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Complement pathways

Valter D Longo
The identification of conserved genes and pathways that regulate lifespan but also healthspan has resulted in an improved understanding of the link between nutrients, signal transduction proteins, and aging but has also provided evidence for the existence of multiple "longevity programs," which are selected based on the availability of nutrients. Periodic fasting and other dietary restrictions can promote entry into a long-lasting longevity program characterized by cellular protection and optimal function but can also activate regenerative processes that lead to rejuvenation, which are independent of the aging rate preceding the restricted period...
October 17, 2018: Aging Cell
Sophie Chauvet, Lubka T Roumenina, Pierre Aucouturier, Maria-Chiara Marinozzi, Marie-Agnès Dragon-Durey, Alexandre Karras, Yahsou Delmas, Moglie Le Quintrec, Dominique Guerrot, Noémie Jourde-Chiche, David Ribes, Pierre Ronco, Frank Bridoux, Véronique Fremeaux-Bacchi
C3 glomerulopathy (C3G) results from acquired or genetic abnormalities in the complement alternative pathway (AP). C3G with monoclonal immunoglobulin (MIg-C3G) was recently included in the spectrum of "monoclonal gammopathy of renal significance." However, mechanisms of complement dysregulation in MIg-C3G are not described and the pathogenic effect of the monoclonal immunoglobulin is not understood. The purpose of this study was to investigate the mechanisms of complement dysregulation in a cohort of 41 patients with MIg-C3G...
2018: Frontiers in Immunology
Sarah A Wall, Qiuhong Zhao, Martha Yearsley, Luke Blower, Akwasi Agyeman, Parvathi Ranganathan, Shangbin Yang, Haiwa Wu, Matthew Bostic, Samantha Jaglowski, Jonathan E Brammer, Basem William, Hannah Choe, Alice S Mims, Sam Penza, Yvonne Efebera, Steven Devine, Spero Cataland, Stella M Davies, Sumithira Vasu
Transplant-associated thrombotic microangiopathy (TA-TMA), a complication of hematopoietic cell transplant (HCT), is associated with significant morbidity and mortality. The pathophysiology and overlap of TA-TMA with other posttransplant complications such as graft-versus-host disease (GVHD) is poorly understood. We retrospectively identified cases of TA-TMA among patients with grade 3/4 gastrointestinal (GI) GVHD, reviewed intestinal biopsy specimens, and performed correlative testing of biomarkers associated with TA-TMA...
October 23, 2018: Blood Advances
Jennetta W Hammond, Wen Q Qiu, Daniel F Marker, Jeffrey M Chamberlain, Will Greaves-Tunnell, Matthew J Bellizzi, Shao-Ming Lu, Harris A Gelbard
Microglial activation, increased proinflammatory cytokine production, and a reduction in synaptic density are key pathological features associated with HIV-associated neurocognitive disorders (HAND). Even with combination antiretroviral therapy (cART), more than 50% of HIV-positive individuals experience some type of cognitive impairment. Although viral replication is inhibited by cART, HIV proteins such as Tat are still produced within the nervous system that are neurotoxic, involved in synapse elimination, and provoke enduring neuroinflammation...
October 16, 2018: Glia
Rafael Bayarri-Olmos, Nikolaj Kirketerp-Moller, Laura Pérez-Alós, Karsten Skjodt, Mikkel-Ole Skjoedt, Peter Garred
Collectin-11 (CL-11) is a pattern recognition molecule of the lectin pathway of complement with diverse functions spanning from host defense to embryonic development. CL-11 is found in the circulation in heterocomplexes with the homologous collectin-10 (CL-10). Abnormal CL-11 plasma levels are associated with the presence of disseminated intravascular coagulation, urinary schistosomiasis, and congenital disorders. Although there has been a marked development in the characterization of CL-11 there is still a scarcity of clinical tools for its analysis...
2018: Frontiers in Immunology
Kamil Bojarczuk, Kirsty Wienand, Jeremy A Ryan, Linfeng Chen, Mariana Villalobos-Ortiz, Elisa Mandato, Joanna Stachura, Anthony Letai, Lee N Lawton, Bjoern Chapuy, Margaret A Shipp
Inhibition of the B-cell receptor (BCR) signaling pathway is a promising treatment strategy in multiple B-cell malignancies. However, the role of BCR blockade in diffuse large B-cell lymphoma (DLBCL) remains undefined. We recently characterized primary DLBCL subsets with distinct genetic bases for perturbed BCR/PI3K signaling and dysregulated BCL-2 expression. Herein, we explore the activity of PI3K inhibitors and BCL-2 blockade in a panel of functionally and genetically characterized DLBCL cell line models...
October 15, 2018: Blood
Roy Al Ahmar, Brandon D Kirby, Hongwei D Yu
Mucoidy due to alginate overproduction by the Gram-negative bacterium Pseudomonas aeruginosa facilitates chronic lung infections in patients with Cystic Fibrosis (CF). We previously reported that disruption in de novo synthesis of pyrimidines resulted in conversion to a non-mucoid small colony variant (SCV) in the mucoid P. aeruginosa strain (PAO581), which has a truncated anti-sigma factor MucA25 that cannot sequester sigma factor AlgU/T. Here we showed that supplementation with the nitrogenous bases uracil or cytosine in growth medium complemented SCV to normal growth, and non-mucoidy to mucoidy in these mucA25 mutants...
October 15, 2018: Journal of Bacteriology
Joseph O'Flynn, Juha Kotimaa, Ria Faber-Krol, Karin Koekkoek, Ngaisah Klar-Mohamad, Angela Koudijs, Wilhelm J Schwaeble, Cordula Stover, Mohamed R Daha, Cees van Kooten
Properdin is the only known positive regulator of complement activation by stabilizing the alternative pathway convertase through C3 binding, thus prolonging its half-life. Recent in vitro studies suggest that properdin may act as a specific pattern recognition molecule. To better understand the role of properdin in vivo, we used an experimental model of acute anti-glomerular basement membrane disease with wild-type, C3- and properdin knockout mice. The model exhibited severe proteinuria, acute neutrophil infiltration and activation, classical and alternative pathway activation, and progressive glomerular deposition of properdin, C3 and C9...
October 10, 2018: Kidney International
Marianne Dor, Simone Eperon, Patrice H Lalive, Yan Guex-Crosier, Mehrad Hamedani, Cindy Salvisberg, Natacha Turck
Considering absence of invasiveness and side effects, tears emerge as a particularly attractive fluid for biomarker discovery and therefore for daily clinical use. However, to date this fluid remains poorly studied in healthy condition. Here, we present an updated in-depth characterisation of the human healthy tear protein composition using proteomics approach. Both eyes of 8 healthy controls (4 men and 4 women, average age: 38 ± 18) were collected using the Schirmer's strip method. After liquid digestion and off-gel electrophoresis fractionation, three independent proteomics analyses were performed on a LTQ-Orbitrap Velos Pro...
October 12, 2018: Experimental Eye Research
Neha Arora, Durgesh Dubey, Meenakshi Sharma, Alok Patel, Anupam Guleria, Parul A Pruthi, Dinesh Kumar, Vikas Pruthi, Krishna Mohan Poluri
Nuclear magnetic resonance (NMR)-based metabolomic approach is a high-throughput fingerprinting technique that allows a rapid snapshot of metabolites without any prior knowledge of the organism. To demonstrate the applicability of NMR-based metabolomics in the field of microalgal-based bioremediation, novel freshwater microalga Scenedesmus sp. IITRIND2 that showed hypertolerance to As(III, V) was chosen for evaluating the metabolic perturbations during arsenic stress in both its oxidation states As(III) and As(V)...
September 30, 2018: ACS Omega
Paolo Macor, Sara Capolla, Francesco Tedesco
Deposits of complement components have been documented in several human tumors suggesting a potential involvement of the complement system in tumor immune surveillance. In vitro and in vivo studies have revealed a double role played by this system in tumor progression. Complement activation in the cancer microenvironment has been shown to promote cancer growth through the release of the chemotactic peptide C5a recruiting myeloid suppressor cells. There is also evidence that tumor progression can be controlled by complement activated on the surface of cancer cells through one of the three pathways of complement activation...
2018: Frontiers in Immunology
Gail A Bishop, Laura L Stunz, Bruce S Hostager
The adaptor protein TNF receptor-associated factor 3 (TRAF3) serves as a powerful negative regulator in multiple aspects of B cell biology. Early in vitro studies in transformed cell lines suggested the potential of TRAF3 to inhibit signaling by its first identified binding receptor, CD40. However, because the canonical TRAF3 binding site on many receptors also mediates binding of other TRAFs, and whole-mouse TRAF3 deficiency is neonatally lethal, an accurate understanding of TRAF3's specific functions was delayed until conditional TRAF3-deficient mice were produced...
2018: Frontiers in Immunology
Hiroyasu Konno, Yasuo Yoshida, Keiji Nagano, Jun Takebe, Yoshiaki Hasegawa
Cyclic dimeric adenosine 3',5'-monophosphate (c-di-AMP), a recently identified secondary messenger in bacteria, plays a role in several bacterial processes, including biofilm formation. It is enzymatically produced by diadenylate cyclase and cleaved by c-di-AMP phosphodiesterase. c-di-AMP is believed to be essential for the viability of bacterial cells that produce it. In the current study, the biochemical and biological roles of GdpP (SMU_2140c) and DhhP (SMU_1297), two distinct Streptococcus mutans phosphodiesterases involved in the pathway producing AMP from c-di-AMP, were investigated...
2018: Frontiers in Microbiology
Diego Santos-Garcia, Ksenia Juravel, Shiri Freilich, Einat Zchori-Fein, Amparo Latorre, Andrés Moya, Shai Morin, Francisco J Silva
Insect lineages feeding on nutritionally restricted diets such as phloem sap, xylem sap, or blood, were able to diversify by acquiring bacterial species that complement lacking nutrients. These bacteria, considered obligate/primary endosymbionts, share a long evolutionary history with their hosts. In some cases, however, these endosymbionts are not able to fulfill all of their host's nutritional requirements, driving the acquisition of additional symbiotic species. Phloem-feeding members of the insect family Aleyrodidae (whiteflies) established an obligate relationship with Candidatus Portiera aleyrodidarum, which provides its hots with essential amino acids and carotenoids...
2018: Frontiers in Microbiology
Jian-Guo Qiu, Da-Yan Shi, Xin Liu, Xi-Xia Zheng, Lei Wang, Qian Li
Urothelial bladder carcinoma is the ninth most common cancer in the world, with an estimated 150,000 deaths per year. Two comprehensive analysis based on The Cancer Genome Atlas urothelial bladder carcinoma reported that chromatin modifier gene mutations were common in bladder cancer. We aimed to find how the mutations and transcriptional profiles of the genes involving in chromatin modification affected the prognosis of patients. The data were retrieved from the Genomic Data Commons data portal and the gene list in pathway Chromatin Modifying Enzymes were obtained from Reactome...
October 14, 2018: Journal of Cellular Physiology
Hanwei Fang, Ana Rita Gomes, Natacha Klages, Paco Pino, Bohumil Maco, Eloise M Walker, Zenon A Zenonos, Fiona Angrisano, Jake Baum, Christian Doerig, David A Baker, Oliver Billker, Mathieu Brochet
In malaria parasites, evolution of parasitism has been linked to functional optimisation. Despite this optimisation, most members of a calcium-dependent protein kinase (CDPK) family show genetic redundancy during erythrocytic proliferation. To identify relationships between phospho-signalling pathways, we here screen 294 genetic interactions among protein kinases in Plasmodium berghei. This reveals a synthetic negative interaction between a hypomorphic allele of the protein kinase G (PKG) and CDPK4 to control erythrocyte invasion which is conserved in P...
October 12, 2018: Nature Communications
Mebratu A Bitew, Chen Ai Khoo, Nitika Neha, David P De Souza, Dedreia Tull, Nadeeka K Wawegama, Hayley J Newton, Fiona M Sansom
Coxiella burnetii is an intracellular Gram-negative bacterium responsible for the important zoonotic disease Q fever. Improved genetic tools and the ability to grow this bacterium in host cell-free media has advanced the study of C. burnetii pathogenesis, but the mechanisms that allow it to survive inside the hostile phagolysosome remain incompletely understood. Previous screening of a transposon mutant library for replication within HeLa cells has suggested that nadB , encoding a putative L-aspartate oxidase required for de novo NAD synthesis, is needed for intracellular replication...
October 12, 2018: Journal of Biological Chemistry
Thiagarayaselvam Aarthy, Fayaj A Mulani, Avinash Pandreka, Ashish Kumar, Sharvani S Nandikol, Saikat Haldar, Hirekodathakallu V Thulasiram
BACKGROUND: Neem tree serves as a cornucopia for triterpenoids called limonoids that are of profound interest to humans due to their diverse biological activities. However, the biosynthetic pathway that plant employs for the production of limonoids remains unexplored for this wonder tree. RESULTS: Herein, we report the tracing of limonoid biosynthetic pathway through feeding experiments using 13 C isotopologues of glucose in neem cell suspension. Growth and development specific limonoid spectrum of neem seedling and time dependent limonoid biosynthetic characteristics of cell lines were established...
October 11, 2018: BMC Plant Biology
Dalton T Snyder, Lucas J Szalwinski, J Mitchell Wells, R Graham Cooks
A new set of operations for tandem mass spectrometry in a linear ion trap is described. Logical MS/MS operations categorize compounds in mixtures based on characteristic structural features as revealed by MS/MS behavior recorded in multiple fragmentation pathways. This approach is a conceptual extension of tandem mass spectrometry in which interrogation of the full data domain is performed by simultaneous implementation of precursor and neutral loss scans. This process can be thought of as moving through the 2D MS/MS data domain along multiple scan lines simultaneously, which allows experiments that explore the 2D data domain of MS/MS to be couched in terms of logical operations, AND, NAND (not and), OR (inclusive or), XOR (exclusive or), NOT, etc...
October 12, 2018: Analyst
Sanjay Khandelwal, Joann Ravi, Lubica Rauova, Alexandra Johnson, Grace M Lee, Jennifer B Gilner, Sreenivasulu Gunti, Abner L Notkins, Maragatha Kuchibhatla, Michael Frank, Mortimer Poncz, Douglas B Cines, Gowthami M Arepally
The mechanisms by which exposure to heparin initiates antibody responses in many, if not most, recipients are poorly understood. We recently demonstrated that antigenic platelet factor 4 (PF4)/heparin complexes activate complement in plasma and bind to B cells. Here, we describe how this process is initiated. We observed wide stable variation in complement activation when PF4/heparin was added to plasma of healthy donors, indicating a responder "phenotype" (high, intermediate or low). Proteomic analysis of plasma from these healthy donors showed a strong correlation between complement activation and plasma IgM levels (r = 0...
October 11, 2018: Blood
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