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1.
BMC Infect Dis ; 22(1): 558, 2022 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-35718768

RESUMO

BACKGROUND: A global pandemic has been declared for coronavirus disease 2019 (COVID-19), which has serious impacts on human health and healthcare systems in the affected areas, including Vietnam. None of the previous studies have a framework to provide summary statistics of the virus variants and assess the severity associated with virus proteins and host cells in COVID-19 patients in Vietnam. METHOD: In this paper, we comprehensively investigated SARS-CoV-2 variants and immune responses in COVID-19 patients. We provided summary statistics of target sequences of SARS-CoV-2 in Vietnam and other countries for data scientists to use in downstream analysis for therapeutic targets. For host cells, we proposed a predictive model of the severity of COVID-19 based on public datasets of hospitalization status in Vietnam, incorporating a polygenic risk score. This score uses immunogenic SNP biomarkers as indicators of COVID-19 severity. RESULT: We identified that the Delta variant of SARS-CoV-2 is most prevalent in southern areas of Vietnam and it is different from other areas in the world using various data sources. Our predictive models of COVID-19 severity had high accuracy (Random Forest AUC = 0.81, Elastic Net AUC = 0.7, and SVM AUC = 0.69) and showed that the use of polygenic risk scores increased the models' predictive capabilities. CONCLUSION: We provided a comprehensive analysis for COVID-19 severity in Vietnam. This investigation is not only helpful for COVID-19 treatment in therapeutic target studies, but also could influence further research on the disease progression and personalized clinical outcomes.


Assuntos
COVID-19 , Infecções por Coronavirus , Pneumonia Viral , Betacoronavirus , COVID-19/tratamento farmacológico , COVID-19/epidemiologia , Estudo de Associação Genômica Ampla , Humanos , SARS-CoV-2/genética , Vietnã/epidemiologia
2.
Mol Genet Genomic Med ; 7(5): e623, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30816000

RESUMO

BACKGROUND: Congenital adrenal hyperplasia (CAH) (OMIM #201910) is a complex disease most often caused by pathogenic variant of the CYP21A2 gene. We have designed an efficient multistep approach to diagnose and classify CAH cases due to CYP21A2 variant and to study the genotype-phenotype relationship. METHODS: A large cohort of 212 Vietnamese patients from 204 families was recruited. We utilized Multiplex Ligation-dependent Probe Amplification to identify large deletion or rearrangement followed by complete gene sequencing of CYP21A2 to map single-nucleotide changes and possible novel variants. RESULTS: Pathogenic variants were identified in 398 out of 408 alleles (97.5%). The variants indexed span across most of the CYP21A2 gene regions. The most common genotypes were: I2g/I2g (15.35%); Del/Del (14.4%); Del/I2g (10.89%); p.R356W/p.R356W (6.44%); and exon 1-3 del/exon 1-3 del (5.44%). In addition to the previously characterized and documented variants, we also discovered six novel variants which were not previously reported, in silico tools were used to support the pathogenicity of these variants. CONCLUSION: The result will contribute in further understanding the genotype-phenotype relationship of CAH patients and to guide better treatment and management of the affected.


Assuntos
Hiperplasia Suprarrenal Congênita/genética , Polimorfismo de Nucleotídeo Único , Esteroide 21-Hidroxilase/genética , Frequência do Gene , Genótipo , Humanos , Fenótipo , Vietnã
3.
J Immunol ; 198(8): 3058-3068, 2017 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-28275136

RESUMO

The Tec tyrosine kinase is expressed in many cell types, including hematopoietic cells, and is a member of the Tec kinase family that also includes Btk. Although the role of Btk in B cells has been extensively studied, the role of Tec kinase in B cells remains largely unclear. It was previously shown that Tec kinase has the ability to partly compensate for loss of Btk activity in B cell differentiation, although the underlying mechanism is unknown. In this study, we confirm that Tec kinase is not essential for normal B cell development when Btk is present, but we also found that Tec-deficient mature B cells showed increased activation, proliferation, and survival upon BCR stimulation, even in the presence of Btk. Whereas Tec deficiency did not affect phosphorylation of phospholipase Cγ or Ca2+ influx, it was associated with significantly increased activation of the intracellular Akt/S6 kinase signaling pathway upon BCR and CD40 stimulation. The increased S6 kinase phosphorylation in Tec-deficient B cells was dependent on Btk kinase activity, as ibrutinib treatment restored pS6 to wild-type levels, although Btk protein and phosphorylation levels were comparable to controls. In Tec-deficient mice in vivo, B cell responses to model Ags and humoral immunity upon influenza infection were enhanced. Moreover, aged mice lacking Tec kinase developed a mild autoimmune phenotype. Taken together, these data indicate that in mature B cells, Tec and Btk may compete for activation of the Akt signaling pathway, whereby the activating capacity of Btk is limited by the presence of Tec kinase.


Assuntos
Linfócitos B/imunologia , Ativação Linfocitária/imunologia , Proteínas Tirosina Quinases/imunologia , Tirosina Quinase da Agamaglobulinemia , Animais , Diferenciação Celular/imunologia , Separação Celular , Modelos Animais de Doenças , Citometria de Fluxo , Humanos , Imuno-Histoquímica , Influenza Humana , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fosforilação , Reação em Cadeia da Polimerase , Receptores de Antígenos de Linfócitos B/imunologia , Transdução de Sinais/imunologia
4.
EMBO J ; 28(14): 2090-9, 2009 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-19536137

RESUMO

DNA damage provokes DNA repair, cell-cycle regulation and apoptosis. This DNA-damage response encompasses gene-expression regulation at the transcriptional and post-translational levels. We show that cellular responses to UV-induced DNA damage are also regulated at the post-transcriptional level by microRNAs. Survival and checkpoint response after UV damage was severely reduced on microRNA-mediated gene-silencing inhibition by knocking down essential components of the microRNA-processing pathway (Dicer and Ago2). UV damage triggered a cell-cycle-dependent relocalization of Ago2 into stress granules and various microRNA-expression changes. Ago2 relocalization required CDK activity, but was independent of ATM/ATR checkpoint signalling, whereas UV-responsive microRNA expression was only partially ATM/ATR independent. Both microRNA-expression changes and stress-granule formation were most pronounced within the first hours after genotoxic stress, suggesting that microRNA-mediated gene regulation operates earlier than most transcriptional responses. The functionality of the microRNA response is illustrated by the UV-inducible miR-16 that downregulates checkpoint-gene CDC25a and regulates cell proliferation. We conclude that microRNA-mediated gene regulation adds a new dimension to the DNA-damage response.


Assuntos
Reparo do DNA , Inativação Gênica , MicroRNAs/genética , Proteínas Argonauta , Proliferação de Células , Células Cultivadas , Grânulos Citoplasmáticos , Fator de Iniciação 2 em Eucariotos/genética , Fator de Iniciação 2 em Eucariotos/metabolismo , Fibroblastos/citologia , Fase G1 , Células HeLa , Humanos , Ribonuclease III/genética , Ribonuclease III/metabolismo , Fase S , Raios Ultravioleta
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