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1.
Eur J Immunol ; 54(4): e2350784, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38308504

RESUMO

Fever is common among individuals seeking healthcare after traveling to tropical regions. Despite the association with potentially severe disease, the etiology is often not determined. Plasma protein patterns can be informative to understand the host response to infection and can potentially indicate the pathogen causing the disease. In this study, we measured 49 proteins in the plasma of 124 patients with fever after travel to tropical or subtropical regions. The patients had confirmed diagnoses of either malaria, dengue fever, influenza, bacterial respiratory tract infection, or bacterial gastroenteritis, representing the most common etiologies. We used multivariate and machine learning methods to identify combinations of proteins that contributed to distinguishing infected patients from healthy controls, and each other. Malaria displayed the most unique protein signature, indicating a strong immunoregulatory response with high levels of IL10, sTNFRI and II, and sCD25 but low levels of sCD40L. In contrast, bacterial gastroenteritis had high levels of sCD40L, APRIL, and IFN-γ, while dengue was the only infection with elevated IFN-α2. These results suggest that characterization of the inflammatory profile of individuals with fever can help to identify disease-specific host responses, which in turn can be used to guide future research on diagnostic strategies and therapeutic interventions.


Assuntos
Infecções Bacterianas , Dengue , Gastroenterite , Malária , Infecções Respiratórias , Humanos , Dengue/diagnóstico , Infecções Respiratórias/complicações , Gastroenterite/complicações , Viagem , Febre/complicações
2.
iScience ; 25(12): 105652, 2022 Dec 22.
Artigo em Inglês | MEDLINE | ID: mdl-36561889

RESUMO

Annually, approximately 10 million people are diagnosed with active tuberculosis (TB), and 1.4 million die of the disease. If left untreated, each person with active TB will infect 10-15 new individuals. The lack of non-sputum-based diagnostic tests leads to delayed diagnoses of active pulmonary TB cases, contributing to continued disease transmission. In this exploratory study, we aimed to identify biomarkers associated with active TB. We assessed the plasma levels of 92 proteins associated with inflammation in individuals with active TB (n = 20), latent TB (n = 14), or healthy controls (n = 10). Using co-expression network analysis, we identified one module of proteins with strong association with active TB. We removed proteins from the module that had low abundance or were associated with non-TB diseases in published transcriptomic datasets, resulting in a 12-protein plasma signature that was highly enriched in individuals with pulmonary and extrapulmonary TB and was further associated with disease severity.

3.
Diabetes ; 65(10): 2888-99, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27659228

RESUMO

Type 2 diabetes and cardiovascular disease are complex disorders involving metabolic and inflammatory mechanisms. Here we investigated whether sCD93, a group XIV c-type lectin of the endosialin family, plays a role in metabolic dysregulation or carotid intima-media thickness (IMT). Although no association was observed between sCD93 and IMT, sCD93 levels were significantly lower in subjects with type 2 diabetes (n = 901, mean ± SD 156.6 ± 40.0 ng/mL) compared with subjects without diabetes (n = 2,470, 164.1 ± 44.8 ng/mL, P < 0.0001). Genetic variants associated with diabetes risk (DIAGRAM Consortium) did not influence sCD93 levels (individually or combined in a single nucleotide polymorphism score). In a prospective cohort, lower sCD93 levels preceded the development of diabetes. Consistent with this, a cd93-deficient mouse model (in addition to apoe deficiency) demonstrated no difference in atherosclerotic lesion development compared with apoe(-/-) cd93-sufficient littermates. However, cd93-deficient mice showed impaired glucose clearance and insulin sensitivity (compared with littermate controls) after eating a high-fat diet. The expression of cd93 was observed in pancreatic islets, and leaky vessels were apparent in cd93-deficient pancreases. We further demonstrated that stress-induced release of sCD93 is impaired by hyperglycemia. Therefore, we propose CD93 as an important component in glucometabolic regulation.


Assuntos
Espessura Intima-Media Carotídea , Glicoproteínas de Membrana/metabolismo , Receptores de Complemento/metabolismo , Animais , Apolipoproteínas E , Aterosclerose/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Células Endoteliais/metabolismo , Feminino , Genótipo , Humanos , Masculino , Glicoproteínas de Membrana/deficiência , Glicoproteínas de Membrana/genética , Camundongos , Camundongos Knockout , Pâncreas/metabolismo , Receptores de Complemento/deficiência , Receptores de Complemento/genética
4.
Biochem Biophys Res Commun ; 311(2): 440-5, 2003 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-14592433

RESUMO

Drosophila melanogaster cells express a multi-substrate deoxyribonucleoside kinase that phosphorylates both purine and pyrimidine deoxyribonucleosides. The subsequent phosphorylation step is catalyzed by nucleoside monophosphate kinases. We have cloned and characterized the D. melanogaster UMP-CMP kinase (Dm.UMP-CMP kinase) to further study the nucleotide metabolizing enzymes in these cells. The kinase, encoded by the dak1 gene, was approximately 60% similar to the human UMP-CMP kinase and predominantly phosphorylated CMP, dCMP, and UMP. Expression analysis showed that the Dm.UMP-CMP kinase mRNA was constitutively expressed throughout the Drosophila development. The open-reading frame of the Dm.UMP-CMP kinase cDNA was extended in the 5'-region compared to UMP-CMP kinases of other species. The extended region encoded an N-terminal sequence with properties characteristic of a mitochondrial import signal. Expression of the enzyme in fusion with the green fluorescent protein verified that the N-terminal signal targeted the enzyme to mitochondria. This is the first time a mitochondrial pyrimidine nucleoside monophosphate kinase has been cloned from any organism and we discuss the implication of this finding for deoxyribonucleoside salvage in both Drosophila and other organisms.


Assuntos
Clonagem Molecular/métodos , DNA Complementar/metabolismo , Drosophila melanogaster/enzimologia , Regulação Enzimológica da Expressão Gênica/fisiologia , Mitocôndrias/enzimologia , Núcleosídeo-Fosfato Quinase/metabolismo , Transdução de Sinais/fisiologia , Sequência de Aminoácidos , Animais , Células Cultivadas , DNA Complementar/genética , Drosophila melanogaster/genética , Humanos , Mitocôndrias/genética , Dados de Sequência Molecular , Núcleosídeo-Fosfato Quinase/química , Núcleosídeo-Fosfato Quinase/genética , Fosforilação , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Análise de Sequência de Proteína , Especificidade por Substrato
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