Mitochondrial function as a determinant of life span

Average human life expectancy has progressively increased over many decades largely due to improvements in nutrition, vaccination, antimicrobial agents, and effective treatment/prevention of cardiovascular disease, cancer, etc. Maximal life span, in contrast, has changed very little. Caloric restriction (CR) increases maximal life span in many species, in concert with improvements in mitochondrial function. These effects have yet to be demonstrated in humans, and the duration and level of CR required to extend life span in animals is not realistic in humans. Physical activity (voluntary exercise) continues to hold much promise for increasing healthy life expectancy in humans, but remains to show any impact to increase maximal life span. However, longevity in Caenorhabditis elegans is related to activity levels, possibly through maintenance of mitochondrial function throughout the life span. In humans, we reported a progressive decline in muscle mitochondrial DNA abundance and protein synthesis with age. Other investigators also noted age-related declines in muscle mitochondrial function, which are related to peak oxygen uptake. Long-term aerobic exercise largely prevented age-related declines in mitochondrial DNA abundance and function in humans and may increase spontaneous activity levels in mice. Notwithstanding, the impact of aerobic exercise and activity levels on maximal life span is uncertain. It is proposed that age-related declines in mitochondrial content and function not only affect physical function, but also play a major role in regulation of life span. Regular aerobic exercise and prevention of adiposity by healthy diet may increase healthy life expectancy and prolong life span through beneficial effects at the level of the mitochondrion

Landscape of X chromosome inactivation across human tissues

© 2017 Macmillan Publishers Limited, part of Springer Nature. All rights reserved. X chromosome inactivation (XCI) silences transcription from one of the two X chromosomes in female mammalian cells to balance expression dosage between XX females and XY males. XCI is, however, incomplete in humans: up to one-third of X-chromosomal genes are expressed from both the active and inactive X chromosomes (Xa and Xi, respectively) in female cells, with the degree of 'escape' from inactivation varying between genes and individuals1,2. The extent to which XCI is shared between cells and tissues remains poorly characterized3,4, as does the degree to which incomplete XCI manifests as detectable sex differences in gene expression5 and phenotypic traits6. Here we describe a systematic survey of XCI, integrating over 5,500 transcriptomes from 449 individuals spanning 29 tissues from GTEx (v6p release) and 940 single-cell transcriptomes, combined with genomic sequence data. We show that XCI at 683 X-chromosomal genes is generally uniform across human tissues, but identify examples of heterogeneity between tissues, individuals and cells. We show that incomplete XCI affects at least 23% of X-chromosomal genes, identify seven genes that escape XCI with support from multiple lines of evidence and demonstrate that escape from XCI results in sex biases in gene expression, establishing incomplete XCI as a mechanism that is likely to introduce phenotypic diversity6,7. Overall, this updated catalogue of XCI across human tissues helps to increase our understanding of the extent and impact of the incompleteness in the maintenance of XCI

Exploring the phenotypic consequences of tissue specific gene expression variation inferred from GWAS summary statistics

© 2018 The Author(s). Scalable, integrative methods to understand mechanisms that link genetic variants with phenotypes are needed. Here we derive a mathematical expression to compute PrediXcan (a gene mapping approach) results using summary data (S-PrediXcan) and show its accuracy and general robustness to misspecified reference sets. We apply this framework to 44 GTEx tissues and 100+ phenotypes from GWAS and meta-analysis studies, creating a growing public catalog of associations that seeks to capture the effects of gene expression variation on human phenotypes. Replication in an independent cohort is shown. Most of the associations are tissue specific, suggesting context specificity of the trait etiology. Colocalized significant associations in unexpected tissues underscore the need for an agnostic scanning of multiple contexts to improve our ability to detect causal regulatory mechanisms. Monogenic disease genes are enriched among significant associations for related traits, suggesting that smaller alterations of these genes may cause a spectrum of milder phenotypes

The impact of rare variation on gene expression across tissues

© 2017 Macmillan Publishers Limited, part of Springer Nature. All rights reserved. Rare genetic variants are abundant in humans and are expected to contribute to individual disease risk1-4. While genetic association studies have successfully identified common genetic variants associated with susceptibility, these studies are not practical for identifying rare variants1,5. Efforts to distinguish pathogenic variants from benign rare variants have leveraged the genetic code to identify deleterious protein-coding alleles1,6,7, but no analogous code exists for non-coding variants. Therefore, ascertaining which rare variants have phenotypic effects remains a major challenge. Rare non-coding variants have been associated with extreme gene expression in studies using single tissues8-11, but their effects across tissues are unknown. Here we identify gene expression outliers, or individuals showing extreme expression levels for a particular gene, across 44 human tissues by using combined analyses of whole genomes and multi-tissue RNA-sequencing data from the Genotype-Tissue Expression (GTEx) project v6p release12. We find that 58% of underexpression and 28% of overexpression outliers have nearby conserved rare variants compared to 8% of non-outliers. Additionally, we developed RIVER (RNA-informed variant effect on regulation), a Bayesian statistical model that incorporates expression data to predict a regulatory effect for rare variants with higher accuracy than models using genomic annotations alone. Overall, we demonstrate that rare variants contribute to large gene expression changes across tissues and provide an integrative method for interpretation of rare variants in individual genomes

Higher Fusion Power Gain with Current and Pressure Profile Control in Strongly Shaped DIII-D Tokamak Plasmas.

Fusion power has been increased by a factor of 3 in DIII-D by tailoring the pressure profile to avoid the kink instability in H-mode plasmas. The resulting plasmas are found to have neoclassical ion confinement. This reduction in transport losses in beam-heated plasmas with negative central shear is correlated with a dramatic reduction in density fluctuations. Improved magnetohydrodynamic stability is achieved by controlling the plasma pressure profile width. In deuterium plasmas the highest gain Q (the ratio of fusion power to input power), was 0.0015, corresponding to an equivalent Q of 0.32 in a deuterium-tritium plasma. © 1996 The American Physical Society

Higher fusion power gain with profile control in DIII-D tokamak plasmas

Strong shaping, favourable for stability and improved energy confinement, together with a significant expansion of the central region of improved confinement in negative central magnetic shear target plasmas, increased the maximum fusion power produced in DIII-D by a factor of 3. Using deuterium plasmas, the highest fusion power gain, the ratio of fusion power to input power, Q, was 0.0015, corresponding to an equivalent Q of 0.32 in a deuterium-tritium plasma, which is similar to values achieved in tokamaks of larger size and magnetic field. A simple transformation relating Q to the stability parameters is presented

Higher fusion power gain with profile control in DIII-D tokamak plasmas

Strong shaping, favourable for stability and improved energy confinement, together with a significant expansion of the central region of improved confinement in negative central magnetic shear target plasmas, increased the maximum fusion power produced in DIII-D by a factor of 3. Using deuterium plasmas, the highest fusion power gain, the ratio of fusion power to input power, Q, was 0.0015, corresponding to an equivalent Q of 0.32 in a deuterium-tritium plasma, which is similar to values achieved in tokamaks of larger size and magnetic field. A simple transformation relating Q to the stability parameters is presented