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[PMID]:29349451
[Au] Autor:Habka S; Sohn WY; Vaquero-Vara V; Géléoc M; Tardivel B; Brenner V; Gloaguen E; Mons M
[Ad] Endereço:LIDYL, CEA, CNRS, Université Paris Saclay, CEA Saclay, Bât 522, 91191 Gif-sur-Yvette, France. michel.mons@cea.fr.
[Ti] Título:On the turn-inducing properties of asparagine: the structuring role of the amide side chain, from isolated model peptides to crystallized proteins.
[So] Source:Phys Chem Chem Phys;20(5):3411-3423, 2018 Jan 31.
[Is] ISSN:1463-9084
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Asparagine (Asn) is a powerful turn-inducer residue, with a large propensity to occupy the second position in the central region of ß-turns of proteins. The present work aims at investigating the role of a local anchoring between the Asn side chain and the main chain in this remarkable property. For this purpose, the H-bonding patterns of an asparagine residue in an isolated protein chain fragment forming a γ- or a ß-turn have been determined using IR/UV double resonance gas phase spectroscopy on laser-desorbed, jet-cooled short models in conjunction with relevant quantum chemistry calculations. These gas phase data provide evidence for an original double anchoring linking the Asn primary amide side chain (SC), which adopts a gauche+ rotameric form, to its main chain (MC) local environment. From both IR spectroscopic evidence (H-bond induced red shifts) and quantum chemistry, Asn SC is found to behave as a stronger H-bond acceptor than donor, resulting in stronger MC→SC H-bonds than SC→MC ones. These gas phase structural data, relevant to a hydrophobic environment, have been used as a reference to assess the anchoring taking place in high resolution crystallized proteins of the Protein Data Bank. This approach reveals that, when the SC adopts a gauche+ orientation, the stronger MC→SC bonds are preserved in many cases whereas the SC→MC bonds are always disrupted, in qualitative agreement with the gas phase ranking of these interactions. Most interestingly, when Asn occupies the second position of central part of a ß-turn (i.e., the very turn-inducer position), the MC→SC H-bonds are also disrupted and replaced by a water-mediated SC to MC anchoring. Owing to the specific features of the hydrated Asn side chain, we propose that it could be a turn precursor structure, able to facilitate turn formation in the early events of the folding process.
[Mh] Termos MeSH primário: Asparagina/química
Peptídeos/química
[Mh] Termos MeSH secundário: Amidas/química
Gases/química
Ligações de Hidrogênio
Estrutura Secundária de Proteína
Teoria Quântica
Espectrofotometria Infravermelho
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Amides); 0 (Gases); 0 (Peptides); 7006-34-0 (Asparagine)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180226
[Lr] Data última revisão:
180226
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180120
[St] Status:MEDLINE
[do] DOI:10.1039/c7cp07605c


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[PMID]:29232127
[Au] Autor:Wu J; Sabag-Daigle A; Metz TO; Deatherage Kaiser BL; Gopalan V; Behrman EJ; Wysocki VH; Ahmer BMM
[Ad] Endereço:Department of Chemistry and Biochemistry, The Ohio State University , Columbus, Ohio 43210, United States.
[Ti] Título:Measurement of Fructose-Asparagine Concentrations in Human and Animal Foods.
[So] Source:J Agric Food Chem;66(1):212-217, 2018 Jan 10.
[Is] ISSN:1520-5118
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The food-borne bacterial pathogen, Salmonella enterica, can utilize fructose-asparagine (F-Asn) as its sole carbon and nitrogen source. F-Asn is the product of an Amadori rearrangement following the nonenzymatic condensation of glucose and asparagine. Heating converts F-Asn via complex Maillard reactions to a variety of molecules that contribute to the color, taste, and aroma of heated foods. Among these end derivatives is acrylamide, which is present in some foods, especially in fried potatoes. The F-Asn utilization pathway in Salmonella, specifically FraB, is a potential drug target because inhibition of this enzyme would lead to intoxication of Salmonella in the presence of F-Asn. However, F-Asn would need to be packaged with the FraB inhibitor or available in human foods. To determine if there are foods that have sufficient F-Asn, we measured F-Asn concentrations in a variety of human and animal foods. The 400 pmol/mg F-Asn found in mouse chow is sufficient to intoxicate a Salmonella fraB mutant in mouse models of salmonellosis, and several human foods were found to have F-Asn at this level or higher (fresh apricots, lettuce, asparagus, and canned peaches). Much higher concentrations (11 000-35 000 pmol/mg dry weight) were found in heat-dried apricots, apples, and asparagus. This report reveals possible origins of F-Asn as a nutrient source for Salmonella and identifies foods that could be used together with a FraB inhibitor as a therapeutic agent for Salmonella.
[Mh] Termos MeSH primário: Ração Animal/análise
Asparagina/análise
Asparagus (Planta)/química
Frutose/análise
Malus/química
Prunus armeniaca/química
Solanum tuberosum/química
[Mh] Termos MeSH secundário: Animais
Asparagus (Planta)/microbiologia
Temperatura Alta
Seres Humanos
Reação de Maillard
Malus/microbiologia
Prunus armeniaca/microbiologia
Salmonella enterica/genética
Salmonella enterica/metabolismo
Solanum tuberosum/microbiologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
30237-26-4 (Fructose); 7006-34-0 (Asparagine)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180205
[Lr] Data última revisão:
180205
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171213
[St] Status:MEDLINE
[do] DOI:10.1021/acs.jafc.7b04237


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[PMID]:28452462
[Au] Autor:Yang Q; An Y; Zhu S; Zhang R; Loke CM; Cipollo JF; Wang LX
[Ad] Endereço:Department of Chemistry and Biochemistry, University of Maryland , College Park, Maryland 20742, United States.
[Ti] Título:Glycan Remodeling of Human Erythropoietin (EPO) Through Combined Mammalian Cell Engineering and Chemoenzymatic Transglycosylation.
[So] Source:ACS Chem Biol;12(6):1665-1673, 2017 06 16.
[Is] ISSN:1554-8937
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The tremendous structural heterogeneity of N-glycosylation of glycoproteins poses a great challenge for deciphering the biological functions of specific glycoforms and for developing protein-based therapeutics. We have previously reported a chemoenzymatic glycan remodeling method for producing homogeneous glycoforms of N-glycoproteins including intact antibodies, which consist of endoglycosidase-catalyzed deglycosylation and novel glycosynthase-catalyzed transglycosylation, but its application to complex glycoproteins carrying multiple N-glycans remains to be examined. We report here site-selective chemoenzymatic glycosylation remodeling of recombinant human erythropoietin (EPO) that contains three N-glycans. We found that the generation of a HEK293S GnT I knockout FUT8 overexpressing cell line enabled the production of an unusual Man GlcNAc Fuc glycoform, which could be converted to the core-fucosylated GlcNAc-EPO intermediate acceptor for enzymatic transglycosylation. With this acceptor, homogeneous sialylated glycoform or azide-tagged glycoform were produced using the glycosynthase (EndoF3-D165A) catalyzed transglycosylation. Interestingly, a remarkable site-selectivity was observed in the transglycosylation reactions, leading to the introduction of two N-glycans selectively at the Asn-38 and Asn-83 sites, which was confirmed by a detailed MS/MS analysis of the transglycosylation product. Finally, a different N-glycan was attached at the third (Asn-24) site by pushing the enzymatic transglycosylation with a distinct glycan oxazoline, achieving the site-selective glycosylation modification of the protein. This study represents the first example of site-selective chemoenzymatic glycan engineering of complex glycoproteins carrying multiple N-glycans.
[Mh] Termos MeSH primário: Engenharia Celular/métodos
Eritropoetina/metabolismo
Polissacarídeos/metabolismo
Engenharia de Proteínas/métodos
[Mh] Termos MeSH secundário: Asparagina/metabolismo
Glicosilação
Células HEK293
Seres Humanos
Espectrometria de Massas em Tandem
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL
[Nm] Nome de substância:
0 (Polysaccharides); 11096-26-7 (Erythropoietin); 7006-34-0 (Asparagine)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:180201
[Lr] Data última revisão:
180201
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170429
[St] Status:MEDLINE
[do] DOI:10.1021/acschembio.7b00282


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[PMID]:29311443
[Au] Autor:Yokozeki T; Nishikawa K; Ogiso M; Fujita K
[Ad] Endereço:Japan Food Research Laboratories.
[Ti] Título:[Development of an HPLC-UV Method for Free Asparagine in Grains].
[So] Source:Shokuhin Eiseigaku Zasshi;58(6):247-252, 2017.
[Is] ISSN:1882-1006
[Cp] País de publicação:Japan
[La] Idioma:jpn
[Ab] Resumo:A novel analytical method was developed for the determination of free asparagine (Asn), which is a precursor of acrylamide, in grains. Asn was extracted from a sample with 5% (w/v) aqueous trichloroacetic acid solution, and the crude extract was cleaned up using a reversed-phase solid-phase cartridge. The cleaned extract was derivatized with dansyl chloride and analyzed by HPLC-UV. HPLC separation was performed by gradient elution on a ODS column using 0.01 mol/L ammonium acetate and acetonitrile mixture as the mobile phase. The calibration curve was linear in the range of 0.5-100 µg/mL. The mean recoveries from potato starch, non-glutinous rice flour and whole wheat flour ranged from 97.7 to 102.6%, the repeatability (RSDs) ranged from 0.8 to 2.0%, and the within-laboratory reproducibility (RSDwr) ranged from 1.4 to 6.2%. Limits of quantitation (LOQs) were 13 mg/kg for potato starch and 4 mg/kg for non-glutinous rice flour. The quantitative values obtained for about 15 kinds of grains using this developed method were approximately equal to those obtained with an automatic amino acid analyzer.
[Mh] Termos MeSH primário: Asparagina/análise
Cromatografia Líquida de Alta Pressão/métodos
Grãos Comestíveis/química
Análise de Alimentos/métodos
Contaminação de Alimentos/análise
[Mh] Termos MeSH secundário: Acrilamida
Farinha/análise
Reprodutibilidade dos Testes
Raios Ultravioleta
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
20R035KLCI (Acrylamide); 7006-34-0 (Asparagine)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180123
[Lr] Data última revisão:
180123
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180110
[St] Status:MEDLINE
[do] DOI:10.3358/shokueishi.58.247


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[PMID]:28873573
[Au] Autor:Curtis TY; Powers SJ; Wang R; Halford NG
[Ad] Endereço:Plant Science Department, Rothamsted Research, Harpenden, Hertfordshire AL5 2JQ, United Kingdom. Electronic address: tanyayankova@msn.com.
[Ti] Título:Effects of variety, year of cultivation and sulphur supply on the accumulation of free asparagine in the grain of commercial wheat varieties.
[So] Source:Food Chem;239:304-313, 2018 Jan 15.
[Is] ISSN:0308-8146
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Free asparagine concentration, which is the determining factor for acrylamide-forming potential in cereals, was measured in grain from wheat grown in field trials in the United Kingdom in 2011-2012 and 2012-2013. There were 25 varieties in 2012 and 59 in 2013, with eleven present in both trials. The trials were split-plot, with half of each plot supplied with sulphur and the other half not. The varietal means (mmol per kg) for free asparagine in the sulphur-fed wheat ranged from 1.521 to 2.687 in 2011-2012 and 0.708 to 11.29 in 2012-2013. Eight varieties were identified as having consistently low free asparagine concentration. There was a differential response of varieties to sulphur, and much higher levels of free asparagine in 2012-2013 versus 2011-2012. Given the short commercial lifespan of some wheat varieties, it is concluded that information on free asparagine concentration should be made available when a variety is launched.
[Mh] Termos MeSH primário: Triticum
[Mh] Termos MeSH secundário: Asparagina
Grãos Comestíveis
Enxofre
Reino Unido
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
7006-34-0 (Asparagine); 70FD1KFU70 (Sulfur)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:180116
[Lr] Data última revisão:
180116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170907
[St] Status:MEDLINE


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[PMID]:29253009
[Au] Autor:Hafstrand I; Badia-Martinez D; Josey BJ; Norström M; Buratto J; Pellegrino S; Duru AD; Sandalova T; Achour A
[Ad] Endereço:Science for Life Laboratory, Department of Medicine Solna, Karolinska Institutet, and Department of Infectious Diseases, Karolinska University Hospital, Solna, Stockholm, Sweden.
[Ti] Título:Crystal structures of H-2Db in complex with the LCMV-derived peptides GP92 and GP392 explain pleiotropic effects of glycosylation on antigen presentation and immunogenicity.
[So] Source:PLoS One;12(12):e0189584, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Post-translational modifications significantly broaden the epitope repertoire for major histocompatibility class I complexes (MHC-I) and may allow viruses to escape immune recognition. Lymphocytic choriomeningitis virus (LCMV) infection of H-2b mice generates CD8+ CTL responses directed towards several MHC-I-restricted epitopes including the peptides GP92 (CSANNSHHYI) and GP392 (WLVTNGSYL), both with a N-glycosylation site. Interestingly, glycosylation has different effects on the immunogenicity and association capacity of these two epitopes to H-2Db. To assess the structural bases underlying these functional results, we determined the crystal structures of H-2Db in complex with GP92 (CSANNSHHYI) and GP392 (WLVTNGSYL) to 2.4 and 2.5 Å resolution, respectively. The structures reveal that while glycosylation of GP392 most probably impairs binding, the glycosylation of the asparagine residue in GP92, which protrudes towards the solvent, possibly allows for immune escape and/or forms a neo-epitope that may select for a different set of CD8 T cells. Altogether, the presented results provide a structural platform underlying the effects of post-translational modifications on epitope binding and/or immunogenicity, resulting in viral immune escape.
[Mh] Termos MeSH primário: Apresentação do Antígeno
Antígenos Virais/imunologia
Antígenos H-2/imunologia
Vírus da Coriomeningite Linfocítica/imunologia
[Mh] Termos MeSH secundário: Animais
Asparagina/química
Linfócitos T CD8-Positivos/metabolismo
Cristalografia por Raios X
Epitopos/imunologia
Glicosilação
Camundongos
Peptídeos/imunologia
Processamento de Proteína Pós-Traducional
Solventes
Linfócitos T Citotóxicos/imunologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antigens, Viral); 0 (Epitopes); 0 (H-2 Antigens); 0 (Peptides); 0 (Solvents); 7006-34-0 (Asparagine)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180108
[Lr] Data última revisão:
180108
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171219
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0189584


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[PMID]:29047356
[Au] Autor:Marian AJ
[Ad] Endereço:Center for Cardiovascular Genetics, Institute of Molecular Medicine, University of Texas Health Sciences Center at Houston, 6770 Bertner Street, DAC900, Houston, TX, 77030, USA. Ali.J.Marian@uth.tmc.edu.
[Ti] Título:Non-syndromic cardiac progeria in a patient with the rare pathogenic p.Asp300Asn variant in the LMNA gene.
[So] Source:BMC Med Genet;18(1):116, 2017 Oct 18.
[Is] ISSN:1471-2350
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Mutations in LMNA gene, encoding Lamin A/C, cause a diverse array of phenotypes, collectively referred to as laminopathies. The most common manifestation is dilated cardiomyopathy (DCM), occurring in conjunction with variable skeletal muscle involvement but without involvement of the coronary arteries. Much less commonly, LMNA mutations cause progeroid syndromes, whereby an early-onset coronary artery disease (CAD) is the hallmark of the disease. We report a hitherto unreported compound cardiac phenotype, dubbed as "non-syndromic cardiac progeria", in a young patient who carried a rare pathogenic variant in the LMNA gene and developed progressive degeneration of various cardiac structures, as seen in the elderly. The phenotype resembled the progeroid syndromes, except that it was restricted to the heart and did not involve other organs. CASE PRESENTATION: The patient was a well-developed Caucasian female who presented at age 29 years with an acute myocardial infarction (MI) and was found to have extensive CAD. She had none of the conventional risk factors for atherosclerosis. She underwent coronary artery bypass surgery but continued to require multiple percutaneous coronary interventions for symptomatic obstructive coronary lesions. During the course of next 10 years, she developed mitral regurgitation, degenerative mitral and aortic valve diseases, atrial flutter, and progressive conduction defects. She died from progressive heart failure with predominant involvement of the right ventricle and severe tricuspid regurgitation. Cardiac phenotype in this young patient resembled degenerative cardiac diseases of the elderly and the progeroid syndromes. However, in contrast to the progeroid syndromes, the phenotype was restricted to the heart and did not involve other organs. Thus, the phenotype was dubbed as a non-syndromic cardiac progeria. Genetic screening of several cardiomyopathy genes, including LMNA, which is a causal gene for progeroid syndromes, led to identification of a very rare pathogenic p.Asp300Asn variant in the LMNA gene. CONCLUSIONS: We infer that the LMNA p.Asp300Asn mutation is pathogenic in non-syndromic cardiac progeria. Mutations involving codon 300 in the LMNA gene have been associated with progeroid syndromes involving multiple organs. Collectively, the data provide credence to the causal role of p.Asp300Asn mutation in the pathogenesis of non-syndromic cardiac progeria.
[Mh] Termos MeSH primário: Lamina Tipo A/genética
Mutação de Sentido Incorreto
Progéria/genética
[Mh] Termos MeSH secundário: Adulto
Sequência de Aminoácidos
Asparagina/genética
Ácido Aspártico/genética
Sequência de Bases
Doença da Artéria Coronariana/diagnóstico
Doença da Artéria Coronariana/genética
Doença da Artéria Coronariana/fisiopatologia
Ecocardiografia/métodos
Eletrocardiografia/métodos
Evolução Fatal
Feminino
Seres Humanos
Infarto do Miocárdio/diagnóstico
Infarto do Miocárdio/genética
Infarto do Miocárdio/fisiopatologia
Linhagem
Progéria/diagnóstico
Progéria/fisiopatologia
Homologia de Sequência de Aminoácidos
[Pt] Tipo de publicação:CASE REPORTS; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (LMNA protein, human); 0 (Lamin Type A); 30KYC7MIAI (Aspartic Acid); 7006-34-0 (Asparagine)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171030
[Lr] Data última revisão:
171030
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171020
[St] Status:MEDLINE
[do] DOI:10.1186/s12881-017-0480-x


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[PMID]:28880909
[Au] Autor:Mastrangeli R; Satwekar A; Cutillo F; Ciampolillo C; Palinsky W; Longobardi S
[Ad] Endereço:Biotech Development Programme, Merck Serono S.p.A. (an affiliate of Merck KGaA, Darmstadt, Germany), Guidonia Montecelio, Rome, Italy.
[Ti] Título:In-vivo biological activity and glycosylation analysis of a biosimilar recombinant human follicle-stimulating hormone product (Bemfola) compared with its reference medicinal product (GONAL-f).
[So] Source:PLoS One;12(9):e0184139, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Recombinant human follicle-stimulating hormone (r-hFSH) is widely used in fertility treatment. Although biosimilar versions of r-hFSH (follitropin alfa) are currently on the market, given their structural complexity and manufacturing process, it is important to thoroughly evaluate them in comparison with the reference product. This evaluation should focus on how they differ (e.g., active component molecular characteristics, impurities and potency), as this could be associated with clinical outcome. This study compared the site-specific glycosylation profile and batch-to-batch variability of the in-vivo bioactivity of Bemfola, a biosimilar follitropin alfa, with its reference medicinal product GONAL-f. The focus of this analysis was the site-specific glycosylation at asparagine (Asn) 52 of the α-subunit of FSH, owing to the pivotal role of Asn52 glycosylation in FSH receptor (FSHR) activation/signalling. Overall, Bemfola had bulkier glycan structures and greater sialylation than GONAL-f. The nominal specific activity for both Bemfola and GONAL-f is 13,636 IU/mg. Taking into account both the determined potency and the nominal amount the average specific activity of Bemfola was 14,522 IU/mg (105.6% of the nominal value), which was greater than the average specific activity observed for GONAL-f (13,159 IU/mg; 97.3% of the nominal value; p = 0.0048), although this was within the range stated in the product label. A higher batch-to-batch variability was also observed for Bemfola versus GONAL-f (coefficient of variation: 8.3% vs 5.8%). A different glycan profile was observed at Asn52 in Bemfola compared with GONAL-f (a lower proportion of bi-antennary structures [~53% vs ~77%], and a higher proportion of tri-antennary [~41% vs ~23%] and tetra-antennary structures [~5% vs <1%]). These differences in the Asn52 glycan profile might potentially lead to differences in FSHR activation. This, together with the greater bioactivity and higher batch-to-batch variability of Bemfola, could partly explain the reported differences in clinical outcomes. The clinical relevance of the differences observed between GONAL-f and Bemfola should be further investigated.
[Mh] Termos MeSH primário: Medicamentos Biossimilares/farmacologia
Hormônio Foliculoestimulante Humano/farmacologia
Hormônio Foliculoestimulante/farmacologia
Proteínas Recombinantes/farmacologia
[Mh] Termos MeSH secundário: Asparagina/metabolismo
Fucose/metabolismo
Glicopeptídeos/química
Glicosilação/efeitos dos fármacos
Seres Humanos
Ácido N-Acetilneuramínico/metabolismo
Mapeamento de Peptídeos
Polissacarídeos/metabolismo
Subunidades Proteicas/metabolismo
Padrões de Referência
[Pt] Tipo de publicação:COMPARATIVE STUDY; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Biosimilar Pharmaceuticals); 0 (Follicle Stimulating Hormone, Human); 0 (Glycopeptides); 0 (Polysaccharides); 0 (Protein Subunits); 0 (Recombinant Proteins); 0 (follitropin alfa); 28RYY2IV3F (Fucose); 7006-34-0 (Asparagine); 9002-68-0 (Follicle Stimulating Hormone); GZP2782OP0 (N-Acetylneuraminic Acid)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170908
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0184139


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[PMID]:28821532
[Au] Autor:Bowes J; Ashcroft J; Dand N; Jalali-Najafabadi F; Bellou E; Ho P; Marzo-Ortega H; Helliwell PS; Feletar M; Ryan AW; Kane DJ; Korendowych E; Simpson MA; Packham J; McManus R; Brown MA; Smith CH; Barker JN; McHugh N; FitzGerald O; Warren RB; Barton A
[Ad] Endereço:Arthritis Research UK Centre for Genetics and Genomics, Centre for Musculoskeletal Research, Manchester Academic Health Science Centre, University of Manchester, Manchester, UK.
[Ti] Título:Cross-phenotype association mapping of the MHC identifies genetic variants that differentiate psoriatic arthritis from psoriasis.
[So] Source:Ann Rheum Dis;76(10):1774-1779, 2017 Oct.
[Is] ISSN:1468-2060
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:OBJECTIVES: Psoriatic arthritis (PsA) is a chronic inflammatory arthritis, with a strong heritable component, affecting patients with psoriasis. Here we attempt to identify genetic variants within the major histocompatibility complex (MHC) that differentiate patients with PsA from patients with cutaneous psoriasis alone (PsC). METHODS: 2808 patients with PsC, 1945 patients with PsA and 8920 population controls were genotyped. We imputed SNPs, amino acids and classical HLA alleles across the MHC and tested for association with PsA compared to population controls and the PsC patient group. In addition we investigated the impact of the age of disease onset on associations. RESULTS: HLA-C*06:02 was protective of PsA compared to PsC (p=9.57×10 , OR 0.37). The HLA-C*06:02 risk allele was associated with a younger age of psoriasis onset in all patients (p=1.01×10 ). After controlling for the age of psoriasis onset no association of PsA to HLA-C*06:02 (p=0.07) was observed; instead, the most significant association was to amino acid at position 97 of HLA-B (p=1.54×10 ) where the presence of asparagine or serine residue increased PsA risk. Asparagine at position 97 of HLA-B defines the HLA-B*27 alleles. CONCLUSIONS: By controlling for the age of psoriasis onset, we show, for the first time, that is not associated with PsA and that amino acid position 97 of HLA-B differentiates PsA from PsC. This amino acid also represents the largest genetic effect for ankylosing spondylitis, thereby refining the genetic overlap of these two spondyloarthropathies. Correcting for bias has important implications for cross-phenotype genetic studies.
[Mh] Termos MeSH primário: Artrite Psoriásica/genética
Antígeno HLA-B27/genética
Antígenos HLA-C/genética
Complexo Principal de Histocompatibilidade/genética
[Mh] Termos MeSH secundário: Adolescente
Adulto
Idade de Início
Alelos
Asparagina
Estudos de Casos e Controles
Genótipo
Seres Humanos
Fenótipo
Polimorfismo de Nucleotídeo Único
Psoríase/genética
Serina
Adulto Jovem
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (HLA-B27 Antigen); 0 (HLA-C Antigens); 0 (HLA-C*06:02 antigen); 452VLY9402 (Serine); 7006-34-0 (Asparagine)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171013
[Lr] Data última revisão:
171013
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170820
[St] Status:MEDLINE
[do] DOI:10.1136/annrheumdis-2017-211414


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[PMID]:28813452
[Au] Autor:Uppal K; Salinas JL; Monteiro WM; Val F; Cordy RJ; Liu K; Melo GC; Siqueira AM; Magalhaes B; Galinski MR; Lacerda MVG; Jones DP
[Ad] Endereço:Clinical Biomarkers Laboratory, Division of Pulmonary Medicine, Department of Medicine, Emory University, Atlanta, Georgia, United States of America.
[Ti] Título:Plasma metabolomics reveals membrane lipids, aspartate/asparagine and nucleotide metabolism pathway differences associated with chloroquine resistance in Plasmodium vivax malaria.
[So] Source:PLoS One;12(8):e0182819, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Chloroquine (CQ) is the main anti-schizontocidal drug used in the treatment of uncomplicated malaria caused by Plasmodium vivax. Chloroquine resistant P. vivax (PvCR) malaria in the Western Pacific region, Asia and in the Americas indicates a need for biomarkers of resistance to improve therapy and enhance understanding of the mechanisms associated with PvCR. In this study, we compared plasma metabolic profiles of P. vivax malaria patients with PvCR and chloroquine sensitive parasites before treatment to identify potential molecular markers of chloroquine resistance. METHODS: An untargeted high-resolution metabolomics analysis was performed on plasma samples collected in a malaria clinic in Manaus, Brazil. Male and female patients with Plasmodium vivax were included (n = 46); samples were collected before CQ treatment and followed for 28 days to determine PvCR, defined as the recurrence of parasitemia with detectable plasma concentrations of CQ ≥100 ng/dL. Differentially expressed metabolic features between CQ-Resistant (CQ-R) and CQ-Sensitive (CQ-S) patients were identified using partial least squares discriminant analysis and linear regression after adjusting for covariates and multiple testing correction. Pathway enrichment analysis was performed using Mummichog. RESULTS: Linear regression and PLS-DA methods yielded 69 discriminatory features between CQ-R and CQ-S groups, with 10-fold cross-validation classification accuracy of 89.6% using a SVM classifier. Pathway enrichment analysis showed significant enrichment (p<0.05) of glycerophospholipid metabolism, glycosphingolipid metabolism, aspartate and asparagine metabolism, purine and pyrimidine metabolism, and xenobiotics metabolism. Glycerophosphocholines levels were significantly lower in the CQ-R group as compared to CQ-S patients and also to independent control samples. CONCLUSIONS: The results show differences in lipid, amino acids, and nucleotide metabolism pathways in the plasma of CQ-R versus CQ-S patients prior to antimalarial treatment. Metabolomics phenotyping of P. vivax samples from patients with well-defined clinical CQ-resistance is promising for the development of new tools to understand the biological process and to identify potential biomarkers of PvCR.
[Mh] Termos MeSH primário: Cloroquina/farmacologia
Resistência a Medicamentos
Malária Vivax/sangue
Malária Vivax/parasitologia
Redes e Vias Metabólicas
Metaboloma
Metabolômica
Plasmodium vivax/efeitos dos fármacos
[Mh] Termos MeSH secundário: Adulto
Asparagina/metabolismo
Biomarcadores
Cloroquina/uso terapêutico
Análise por Conglomerados
Biologia Computacional/métodos
Feminino
Seres Humanos
Malária Vivax/diagnóstico
Malária Vivax/tratamento farmacológico
Masculino
Lipídeos de Membrana
Metabolômica/métodos
Meia-Idade
Nucleotídeos/metabolismo
Adulto Jovem
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Biomarkers); 0 (Membrane Lipids); 0 (Nucleotides); 7006-34-0 (Asparagine); 886U3H6UFF (Chloroquine)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171018
[Lr] Data última revisão:
171018
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170817
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0182819



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