Metabolomic profiles predict individual multidisease outcomes

Publisher Copyright: © 2022, The Author(s).Risk stratification is critical for the early identification of high-risk individuals and disease prevention. Here we explored the potential of nuclear magnetic resonance (NMR) spectroscopy-derived metabolomic profiles to inform on multidisease risk beyond conventional clinical predictors for the onset of 24 common conditions, including metabolic, vascular, respiratory, musculoskeletal and neurological diseases and cancers. Specifically, we trained a neural network to learn disease-specific metabolomic states from 168 circulating metabolic markers measured in 117,981 participants with ~1.4 million person-years of follow-up from the UK Biobank and validated the model in four independent cohorts. We found metabolomic states to be associated with incident event rates in all the investigated conditions, except breast cancer. For 10-year outcome prediction for 15 endpoints, with and without established metabolic contribution, a combination of age and sex and the metabolomic state equaled or outperformed established predictors. Moreover, metabolomic state added predictive information over comprehensive clinical variables for eight common diseases, including type 2 diabetes, dementia and heart failure. Decision curve analyses showed that predictive improvements translated into clinical utility for a wide range of potential decision thresholds. Taken together, our study demonstrates both the potential and limitations of NMR-derived metabolomic profiles as a multidisease assay to inform on the risk of many common diseases simultaneously.Peer reviewe

Low RUNX3 expression alters dendritic cell function in patients with systemic sclerosis and contributes to enhanced fibrosis

Objectives Systemic sclerosis (SSc) is an autoimmune disease with unknown pathogenesis manifested by inflammation, vasculopathy and fibrosis in skin and internal organs. Type I interferon signature found in SSc propelled us to study plasmacytoid dendritic cells (pDCs) in this disease. We aimed to identify candidate pathways underlying pDC aberrancies in SSc and to validate its function on pDC biology.Methods In total, 1193 patients with SSc were compared with 1387 healthy donors and 8 patients with localised scleroderma. PCR-based transcription factor profiling and methylation status analyses, single nucleotide polymorphism genotyping by sequencing and flow cytometry analysis were performed in pDCs isolated from the circulation of healthy controls or patients with SSc. pDCs were also cultured under hypoxia, inhibitors of methylation and hypoxia-inducible factors and runt-related transcription factor 3 (RUNX3) levels were determined. To study Runx3 function, Itgax-Cre: Runx3(f/f) mice were used in in vitro functional assay and bleomycin-induced SSc skin inflammation and fibrosis model.Results Here, we show downregulation of transcription factor RUNX3 in SSc pDCs. A higher methylation status of the RUNX3 gene, which is associated with polymorphism rs6672420, correlates with lower RUNX3 expression and SSc susceptibility. Hypoxia is another factor that decreases RUNX3 level in pDC. Mouse pDCs deficient of Runx3 show enhanced maturation markers on CpG stimulation. In vivo, deletion of Runx3 in dendritic cell leads to spontaneous induction of skin fibrosis in untreated mice and increased severity of bleomycin-induced skin fibrosis.Conclusions We show at least two pathways potentially causing low RUNX3 level in SSc pDCs, and we demonstrate the detrimental effect of loss of Runx3 in SSc model further underscoring the role of pDCs in this disease

Metabolomic profiles predict individual multidisease outcomes

Publisher Copyright: © 2022, The Author(s).Risk stratification is critical for the early identification of high-risk individuals and disease prevention. Here we explored the potential of nuclear magnetic resonance (NMR) spectroscopy-derived metabolomic profiles to inform on multidisease risk beyond conventional clinical predictors for the onset of 24 common conditions, including metabolic, vascular, respiratory, musculoskeletal and neurological diseases and cancers. Specifically, we trained a neural network to learn disease-specific metabolomic states from 168 circulating metabolic markers measured in 117,981 participants with ~1.4 million person-years of follow-up from the UK Biobank and validated the model in four independent cohorts. We found metabolomic states to be associated with incident event rates in all the investigated conditions, except breast cancer. For 10-year outcome prediction for 15 endpoints, with and without established metabolic contribution, a combination of age and sex and the metabolomic state equaled or outperformed established predictors. Moreover, metabolomic state added predictive information over comprehensive clinical variables for eight common diseases, including type 2 diabetes, dementia and heart failure. Decision curve analyses showed that predictive improvements translated into clinical utility for a wide range of potential decision thresholds. Taken together, our study demonstrates both the potential and limitations of NMR-derived metabolomic profiles as a multidisease assay to inform on the risk of many common diseases simultaneously.Peer reviewe

L'énergie à découvert

L'énergie est devenue une question vitale pour les sociétés, le citoyen, l'humanité tout entière. Sujet scientifique, économique, politique et écologique majeur, elle suscite des débats, parfois violents, sur les choix à faire aujourd'hui et leurs conséquences pour l'avenir des hommes et de la planète. Mais, alors que se tient le grand débat national sur la transition énergétique, comment se forger une opinion objective sans connaître les données scientifiques les plus complètes sur les potentiels et les limites de chaque source d'énergie ? Ce livre les met enfin à la disposition du public. L'énergie, qu'est-ce que c'est ? Quelles sont les grandes lois physiques qui la gouvernent ? Comment la produire, la transporter, la stocker ? Le solaire, la biomasse, l'éolien, l'hydraulique sont-ils des solutions alternatives suffisantes ? Et quelle part leur réserver à l'avenir ? Les nombreux articles de ce livre (près de 130) proposent au citoyen des outils pour se faire une opinion face à ces questions. Physiciens, chimistes, biologistes, géophysiciens, environnementalistes, géographes, économistes, y précisent, chiffres et schémas à l'appui, la place respective des énergies fossiles, du nucléaire et des énergies renouvelables. Au-delà, ils expliquent quelles sont les perspectives offertes par la science sur le mix énergétique, le problème du stockage, l'amélioration de nos usages de l'énergie, ses impacts environnementaux et sanitaires