Urinary metabolic phenotyping of mucopolysaccharidosis type I combining untargeted and targeted strategies with data modeling

International audienceBackground =Application of metabolic phenotyping could expand the pathophysiological knowledge of mucopolysaccharidoses (MPS) and may reveal the comprehensive metabolic impairments in MPS. However, few studies applied this approach to MPS.Methods =We applied targeted and untargeted metabolic profiling in urine samples obtained from a French cohort comprising 19 MPS I and 15 MPS I treated patients along with 66 controls. For that purpose, we used ultra-high-performance liquid chromatography combined with ion mobility and high-resolution mass spectrometry following a protocol designed for large-scale metabolomics studies regarding robustness and reproducibility. Furthermore, 24 amino acids have been quantified using liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS). Keratan sulfate, Heparan sulfate and Dermatan sulfate concentrations have also been measured using an LC-MS/MS method. Univariate and multivariate data analyses have been used to select discriminant metabolites. The mummichog algorithm has been used for pathway analysis.Results =The studied groups yielded distinct biochemical phenotypes using multivariate data analysis. Univariate statistics also revealed metabolites that differentiated the groups. Specifically, metabolites related to the amino acid metabolism. Pathway analysis revealed that several major amino acid pathways were dysregulated in MPS. Comparison of targeted and untargeted metabolomics data with in silico results yielded arginine, proline and glutathione metabolisms being the most affected.Conclusion =This study is one of the first metabolic phenotyping studies of MPS I. The findings might help to generate new hypotheses about MPS pathophysiology and to develop further targeted studies of a smaller number of potentially key metabolites

Properly Substituted Analogues of BIX-01294 Lose Inhibition of G9a Histone Methyltransferase and Gain Selective Anti-DNA Methyltransferase 3A Activity

International audienceChemical manipulations performed on the histone H3 lysine 9 methyltransferases (G9a/GLP) inhibitor BIX-01294 afforded novel desmethoxyquinazolines able to inhibit the DNA methyltransferase DNMT3A at low micromolar levels without any significant inhibition of DNMT1 and G9a. In KG-1 cells such compounds, when tested at sub-toxic doses, induced the luciferase re-expression in a stable construct controlled by a cytomegalovirus (CMV) promoter silenced by methylation (CMV-luc assay). Finally, in human lymphoma U-937 and RAJI cells, the N-(1-benzylpiperidin-4-yl)-2-(4-phenylpiperazin-1-yl)quinazolin-4-amine induced the highest proliferation arrest and cell death induction starting from 10 µM, in agreement with its DNMT3A inhibitory potency

Visions for nature and nature’s contributions to people for the 21st century : Report from an IPBES visioning workshop held on 4-8 September 2017 in Auckland, New Zealand

Existing scenarios of biodiversity and ecosystem services (BES) have important limitations and gaps that constrain their usefulness for the Intergovernmental Platform on Biodiversity and Ecosystem Services (IPBES). Specifically, they fail to incorporate policy objectives related to nature conservation and social-ecological feedbacks, they do not address the linkages between biodiversity and ecosystem services, and they are typically relevant at only a particular spatial scale. In addition, nature and its benefits are treated as the consequence of human decisions, but are not at the centre of the analysis. To address these issues, the IPBES Scenarios and Models Expert Group initiated the development of a set of Multiscale Scenarios for Nature Futures based on positive visions for human relationships with nature.The first step of this process was a visioning workshop with stakeholders and experts on 4-8 September 2017 in Auckland, New Zealand. A total of 73 participants from inter-governmental organisations, national government organisations, non-governmental organisations, academia and the private sector, from 31 countries, and with a range of sectoral expertise on biodiversity topics, from urban development to agriculture to fisheries, worked together in a visioning exercise. This report documents the results from this visioning workshop to inform further stakeholder consultation and the development of the associated multiscale scenarios by modelers and experts. This creative visioning exercise was carried out in four steps based on a suite of participatory methods that were used to develop visions of alternative futures. First the participants identified important themes to develop the visions. Next, thematic groups identified the main trends for BES in each theme and a set of “Seeds” of emerging initiatives leading to positive futures for our relationship with nature. Implications of what would happen across a range of sectors were identified for each seed. Then a pathway analysis of how the current regime in each theme may be transformed into the future desirable regime was carriedout. Narratives were then built for the visions emerging from each group. Finally, commonalities of visions across the groups were identified, and the regional relevance of each vision for different parts of the world was assessed

Visions for nature and nature’s contributions to people for the 21st century : Report from an IPBES visioning workshop held on 4-8 September 2017 in Auckland, New Zealand

Existing scenarios of biodiversity and ecosystem services (BES) have important limitations and gaps that constrain their usefulness for the Intergovernmental Platform on Biodiversity and Ecosystem Services (IPBES). Specifically, they fail to incorporate policy objectives related to nature conservation and social-ecological feedbacks, they do not address the linkages between biodiversity and ecosystem services, and they are typically relevant at only a particular spatial scale. In addition, nature and its benefits are treated as the consequence of human decisions, but are not at the centre of the analysis. To address these issues, the IPBES Scenarios and Models Expert Group initiated the development of a set of Multiscale Scenarios for Nature Futures based on positive visions for human relationships with nature.The first step of this process was a visioning workshop with stakeholders and experts on 4-8 September 2017 in Auckland, New Zealand. A total of 73 participants from inter-governmental organisations, national government organisations, non-governmental organisations, academia and the private sector, from 31 countries, and with a range of sectoral expertise on biodiversity topics, from urban development to agriculture to fisheries, worked together in a visioning exercise. This report documents the results from this visioning workshop to inform further stakeholder consultation and the development of the associated multiscale scenarios by modelers and experts. This creative visioning exercise was carried out in four steps based on a suite of participatory methods that were used to develop visions of alternative futures. First the participants identified important themes to develop the visions. Next, thematic groups identified the main trends for BES in each theme and a set of “Seeds” of emerging initiatives leading to positive futures for our relationship with nature. Implications of what would happen across a range of sectors were identified for each seed. Then a pathway analysis of how the current regime in each theme may be transformed into the future desirable regime was carriedout. Narratives were then built for the visions emerging from each group. Finally, commonalities of visions across the groups were identified, and the regional relevance of each vision for different parts of the world was assessed