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- Bethlehem, RAI, et al.
(författare)
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Brain charts for the human lifespan
- 2022
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 604:79057906, s. 525-
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Tidskriftsartikel (refereegranskat)abstract
- Over the past few decades, neuroimaging has become a ubiquitous tool in basic research and clinical studies of the human brain. However, no reference standards currently exist to quantify individual differences in neuroimaging metrics over time, in contrast to growth charts for anthropometric traits such as height and weight1. Here we assemble an interactive open resource to benchmark brain morphology derived from any current or future sample of MRI data (http://www.brainchart.io/). With the goal of basing these reference charts on the largest and most inclusive dataset available, acknowledging limitations due to known biases of MRI studies relative to the diversity of the global population, we aggregated 123,984 MRI scans, across more than 100 primary studies, from 101,457 human participants between 115 days post-conception to 100 years of age. MRI metrics were quantified by centile scores, relative to non-linear trajectories2 of brain structural changes, and rates of change, over the lifespan. Brain charts identified previously unreported neurodevelopmental milestones3, showed high stability of individuals across longitudinal assessments, and demonstrated robustness to technical and methodological differences between primary studies. Centile scores showed increased heritability compared with non-centiled MRI phenotypes, and provided a standardized measure of atypical brain structure that revealed patterns of neuroanatomical variation across neurological and psychiatric disorders. In summary, brain charts are an essential step towards robust quantification of individual variation benchmarked to normative trajectories in multiple, commonly used neuroimaging phenotypes.
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- Watanabe, A., et al.
(författare)
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Association of aberrant ASNS imprinting with asparaginase sensitivity and chromosomal abnormality in childhood BCP-ALL
- 2020
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Ingår i: Blood. - : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 136:20, s. 2319-2333
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Tidskriftsartikel (refereegranskat)abstract
- Karyotype is an important prognostic factor in childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL), but the underlying pharmacogenomics remain unknown. Asparaginase is an integral component in current chemotherapy for childhood BCP-ALL. Asparaginase therapy depletes serum asparagine. Normal hematopoietic cells can produce asparagine by asparagine synthetase (ASNS) activity, but ALL cells are unable to synthesize adequate amounts of asparagine. The ASNS gene has a typical CpG island in its promoter. Thus, methylation of the ASNS CpG island could be one of the epigenetic mechanisms for ASNS gene silencing in BCP-ALL. To gain deep insights into the pharmacogenomics of asparaginase therapy, we investigated the association of ASNS methylation status with asparaginase sensitivity. The ASNS CpG island is largely unmethylated in normal hematopoietic cells, but it is allele-specifically methylated in BCP-ALL cells. The ASNS gene is located at 7q21, an evolutionally conserved imprinted gene cluster. ASNS methylation in childhood BCP-ALL is associated with an aberrant methylation of the imprinted gene cluster at 7q21. Aberrant methylation of mouse Asns and a syntenic imprinted gene cluster is also confirmed in leukemic spleen samples from ETV6-RUNX1 knockin mice. In 3 childhood BCP-ALL cohorts, ASNS is highly methylated in BCP-ALL patients with favorable karyotypes but is mostly unmethylated in BCP-ALL patients with poor prognostic karyotypes. Higher ASNS methylation is associated with higher L-asparaginase sensitivity in BCP-ALL through lower ASNS gene and protein expression levels. These observations demonstrate that silencing of the ASNS gene as a result of aberrant imprinting is a pharmacogenetic mechanism for the leukemia-specific activity of asparaginase therapy in BCP-ALL.
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- Nocente, M., et al.
(författare)
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Generation and observation of fast deuterium ions and fusion-born alpha particles in JET D-He-3 plasmas with the 3-ion radio-frequency heating scenario
- 2020
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Ingår i: Nuclear Fusion. - : IOP PUBLISHING LTD. - 0029-5515 .- 1741-4326. ; 60:12
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Tidskriftsartikel (refereegranskat)abstract
- Dedicated experiments to generate energetic D ions and D-(3) He fusion-born alpha particles were performed at the Joint European Torus (JET) with the ITER-like wall (ILW). Using the 3-ion D-(D-NBI)-(3) He radio frequency (RF) heating scenario, deuterium ions from neutral beam injection (NBI) were accelerated in the core of mixed D-(3) He plasmas to higher energies with ion cyclotron resonance frequency (ICRF) waves, in turn leading to a core-localized source of alpha particles. The fast-ion distribution of RF-accelerated D-NBI ions was controlled by varying the ICRF and NBI power (P-ICRF approximate to 4-6 MW, P-NBI approximate to 3-20 MW), resulting in rather high D-D neutron (approximate to 1x10(16) s(-1)) and D-(3) He alpha rates (approximate to 2x10(16) s(-1)) at moderate input heating power. Theory and TRANSP analysis shows that large populations of co-passing MeV-range D ions were generated using the D-(D-NBI)-(3) He 3-ion ICRF scenario. This important result is corroborated by several experimental observations, in particular gamma-ray measurements. The developed experimental scenario at JET provides unique conditions for probing several aspects of future burning plasmas, such as the contribution from MeV range ions to global confinement, but without introducing tritium. Dominant fast-ion core electron heating with T-i approximate to T-e and a rich variety of fast-ion driven Alfven eigenmodes (AEs) were observed in these D-(3) He plasmas. The observed AE activities do not have a detrimental effect on the thermal confinement and, in some cases, may be driven by the fusion born alpha particles. A strong continuous increase in neutron rate was observed during long-period sawteeth (>1 s), accompanied by the observation of reversed shear AEs, which implies that a non monotonic q profile was systematically developed in these plasmas, sustained by the large fast-ion populations generated by the 3-ion ICRF scenario.
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