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andrea amalfitano

Anthony Antonellis, Stephanie N Oprescu, Laurie B Griffin, Amer Heider, Andrea Amalfitano, Jeffrey W Innis
Aminoacyl-tRNA synthetases (ARSs) are ubiquitously expressed enzymes that ligate amino acids onto tRNA molecules. Genes encoding ARSs have been implicated in phenotypically diverse dominant and recessive human diseases. The charging of tRNAPHE with phenylalanine is performed by a tetrameric enzyme that contains two alpha (FARSA) and two beta (FARSB) subunits. To date, mutations in the genes encoding these subunits (FARSA and FARSB) have not been implicated in any human disease. Here, we describe a patient with a severe, lethal, multisystem, developmental phenotype who was compound heterozygous for FARSB variants: p...
March 23, 2018: Human Mutation
Nermin M Kady, Xuwen Liu, Todd A Lydic, Meesum H Syed, Svetlana Navitskaya, Qi Wang, Sandra S Hammer, Sandra O'Reilly, Chao Huang, Sergey S Seregin, Andrea Amalfitano, Vince A Chiodo, Sanford L Boye, William W Hauswirth, David A Antonetti, Julia V Busik
Tight junctions (TJs) involve close apposition of transmembrane proteins between cells. Although TJ proteins have been studied in detail, the role of lipids is largely unknown. We addressed the role of very long-chain (VLC ≥26) ceramides in TJs using diabetes-induced loss of the blood-retinal barrier as a model. VLC fatty acids that incorporate into VLC ceramides are produced by elongase elongation of very long-chain fatty acids protein 4 (ELOVL4). ELOVL4 is significantly reduced in the diabetic retina. Overexpression of ELOVL4 significantly decreased basal permeability, inhibited vascular endothelial growth factor (VEGF)- and interleukin-1β-induced permeability, and prevented VEGF-induced decrease in occludin expression and border staining of TJ proteins ZO-1 and claudin-5...
April 2018: Diabetes
Michael D Rizzo, Robert B Crawford, Joseph E Henriquez, Yasser A Aldhamen, Peter Gulick, Andrea Amalfitano, Norbert E Kaminski
OBJECTIVE: Chronic immune activation and elevated numbers of circulating activated monocytes (CD16) are implicated in HIV-associated neuroinflammation. The objective was to compare the level of circulating CD16 monocytes and IFN-γ-inducible protein 10 (IP-10) between HIV-infected cannabis users (HIV+MJ+) and noncannabis users (HIV+MJ-) and determine whether in-vitro Δ-Tetrahydrocannabinol (THC), a constituent of cannabis, affected CD16 expression as well as IP-10 production by monocytes...
February 20, 2018: AIDS
David P W Rastall, Andrea Amalfitano
Purpose of review Lysosomal storage disorders (LSDs) are a class of genetic disorders that are a testing ground for the invention of novel therapeutics including enzyme replacement therapy (ERT), substrate reduction therapy (SRT), gene therapy, and hematopoietic stem cell transplant (HSCT). This review summarizes recently approved drugs, then examines the successful clinical trials in gene therapy and HSCT. Recent findings The FDA has recently approved a second SRT by reversing an earlier FDA decision, suggesting a favorable regulatory landscape going forward...
November 4, 2017: Current Treatment Options in Neurology
Cristiana Callieri, Stefano Amalfitano, Gianluca Corno, Andrea Di Cesare, Roberto Bertoni, Ester M Eckert
Planktonic cyanobacteria belonging to the genus Synechococcus are ubiquitously distributed in marine and fresh waters, substantially contributing to total carbon fixation on a global scale. While their ecological relevance is acknowledged, increasing resolution in molecular techniques allows disentangling cyanobacteria's role at the micro-scale, where complex microbial interactions may drive the overall community assembly. The interplay between phylogenetically different Synechococcus clades and their associated bacterial communities can affect their ecological fate and susceptibility to protistan predation...
December 2017: Journal of Phycology
David P W Rastall, Fadel S Alyaquob, Patrick O'Connell, Yuliya Pepelyayeva, Douglas Peters, Sarah Godbehere-Roosa, Cristiane Pereira-Hicks, Yasser A Aldhamen, Andrea Amalfitano
Specific variants of endoplasmic reticulum-associated aminopeptidase 1 (ERAP1) identified by genome-wide association study modify the risk for developing ankylosing spondylitis. We previously confirmed that disease-associated ERAP1 variants have altered enzymatic abilities that can impact upon the production of pro-inflammatory cytokines from cells expressing the same ERAP1 variants. To determine if these ERAP1 variants also impacted immune responses in vivo, we generated two strains of transgenic mice expressing human ERAP1 genes containing non-synonymous single-nucleotide polymorphisms associated with an increased (ERAP1-High) or decreased (ERAP1-Low) risk for developing autoimmune disease...
June 1, 2017: International Immunology
Elisabet Ejarque, Anna Freixa, Eusebi Vazquez, Alba Guarch, Stefano Amalfitano, Stefano Fazi, Anna M Romaní, Andrea Butturini
Understanding DOM transport and reactivity in rivers is essential to having a complete picture of the global carbon cycle. In this study, we explore the effects of hydrological variability and downstream transport on dissolved organic matter (DOM) dynamics in a Mediterranean river. We sampled the main stem of the river Tordera from the source to the sea, over a range of fifteen hydrological conditions including extreme events (flood and drought). By exploring spatial and temporal gradients of DOM fluorescence properties, river hydrology was found to be a significant predictor of DOM spatial heterogeneity...
December 1, 2017: Science of the Total Environment
Dionisia Quiroga, Yasser A Aldhamen, Sarah Godbehere, Laura Harding, Andrea Amalfitano
Recombinant adenovirus serotype 5 (Ad5) vectors are promising vaccine candidates due to their intrinsic immunogenicity and potent transgene expression; however, widespread preexisting Ad5 immunity has been considered a developmental impediment to the use of traditional, or conventional, E1 and E3 gene-deleted Ad5 (Ad5[E1-]) vaccines. Even in the presence of anti-Ad5 immunity, recent murine and human studies have confirmed E2b gene-deleted Ad5 (Ad5[E1-,E2b-]) vaccines to be highly efficacious inducers of transgene-specific memory responses and significantly less toxic options than Ad5[E1-] vaccines...
June 2017: Clinical and Vaccine Immunology: CVI
Yasser A Aldhamen, David P W Rastall, Weimin Chen, Sergey S Seregin, Cristiane Pereira-Hicks, Sarah Godbehere, Norbert E Kaminski, Andrea Amalfitano
The CD2-like receptor activating cytotoxic cell (CRACC) receptor is a member of the SLAM family of receptors that are found on several types of immune cells. We previously demonstrated that increasing the abundance of the adaptor protein EAT-2 during vaccination enhanced innate and adaptive immune responses to vaccine antigens. Engagement of the CRACC receptor in the presence of the EAT-2 adaptor generally results in immune cell activation, while activating CRACC signaling in cells that lack EAT-2 adaptor inhibits their effector and regulatory functions...
June 8, 2016: Vaccine
Fadel S Alyaqoub, Yasser A Aldhamen, Benjamin J Koestler, Eric L Bruger, Sergey S Seregin, Cristiane Pereira-Hicks, Sarah Godbehere, Christopher M Waters, Andrea Amalfitano
There is a compelling need for more effective vaccine adjuvants to augment induction of Ag-specific adaptive immune responses. Recent reports suggested the bacterial second messenger bis-(3'-5')-cyclic-dimeric-guanosine monophosphate (c-di-GMP) acts as an innate immune system modulator. We recently incorporated a Vibrio cholerae diguanylate cyclase into an adenovirus vaccine, fostering production of c-di-GMP as well as proinflammatory responses in mice. In this study, we recombined a more potent diguanylate cyclase gene, VCA0848, into a nonreplicating adenovirus serotype 5 (AdVCA0848) that produces elevated amounts of c-di-GMP when expressed in mammalian cells in vivo...
February 15, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
David Pw Rastall, Andrea Amalfitano
Lysosomal storage disorders (LSDs) are a group of genetic diseases that result in metabolic derangements of the lysosome. Most LSDs are due to the genetic absence of a single catabolic enzyme, causing accumulation of the enzyme's substrate within the lysosome. Over time, tissue-specific substrate accumulations result in a spectrum of symptoms and disabilities that vary by LSD. LSDs are promising targets for gene therapy because delivery of a single gene into a small percentage of the appropriate target cells may be sufficient to impact the clinical course of the disease...
2015: Application of Clinical Genetics
Dionisia Quiroga, Yasser A Aldhamen, Daniel M Appledorn, Sarah Godbehere, Andrea Amalfitano
The need for novel, effective adjuvants that are capable of eliciting stronger cellular and humoral adaptive immune responses to antigenic targets is well understood in the vaccine development field. Unfortunately, many adjuvants investigated thus far are either too toxic for human application or too weak to induce a substantial response against difficult antigens, such as tumor-associated antigens (TAAs). In spite of this trend, clinical investigations of recombinant Eimeria antigen (rEA) have revealed this protein to be a non-toxic immunogenic agent with the ability to trigger a Th1-predominant response in both murine and human subjects...
April 2015: Cancer Immunology, Immunotherapy: CII
Yasser A Aldhamen, Yuliya Pepelyayeva, David P W Rastall, Sergey S Seregin, Efthalia Zervoudi, Despoina Koumantou, Charles F Aylsworth, Dionisia Quiroga, Sarah Godbehere, Dimitris Georgiadis, Efstratios Stratikos, Andrea Amalfitano
Endoplasmic reticulum aminopeptidase 1 (ERAP1) gene polymorphisms have been linked to several autoimmune diseases; however, the molecular mechanisms underlying these associations are not well understood. Recently, we demonstrated that ERAP1 regulates key aspects of the innate immune response. Previous studies show ERAP1 to be endoplasmic reticulum-localized and secreted during inflammation. Herein, we investigate the possible roles that ERAP1 polymorphic variants may have in modulating the innate immune responses of human peripheral blood mononuclear cells (hPBMCs) using two experimental methods: extracellular exposure of hPBMCs to ERAP1 variants and adenovirus (Ad)-based ERAP1 expression...
2015: Journal of Innate Immunity
Benjamin J Koestler, Sergey S Seregin, David P W Rastall, Yasser A Aldhamen, Sarah Godbehere, Andrea Amalfitano, Christopher M Waters
The bacterial second messenger cyclic di-GMP (c-di-GMP) stimulates inflammation by initiating innate immune cell recruitment and triggering the release of proinflammatory cytokines and chemokines. These properties make c-di-GMP a promising candidate for use as a vaccine adjuvant, and numerous studies have demonstrated that administration of purified c-di-GMP with different antigens increases protection against infection in animal models. Here, we have developed a novel approach to produce c-di-GMP inside host cells as an adjuvant to exploit a host-pathogen interaction and initiate an innate immune response...
November 2014: Clinical and Vaccine Immunology: CVI
David P W Rastall, Yasser A Aldhamen, Sergey S Seregin, Sarah Godbehere, Andrea Amalfitano
Endoplasmic reticulum aminopeptidase 1 (ERAP1) is a critical component of the adaptive immune system that has been shown to increase or decrease the presentation of specific peptides on MHC class I molecules. Here, we have demonstrated that ERAP1 functions are not only important during the presentation of antigen-derived peptides, but these functions can also completely change which antigen-derived peptides ultimately become selected as immunodominant T-cell epitopes. Our results suggest that ERAP1 may do this by destroying epitopes that would otherwise become immunodominant in the absence of adequate ERAP1 functionality...
December 2014: International Immunology
Yasser A Aldhamen, Sergey S Seregin, Charles F Aylsworth, Sarah Godbehere, Andrea Amalfitano
The signaling lymphocytic activation molecule (SLAM) receptor-associated adaptor Ewing's sarcoma-associated transcript-2 (EAT-2) is primarily expressed in innate immune cells including dendritic cells (DCs), macrophages and NK cells. A recent human HIV vaccine study confirmed that EAT-2 expression was associated with the enhanced immunogenicity induced by the MRKAd5/HIV vaccine. We previously harnessed the capability of EAT-2 to modulate signaling mediated by SLAM receptors and demonstrated that by incorporating EAT-2 expression into vaccines, one could enhance innate and adaptive immune responses in mice, even in the face of pre-existing immunity to the vaccine vectors...
May 2014: International Immunology
Efthalia Zervoudi, Emmanuel Saridakis, James R Birtley, Sergey S Seregin, Emma Reeves, Paraskevi Kokkala, Yasser A Aldhamen, Andrea Amalfitano, Irene M Mavridis, Edward James, Dimitris Georgiadis, Efstratios Stratikos
Intracellular aminopeptidases endoplasmic reticulum aminopeptidases 1 and 2 (ERAP1 and ERAP2), and as well as insulin-regulated aminopeptidase (IRAP) process antigenic epitope precursors for loading onto MHC class I molecules and regulate the adaptive immune response. Their activity greatly affects the antigenic peptide repertoire presented to cytotoxic T lymphocytes and as a result can regulate cytotoxic cellular responses contributing to autoimmunity or immune evasion by viruses and cancer cells. Therefore, pharmacological regulation of their activity is a promising avenue for modulating the adaptive immune response with possible applications in controlling autoimmunity, in boosting immune responses to pathogens, and in cancer immunotherapy...
December 3, 2013: Proceedings of the National Academy of Sciences of the United States of America
Pavlo L Kovalenko, Lisi Yuan, Kelian Sun, Lyudmyla Kunovska, Sergey Seregin, Andrea Amalfitano, Marc D Basson
Although we stimulate enterocytic proliferation to ameliorate short gut syndrome or mucosal atrophy, less effort has been directed at enterocytic differentiation. Schlafen 3 (Slfn3) is a poorly understood protein induced during IEC-6 enterocytic differentiation. We hypothesized that exogenous manipulation of Slfn3 would regulate enterocytic differentiation in vivo. Adenoviral vector coding for Slfn3 cDNA (Ad-GFP-Slfn3) or silencing RNA for Slfn3 (siSlfn3) was introduced intraluminally into rat intestine. We assessed Slfn3, villin, sucrase-isomaltase (SI), Dpp4, and Glut2 by qRT-PCR, Western blot, and immunohistochemistry...
2013: PloS One
Sergey S Seregin, David P W Rastall, Irini Evnouchidou, Charles F Aylsworth, Dionisia Quiroga, Ram P Kamal, Sarah Godbehere-Roosa, Christopher F Blum, Ian A York, Efstratios Stratikos, Andrea Amalfitano
Ankylosing spondylitis (AS) is a chronic systemic arthritic disease that leads to significant disability and loss of quality of life in the ∼0.5% of the worldwide human population it affects. There is currently no cure for AS and mechanisms underlying its pathogenesis remain unclear. AS is highly genetic, with over 70% of the genetic risk being associated with the presence of HLA-B27 and endoplasmic reticulum aminopeptidase-1 (ERAP1) alleles. Furthermore, gene-gene interactions between HLA-B27 and ERAP1 AS risk alleles have recently been confirmed...
December 2013: Autoimmunity
Yasser A Aldhamen, Sergey S Seregin, David P W Rastall, Charles F Aylsworth, Yuliya Pepelyayeva, Christopher J Busuito, Sarah Godbehere-Roosa, Sungjin Kim, Andrea Amalfitano
Endoplasmic reticulum aminopeptidase-1 (ERAP1) is a multifunctional, ubiquitously expressed enzyme whose peptide-trimming role during antigen processing for presentation by MHC I molecules is well established, however, a role for ERAP1 in modulating global innate immune responses has not been described to date. Here we demonstrate that, relative to wild type mice, mice lacking ERAP1 exhibit exaggerated innate immune responses early during pathogen recognition, as characterized by increased activation of splenic and hepatic NK and NKT cells and enhanced production of pro-inflammatory cytokines such as IL12 and MCP1...
2013: PloS One
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