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https://www.readbyqxmd.com/read/28490576/complement-c5a-functions-as-a-master-switch-for-the-ph-balance-in-neutrophils-exerting-fundamental-immunometabolic-effects
#1
Stephanie Denk, Miriam D Neher, David A C Messerer, Rebecca Wiegner, Bo Nilsson, Daniel Rittirsch, Kristina Nilsson-Ekdahl, Sebastian Weckbach, Anita Ignatius, Miriam Kalbitz, Florian Gebhard, Manfred E Weiss, Josef Vogt, Peter Radermacher, Jörg Köhl, John D Lambris, Markus S Huber-Lang
During sepsis, excessive activation of the complement system with generation of the anaphylatoxin C5a results in profound disturbances in crucial neutrophil functions. Moreover, because neutrophil activity is highly dependent on intracellular pH (pHi), we propose a direct mechanistic link between complement activation and neutrophil pHi In this article, we demonstrate that in vitro exposure of human neutrophils to C5a significantly increased pHi by selective activation of the sodium/hydrogen exchanger. Upstream signaling of C5a-mediated intracellular alkalinization was dependent on C5aR1, intracellular calcium, protein kinase C, and calmodulin, and downstream signaling regulated the release of antibacterial myeloperoxidase and lactoferrin...
May 10, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/28430891/development-and-validation-of-diagnostic-criteria-for-ibd-subtypes-with-an-emphasis-on-ibd-unclassified-in-children-a-multicenter-study-from-the-pediatric-ibd-porto-group-of-espghan
#2
Liron Birimberg-Schwartz, David M Zucker, Amichay Akriv, Salvatore Cucchiara, Fiona L Cameron, David C Wilson, Iza Lazowska, Lambri Yianni, Siba Prosad Paul, Claudio Romano, Sanja Kolacek, Stephan Buderus, Anders Pærregaard, Richard K Russell, Johanna C Escher, Dan Turner
Background: The revised Porto criteria identify subtypes of pediatric inflammatory bowel diseases: ulcerative colitis (UC), atypical UC, Inflammatory Bowel Disease Unclassified (IBDU), and Crohn's disease (CD). In continuation of the Porto criteria, we aimed to derive and validate criteria for standardizing the classification of the IBD subtypes. Methods: This was a multicenter retrospective longitudinal study from 23 centers affiliated with the Porto-group of ESPGHAN...
April 18, 2017: Journal of Crohn's & Colitis
https://www.readbyqxmd.com/read/28416449/complement-c3-targeted-therapy-replacing-long-held-assertions-with-evidence-based-discovery
#3
REVIEW
Dimitrios C Mastellos, Edimara S Reis, Daniel Ricklin, Richard J Smith, John D Lambris
Complement dysregulation underlies several inflammatory disorders, and terminal complement inhibition has thus far afforded significant clinical gains. Nonetheless, emerging pathologies, fueled by complement imbalance and therapy-skewing genetic variance, underscore the need for more comprehensive, disease-tailored interventions. Modulation at the level of C3, a multifaceted orchestrator of the complement cascade, opens up prospects for broader therapeutic efficacy by targeting multiple pathogenic pathways modulated by C3-triggered proinflammatory crosstalk...
April 14, 2017: Trends in Immunology
https://www.readbyqxmd.com/read/28372238/metabolite-profiling-and-volatiles-of-pineapple-wine-and-vinegar-obtained-from-pineapple-waste
#4
Arianna Roda, Luigi Lucini, Fabrizio Torchio, Roberta Dordoni, Dante Marco De Faveri, Milena Lambri
Vinegar is an inexpensive commodity, and economic considerations require that a relatively low-cost raw material be used for its production. An investigation into the use of a new, alternative substrate - pineapple waste - is described. This approach enables the utilization of the pineapple's (Ananas comosus) peels and core, which are usually discarded during the processing or consumption of the fruit. Using physical and enzymatic treatments, the waste was saccharified, and the resulting substrate was fermented with Saccharomyces cerevisiae for 7-10days under aerobic conditions at 25°C...
August 15, 2017: Food Chemistry
https://www.readbyqxmd.com/read/28344973/coarse-grained-conformational-sampling-of-protein-structure-improves-the-fit-to-experimental-hydrogen-exchange-data
#5
Didier Devaurs, Dinler A Antunes, Malvina Papanastasiou, Mark Moll, Daniel Ricklin, John D Lambris, Lydia E Kavraki
Monitoring hydrogen/deuterium exchange (HDX) undergone by a protein in solution produces experimental data that translates into valuable information about the protein's structure. Data produced by HDX experiments is often interpreted using a crystal structure of the protein, when available. However, it has been shown that the correspondence between experimental HDX data and crystal structures is often not satisfactory. This creates difficulties when trying to perform a structural analysis of the HDX data. In this paper, we evaluate several strategies to obtain a conformation providing a good fit to the experimental HDX data, which is a premise of an accurate structural analysis...
2017: Frontiers in Molecular Biosciences
https://www.readbyqxmd.com/read/28258193/structural-implications-for-the-formation-and-function-of-the-complement-effector-protein-ic3b
#6
Malvina Papanastasiou, Sophia Koutsogiannaki, Yiannis Sarigiannis, Brian V Geisbrecht, Daniel Ricklin, John D Lambris
Complement-mediated opsonization, phagocytosis, and immune stimulation are critical processes in host defense and homeostasis, with the complement activation fragment iC3b playing a key effector role. To date, however, there is no high-resolution structure of iC3b, and some aspects of its structure-activity profile remain controversial. Here, we employed hydrogen-deuterium exchange mass spectrometry to describe the structure and dynamics of iC3b at a peptide resolution level in direct comparison with its parent protein C3b...
April 15, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/28052876/pericytes-and-immune-cells-contribute-to-complement-activation-in-tubulointerstitial-fibrosis
#7
Sandhya Xavier, Ranjit K Sahu, Susan G Landes, Jing Yu, Ronald P Taylor, Srinivas Ayyadevara, Judit Megyesi, William B Stallcup, Jeremy S Duffield, Edimara S Reis, John D Lambris, Didier Portilla
We have examined the pathogenic role of increased complement expression and activation during kidney fibrosis. Here, we show that PDGFRβ-positive pericytes isolated from mice subjected to obstructive or folic acid injury secrete C1q. This was associated with increased production of proinflammatory cytokines, extracellular matrix components, collagens, and increased Wnt3a-mediated activation of Wnt/β-catenin signaling, which are hallmarks of myofibroblast activation. Real-time PCR, immunoblots, immunohistochemistry, and flow cytometry analysis performed in whole kidney tissue confirmed increased expression of C1q, C1r, and C1s as well as complement activation, which is measured as increased synthesis of C3 fragments predominantly in the interstitial compartment...
March 1, 2017: American Journal of Physiology. Renal Physiology
https://www.readbyqxmd.com/read/28028023/incomplete-inhibition-by-eculizumab-mechanistic-evidence-for-residual-c5-activity-during-strong-complement-activation
#8
Markus J Harder, Nadine Kuhn, Hubert Schrezenmeier, Britta Höchsmann, Inge von Zabern, Christof Weinstock, Thomas Simmet, Daniel Ricklin, John D Lambris, Arne Skerra, Markus Anliker, Christoph Q Schmidt
Eculizumab inhibits the terminal, lytic pathway of complement by blocking the activation of the complement protein C5 and shows remarkable clinical benefits in certain complement-mediated diseases. However, several reports suggest that activation of C5 is not always completely suppressed in patients even under excess of eculizumab over C5, indicating that residual C5 activity may derogate the drug's therapeutic benefit under certain conditions. By using eculizumab and the tick-derived C5 inhibitor coversin, we determined conditions ex vivo in which C5 inhibition is incomplete...
February 23, 2017: Blood
https://www.readbyqxmd.com/read/27992787/method-development-and-validation-for-the-quantitation-of-the-complement-inhibitor-cp40-in-human-and-cynomolgus-monkey-plasma-by-uplc-esi-ms
#9
Alexandra Primikyri, Malvina Papanastasiou, Yiannis Sarigiannis, Sophia Koutsogiannaki, Edimara S Reis, Joel V Tuplano, Ranillo R G Resuello, Bo Nilsson, Daniel Ricklin, John D Lambris
Cp40 is a 14-amino acid cyclic analog of the peptidic complement inhibitor compstatin that binds with sub-nanomolar affinity to complement component C3 and has already shown promise in various models of complement-related diseases. The preclinical and clinical development of this compound requires a robust, accurate, and sensitive method for quantitatively monitoring Cp40 in biological samples. In this study, we describe the development and validation of an ultra-high performance liquid chromatography electrospray mass spectrometry method for the quantitation of Cp40 in human and non-human primate (NHP) plasma...
January 15, 2017: Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences
https://www.readbyqxmd.com/read/27909702/complement-inhibition-enables-tumor-delivery-of-lcmv-glycoprotein-pseudotyped-viruses-in-the-presence-of-antiviral-antibodies
#10
Laura Evgin, Carolina S Ilkow, Marie-Claude Bourgeois-Daigneault, Christiano Tanese de Souza, Lawton Stubbert, Michael S Huh, Victoria A Jennings, Monique Marguerie, Sergio A Acuna, Brian A Keller, Charles Lefebvre, Theresa Falls, Fabrice Le Boeuf, Rebecca A Auer, John D Lambris, J Andrea McCart, David F Stojdl, John C Bell
The systemic delivery of therapeutic viruses, such as oncolytic viruses or vaccines, is limited by the generation of neutralizing antibodies. While pseudotyping of rhabdoviruses with the lymphocytic choriomeningitis virus glycoprotein has previously allowed for multiple rounds of delivery in mice, this strategy has not translated to other animal models. For the first time, we provide experimental evidence that antibodies generated against the lymphocytic choriomeningitis virus glycoprotein mediate robust complement-dependent viral neutralization via activation of the classical pathway...
2016: Molecular Therapy Oncolytics
https://www.readbyqxmd.com/read/27782328/more-than-complementing-tolls-complement-toll-like-receptor-synergy-and-crosstalk-in-innate-immunity-and-inflammation
#11
REVIEW
George Hajishengallis, John D Lambris
Complement and Toll-like receptors (TLRs) play key roles in the host immune response and are swiftly activated by infection or other types of immunological stress. This review focuses on the capacity of complement and TLRs to engage in signaling crosstalk, ostensibly to coordinate immune and inflammatory responses through synergistic or antagonistic (regulatory) interactions. However, overactivation or dysregulation of either system may lead-often synergistically-to exaggerated inflammation and host tissue injury...
November 2016: Immunological Reviews
https://www.readbyqxmd.com/read/27782325/complement-component-c3-the-swiss-army-knife-of-innate-immunity-and-host-defense
#12
REVIEW
Daniel Ricklin, Edimara S Reis, Dimitrios C Mastellos, Piet Gros, John D Lambris
As a preformed defense system, complement faces a delicate challenge in providing an immediate, forceful response to pathogens even at first encounter, while sparing host cells in the process. For this purpose, it engages a tightly regulated network of plasma proteins, cell surface receptors, and regulators. Complement component C3 plays a particularly versatile role in this process by keeping the cascade alert, acting as a point of convergence of activation pathways, fueling the amplification of the complement response, exerting direct effector functions, and helping to coordinate downstream immune responses...
November 2016: Immunological Reviews
https://www.readbyqxmd.com/read/27782322/preformed-mediators-of-defense-gatekeepers-enter-the-spotlight
#13
Daniel Ricklin, John D Lambris
No abstract text is available yet for this article.
November 2016: Immunological Reviews
https://www.readbyqxmd.com/read/27782321/protection-of-host-cells-by-complement-regulators
#14
REVIEW
Christoph Q Schmidt, John D Lambris, Daniel Ricklin
The complement cascade is an ancient immune-surveillance system that not only provides protection from pathogen invasion but has also evolved to participate in physiological processes to maintain tissue homeostasis. The alternative pathway (AP) of complement activation is the evolutionarily oldest part of this innate immune cascade. It is unique in that it is continuously activated at a low level and arbitrarily probes foreign, modified-self, and also unaltered self-structures. This indiscriminate activation necessitates the presence of preformed regulators on autologous surfaces to spare self-cells from the undirected nature of AP activation...
November 2016: Immunological Reviews
https://www.readbyqxmd.com/read/27709886/the-dynamics-behind-the-affinity-controlling-heme-gas-affinity-via-geminate-recombination-and-heme-propionate-conformation-in-the-no-carrier-cytochrome-c
#15
Colin R Andrew, Olga N Petrova, Isabelle Lamarre, Jean-Christophe Lambry, Fabrice Rappaport, Michel Negrerie
Nitric oxide (NO) sensors are heme proteins which may also bind CO and O2. Control of heme-gas affinity and their discrimination are achieved by the structural properties and reactivity of the heme and its distal and proximal environments, leading to several energy barriers. In the bacterial NO sensor cytochrome c' from Alcaligenes xylosoxidans (AXCP), the single Leu16Ala distal mutation boosts the affinity for gas ligands by a remarkable 10(6)-10(8)-fold, transforming AXCP from one of the lowest affinity gas binding proteins to one of the highest...
November 18, 2016: ACS Chemical Biology
https://www.readbyqxmd.com/read/27677785/complement-c3-inhibitor-cp40-attenuates-xenoreactions-in-pig%C3%A2-hearts-perfused-with-human-blood
#16
Jan-Michael Abicht, Ioannis Kourtzelis, Bruno Reichart, Sophia Koutsogiannaki, Alexandra Primikyri, John D Lambris, Triantafyllos Chavakis, Lesca Holdt, Alexander Kind, Sonja Guethoff, Tanja Mayr
BACKGROUND: The complement system plays a crucial role in acute xenogeneic reactions after cardiac transplantation. We used an ex vivo perfusion model to investigate the effect of Cp40, a compstatin analog and potent inhibitor of complement at the level of C3. METHODS: Fifteen wild-type pig hearts were explanted, cardiopleged, and reperfused ex vivo after 150 minutes of cold ischemia. Hearts were challenged in a biventricular working heart mode to evaluate cardiac perfusion and function...
January 2017: Xenotransplantation
https://www.readbyqxmd.com/read/27546448/compstatin-cp40-blocks-hematin-mediated-deposition-of-c3b-fragments-on-erythrocytes-implications-for-treatment-of-malarial-anemia
#17
Margaret A Lindorfer, Erika M Cook, Edimara S Reis, Daniel Ricklin, Antonio M Risitano, John D Lambris, Ronald P Taylor
During malarial anemia, 20 uninfected red blood cells (RBCs) are destroyed for every RBC infected by Plasmodium falciparum (Pf). Increasing evidence indicates an important role for complement in destruction of uninfected RBCs. Products of RBC lysis induced by Pf, including the digestive vacuole and hematin, activate complement and promote C3 fragment deposition on uninfected RBCs. C3-opsonized cells are then subject to extravascular destruction mediated by fixed tissue macrophages which express receptors for C3 fragments...
October 2016: Clinical Immunology: the Official Journal of the Clinical Immunology Society
https://www.readbyqxmd.com/read/27535705/high-fat-diet-induced-complement-activation-mediates-intestinal-inflammation-and-neoplasia-independent-of-obesity
#18
Stephanie K Doerner, Edimara S Reis, Elaine S Leung, Justine S Ko, Jason D Heaney, Nathan A Berger, John D Lambris, Joseph H Nadeau
Obesity and related metabolic disturbances are closely associated with pathologies that represent a significant burden to global health. Epidemiological and molecular evidence links obesity and metabolic status with inflammation and increased risk of cancer. Here, using a mouse model of intestinal neoplasia and strains that are susceptible or resistant to diet-induced obesity, it is demonstrated that high-fat diet-induced inflammation, rather than obesity or metabolic status, is associated with increased intestinal neoplasia...
October 2016: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/27522923/complement-therapeutics
#19
EDITORIAL
Daniel Ricklin, John D Lambris
No abstract text is available yet for this article.
June 2016: Seminars in Immunology
https://www.readbyqxmd.com/read/27511733/systems-analysis-of-the-complement-induced-priming-phase-of-liver-regeneration
#20
Jun S Min, Robert A DeAngelis, Edimara S Reis, Shakti Gupta, Mano R Maurya, Charles Evans, Arun Das, Charles Burant, John D Lambris, Shankar Subramaniam
Liver regeneration is a well-orchestrated process in the liver that allows mature hepatocytes to reenter the cell cycle to proliferate and replace lost or damaged cells. This process is often impaired in fatty or diseased livers, leading to cirrhosis and other deleterious phenotypes. Prior research has established the role of the complement system and its effector proteins in the progression of liver regeneration; however, a detailed mechanistic understanding of the involvement of complement in regeneration is yet to be established...
September 15, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
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