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- Tada, I, et al.
(författare)
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Creating a Reliable Mass Spectral-Retention Time Library for All Ion Fragmentation-Based Metabolomics
- 2019
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Ingår i: Metabolites. - : MDPI AG. - 2218-1989. ; 9:11
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Tidskriftsartikel (refereegranskat)abstract
- Accurate metabolite identification remains one of the primary challenges in a metabolomics study. A reliable chemical spectral library increases the confidence in annotation, and the availability of raw and annotated data in public databases facilitates the transfer of Liquid chromatography coupled to mass spectrometry (LC–MS) methods across laboratories. Here, we illustrate how the combination of MS2 spectra, accurate mass, and retention time can improve the confidence of annotation and provide techniques to create a reliable library for all ion fragmentation (AIF) data with a focus on the characterization of the retention time. The resulting spectral library incorporates information on adducts and in-source fragmentation in AIF data, while noise peaks are effectively minimized through multiple deconvolution processes. We also report the development of the Mass Spectral LIbrary MAnager (MS-LIMA) tool to accelerate library sharing and transfer across laboratories. This library construction strategy improves the confidence in annotation for AIF data in LC–MS-based metabolomics and will facilitate the sharing of retention time and mass spectral data in the metabolomics community.
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- Reinke, SN, et al.
(författare)
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Urinary metabotype of severe asthma evidences decreased carnitine metabolism independent of oral corticosteroid treatment in the U-BIOPRED study
- 2022
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Ingår i: The European respiratory journal. - : European Respiratory Society (ERS). - 1399-3003 .- 0903-1936. ; 59:6
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Tidskriftsartikel (refereegranskat)abstract
- Asthma is a heterogeneous disease with poorly defined phenotypes. Patients with severe asthma often receive multiple treatments including oral corticosteroids (OCS). Treatment may modify the observed metabotype, rendering it challenging to investigate underlying disease mechanisms. Here, we aimed to identify dysregulated metabolic processes in relation to asthma severity and medication.MethodsBaseline urine was collected prospectively from healthy participants (n=100), patients with mild-to-moderate asthma (n=87) and patients with severe asthma (n=418) in the cross-sectional U-BIOPRED cohort; 12–18-month longitudinal samples were collected from patients with severe asthma (n=305). Metabolomics data were acquired using high-resolution mass spectrometry and analysed using univariate and multivariate methods.ResultsA total of 90 metabolites were identified, with 40 significantly altered (p<0.05, false discovery rate <0.05) in severe asthma and 23 by OCS use. Multivariate modelling showed that observed metabotypes in healthy participants and patients with mild-to-moderate asthma differed significantly from those in patients with severe asthma (p=2.6×10−20), OCS-treated asthmatic patients differed significantly from non-treated patients (p=9.5×10−4), and longitudinal metabotypes demonstrated temporal stability. Carnitine levels evidenced the strongest OCS-independent decrease in severe asthma. Reduced carnitine levels were associated with mitochondrial dysfunction via decreases in pathway enrichment scores of fatty acid metabolism and reduced expression of the carnitine transporter SLC22A5 in sputum and bronchial brushings.ConclusionsThis is the first large-scale study to delineate disease- and OCS-associated metabolic differences in asthma. The widespread associations with different therapies upon the observed metabotypes demonstrate the need to evaluate potential modulating effects on a treatment- and metabolite-specific basis. Altered carnitine metabolism is a potentially actionable therapeutic target that is independent of OCS treatment, highlighting the role of mitochondrial dysfunction in severe asthma.
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- Ohashi, K, et al.
(författare)
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Kynurenine aminotransferase activity of Aro8/Aro9 engage tryptophan degradation by producing kynurenic acid in Saccharomyces cerevisiae
- 2017
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Ingår i: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 7:1, s. 12180-
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Tidskriftsartikel (refereegranskat)abstract
- Kynurenic acid (KA) is a tryptophan (Trp) metabolite that is synthesised in a branch of kynurenine (KYN) pathway. KYN aminotransferase (KAT) catalyses deamination of KYN, yielding KA. Although KA synthesis is evolutionarily conserved from bacteria to humans, the cellular benefits of synthesising KA are unclear. In this study, we constructed a KAT-null yeast mutant defective in KA synthesis to clarify the cellular function of KA. Amino acid sequence analysis and LC/MS quantification of KA revealed that Aro8 and Aro9 are the major KATs. KA was significantly decreased in the aro8Δ aro9Δ double mutant. We found that aro8Δ aro9Δ cells did not exhibit obvious defects in growth or oxidative stress response when proper amounts of amino acids are supplied in the media. We further found that aro8Δ aro9Δ cells were sensitive to excess Trp. The Trp sensitivity was not rescued by addition of KA, suggesting that Trp sensitivity is not due to the loss of KA. In conclusion, we propose that KAT activity is required for detoxification of Trp by converting it to the less toxic KA.
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- Zhang, P, et al.
(författare)
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Tackling the Complexity of the Exposome: Considerations from the Gunma University Initiative for Advanced Research (GIAR) Exposome Symposium
- 2019
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Ingår i: Metabolites. - : MDPI AG. - 2218-1989. ; 9:6
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- The attempt to describe complex diseases by solely genetic determination has not been successful. There is increasing recognition that the development of disease is often a consequence of interactions between multiple genetic and environmental factors. To date, much of the research on environmental determinants of disease has focused on single exposures generally measured at a single time point. In order to address this limitation, the concept of the exposome has been introduced as a comprehensive approach, studying the full complement of environmental exposures from conception onwards. However, exposures are vast, dynamic, and diverse, and only a small proportion can be reasonably measured due to limitations in technology and feasibility. In addition, the interplay between genes and exposure as well as between different exposures is complicated and multifaceted, which leads to difficulties in linking disease or health outcomes with exposures. The large numbers of collected samples require well-designed logistics. Furthermore, the immense data sets generated from exposome studies require a significant computational investment for both data analysis and data storage. This report summarizes discussions during an international exposome symposium held at Gunma University in Japan regarding the concept of the exposome, challenges in exposome research, and future perspectives in the field.
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