stefania Lamon-Fava, Saebyeol Jang, and Nirupa R Matthan
Subjects: 0301 basic medicine, Male, medicine.medical_specialty, Swine, Endocrinology, Diabetes and Metabolism, Atorvastatin, Saturated fat, Clinical Biochemistry, Adipose tissue, Inflammation, 030204 cardiovascular system & hematology, Biochemistry, Article, Coronary artery disease, 03 medical and health sciences, chemistry.chemical_compound, Food-Drug Interactions, 0302 clinical medicine, Interferon, Internal medicine, Medicine, Animals, Molecular Biology, Nutrition and Dietetics, business.industry, Cholesterol, Unsaturated fat, medicine.disease, Atherosclerosis, 030104 developmental biology, Endocrinology, chemistry, Adipose Tissue, Gene Expression Regulation, Diet, Western, Swine, Miniature, Female, Interferons, medicine.symptom, Hydroxymethylglutaryl-CoA Reductase Inhibitors, business, Pericardium, medicine.drug
Abstract: Epicardial adipose tissue (EAT) inflammation is thought to potentiate the development of coronary artery disease (CAD). Overall diet quality and statin therapy are important modulators of inflammation and CAD progression. Our objective was to examine the effects and interaction of dietary patterns and statin therapy on EAT gene expression in the Ossabaw pig. Pigs were randomized to 1 of 4 groups; Heart Healthy diet (high in unsaturated fat, unrefined grain, fruits/vegetables [HHD]) or Western diet (high in saturated fat, cholesterol, refined grain [WD]), with or without atorvastatin. Diets were fed in isocaloric amounts for 6 months. A two-factor edge R analysis identified the differential expression of 21 genes. Relative to the HHD, the WD resulted in a significant 12-fold increase of radical s-adenosyl methionine domain containing 2 (RSAD2), a gene induced by interferon signaling. Atorvastatin led to the significant differential expression of 17 genes predominately involved in interferon signaling. Results were similar using the Porcine Translational Research Database. Pathway analysis confirmed the up-regulation of interferon signaling in response to the WD and atorvastatin independently. An expression signature of the largely interferon related differentially expressed genes had no predictive capability on a histological assessment of atherosclerosis in the underlying coronary artery. These results suggest that a WD and atorvastatin evoke an interferon mediated immune response in EAT of the Ossabaw pig, which is not associated with the presence of atherosclerosis.
Published: 2019

149. Helminth-induced regulation of T-cell transfer colitis requires intact and regulated T cell Stat6 signaling in mice

Author: M. Nedim Ince, Sarah Winckler, Joseph F. Urban, David E. Elliott, Ahmed Metwali, and Mark H. Kaplan
Subjects: 0301 basic medicine, T cell, Immunology, Inflammation, T-Lymphocytes, Regulatory, 03 medical and health sciences, Interferon-gamma, Mice, 0302 clinical medicine, Immune system, Th2 Cells, parasitic diseases, medicine, Immunology and Allergy, Animals, Colitis, Intestinal Mucosa, STAT6, Strongylida Infections, Nematospiroides dubius, integumentary system, biology, Interleukin-17, FOXP3, respiratory system, Th1 Cells, biology.organism_classification, medicine.disease, Cell biology, Interleukin-10, Mice, Inbred C57BL, Interleukin 10, 030104 developmental biology, medicine.anatomical_structure, Th17 Cells, Heligmosomoides polygyrus, medicine.symptom, STAT6 Transcription Factor, 030215 immunology, Signal Transduction
Abstract: Infection with parasitic worms (helminths) alters host immune responses and can inhibit pathogenic inflammation. Helminth infection promotes a strong Th2 and T regulatory response while suppressing Th1 and Th17 function. Th2 responses are largely dependent on transcriptional programs directed by Stat6-signaling. We examined the importance of intact T cell Stat6 signaling on helminth-induced suppression of murine colitis that results from T cell transfer into immune-deficient mice. Colonization with the intestinal nematode Heligmosomoides polygyrus bakeri resolves WT T cell transfer colitis. However, if the transferred T cells lack intact Stat6 then helminth exposure failed to attenuate colitis or suppress MLN T cell IFN-γ or IL17 production. Loss of Stat6 signaling resulted in decreased IL10 and increased IFN-γ co-expression by IL-17+ T cells. We also transferred T cells from mice with constitutive T cell expression of activated Stat6 (Stat6VT). These mice developed a severe eosinophilic colitis that also was not attenuated by helminth infection. These results show that T cell expression of intact but regulated Stat6 signaling is required for helminth infection-associated regulation of pathogenic intestinal inflammation.
Published: 2019

150. Interplay of charge-transfer and Mott-Hubbard physics approached by an efficient combination of self-interaction correction and dynamical mean-field theory

Author: Daniel F. Urban, Christian Elsässer, Frank Lechermann, Wolfgang Körner, and Publica
Subjects: Mott-Hubbard, FOS: Physical sciences, 02 engineering and technology, Electronic structure, 01 natural sciences, DFT, condensed scatter, Pseudopotential, Condensed Matter - Strongly Correlated Electrons, Dynamical mean field theory, Atomic orbital, 0103 physical sciences, 010306 general physics, Physics, Condensed Matter - Materials Science, sicDMTF, Valence (chemistry), Strongly Correlated Electrons (cond-mat.str-el), Condensed matter physics, Non-blocking I/O, Materials Science (cond-mat.mtrl-sci), strongly correlated electrons, 021001 nanoscience & nanotechnology, electronic structure, charge-transfer, Condensed Matter::Strongly Correlated Electrons, Density functional theory, 0210 nano-technology
Abstract: Late transition-metal oxides with small charge-transfer energy $\Delta$ raise issues for state-of-the-art correlated electronic structure schemes such as the combination of density functional theory (DFT) with dynamical mean-field theory (DMFT). The accentuated role of the oxygen valence orbitals in these compounds asks for an enhanced description of ligand-based correlations. Utilizing the rocksalt-like NiO as an example, we present an advancement of charge self-consistent DFT+DMFT by including self-interaction correction (SIC) applied to oxygen. This introduces explicit onsite O correlations as well as an improved treatment of intersite $p-d$ correlations. Due to the efficient SIC incorporation in a pseudopotential form, the DFT+sicDMFT framework is an advanced but still versatile method to address the interplay of charge-transfer and Mott-Hubbard physics. We revisit the spectral features of stoichiometric NiO and reveal the qualitative sufficiency of local DMFT self-energies in describing spectral peak structures usually associated with explicit nonlocal processes. For Li$_x$Ni$_{1-x}$O, prominent in-gap states are verified by the present theoretical study., Comment: 8 pages, 6 figures
Published: 2019

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