The Oxygen Paradox, the French Paradox, and age-related diseases

open46openDavies, Joanna M. S.; Cillard, Josiane; Friguet, Bertrand; Cadenas, Enrique; Cadet, Jean; Cayce, Rachael; Fishmann, Andrew; Liao, David; Bulteau, Anne-Laure; Derbré, Frédéric; Rébillard, Amélie; Burstein, Steven; Hirsch, Etienne; Kloner, Robert A.; Jakowec, Michael; Petzinger, Giselle; Sauce, Delphine; Sennlaub, Florian; Limon, Isabelle; Ursini, Fulvio; Maiorino, Matilde; Economides, Christina; Pike, Christian J.; Cohen, Pinchas; Salvayre, Anne Negre; Halliday, Matthew R.; Lundquist, Adam J.; Jakowec, Nicolaus A.; Mechta-Grigoriou, Fatima; Mericskay, Mathias; Mariani, Jean; Li, Zhenlin; Huang, David; Grant, Ellsworth; Forman, Henry J.; Finch, Caleb E.; Sun, Patrick Y.; Pomatto, Laura C. D.; Agbulut, Onnik; Warburton, David; Neri, Christian; Rouis, Mustapha; Cillard, Pierre; Capeau, Jacqueline; Rosenbaum, Jean; Davies, Kelvin J. A.Davies, Joanna M. S.; Cillard, Josiane; Friguet, Bertrand; Cadenas, Enrique; Cadet, Jean; Cayce, Rachael; Fishmann, Andrew; Liao, David; Bulteau, Anne-Laure; Derbré, Frédéric; Rébillard, Amélie; Burstein, Steven; Hirsch, Etienne; Kloner, Robert A.; Jakowec, Michael; Petzinger, Giselle; Sauce, Delphine; Sennlaub, Florian; Limon, Isabelle; Ursini, Fulvio; Maiorino, Matilde; Economides, Christina; Pike, Christian J.; Cohen, Pinchas; Salvayre, Anne Negre; Halliday, Matthew R.; Lundquist, Adam J.; Jakowec, Nicolaus A.; Mechta-Grigoriou, Fatima; Mericskay, Mathias; Mariani, Jean; Li, Zhenlin; Huang, David; Grant, Ellsworth; Forman, HENRY J.; Finch, Caleb E.; Sun, Patrick Y.; Pomatto, Laura C. D.; Agbulut, Onnik; Warburton, David; Neri, Christian; Rouis, Mustapha; Cillard, Pierre; Capeau, Jacqueline; Rosenbaum, Jean; Davies, Kelvin J. A

The RHO-1 RhoGTPase Modulates Fertility and Multiple Behaviors in Adult C. elegans

The Rho family of small GTPases are essential during early embryonic development making it difficult to study their functions in adult animals. Using inducible transgenes expressing either a constitutively active version of the single C. elegans Rho ortholog, RHO-1, or an inhibitor of endogenous Rho (C3 transferase), we demonstrate multiple defects caused by altering Rho signaling in adult C. elegans. Changes in RHO-1 signaling in cholinergic neurons affected locomotion, pharyngeal pumping and fecundity. Changes in RHO-1 signaling outside the cholinergic neurons resulted in defective defecation, ovulation, and changes in C. elegans body morphology. Finally both increased and decreased RHO-1 signaling in adults resulted in death within hours. The multiple post-developmental roles for Rho in C. elegans demonstrate that RhoA signaling pathways continue to be used post-developmentally and the resulting phenotypes provide an opportunity to further study post-developmental Rho signaling pathways using genetic screens

Structural and Functional Evaluation of C. elegans Filamins FLN-1 and FLN-2

Filamins are long, flexible, multi-domain proteins composed of an N-terminal actin-binding domain (ABD) followed by multiple immunoglobulin-like repeats (IgFLN). They function to organize and maintain the actin cytoskeleton, to provide scaffolds for signaling components, and to act as mechanical force sensors. In this study, we used transcript sequencing and homology modeling to characterize the gene and protein structures of the C. elegans filamin orthologs fln-1 and fln-2. Our results reveal that C. elegans FLN-1 is well conserved at the sequence level to vertebrate filamins, particularly in the ABD and several key IgFLN repeats. Both FLN-1 and the more divergent FLN-2 colocalize with actin in vivo. FLN-2 is poorly conserved, with at least 23 IgFLN repeats interrupted by large regions that appear to be nematode-specific. Our results indicate that many of the key features of vertebrate filamins are preserved in C. elegans FLN-1 and FLN-2, and suggest the nematode may be a very useful model system for further study of filamin function

The James Webb Space Telescope Mission

Twenty-six years ago a small committee report, building on earlier studies, expounded a compelling and poetic vision for the future of astronomy, calling for an infrared-optimized space telescope with an aperture of at least $4m$. With the support of their governments in the US, Europe, and Canada, 20,000 people realized that vision as the $6.5m$ James Webb Space Telescope. A generation of astronomers will celebrate their accomplishments for the life of the mission, potentially as long as 20 years, and beyond. This report and the scientific discoveries that follow are extended thank-you notes to the 20,000 team members. The telescope is working perfectly, with much better image quality than expected. In this and accompanying papers, we give a brief history, describe the observatory, outline its objectives and current observing program, and discuss the inventions and people who made it possible. We cite detailed reports on the design and the measured performance on orbit.Comment: Accepted by PASP for the special issue on The James Webb Space Telescope Overview, 29 pages, 4 figure

Author Correction:Study of 300,486 individuals identifies 148 independent genetic loci influencing general cognitive function

Christina M. Lill, who contributed to analysis of data, was inadvertently omitted from the author list in the originally published version of this article. This has now been corrected in both the PDF and HTML versions of the article

The five investigated signs of Shar-Pei autoinflammatory disease share overlapping association signals.

<p>The phenotypes of fever (<b>A</b>. <i>n</i> = 129), arthritis (<b>B</b>. <i>n</i> = 107), vesicular hyaluronosis (<b>C</b>. <i>n</i> = 46), and otitis (<b>D</b>. <i>n</i> = 27) were compared to a subset of healthy controls at least 7 years old (<i>n</i> = 24). The phenotype of amyloidosis (<b>E</b>) required individuals to undergo renal biopsy screening to be declared positive (<i>n</i> = 37) or negative (<i>n</i> = 14) for the deposits. In each panel the top genome-wide significant SNP has been highlighted with an open circle and linkage disequilibrium (<i>r²</i>) between this marker and the others in the region coloured according to strength. A genome wide significant threshold (red dotted line) has been defined using an analysis specific Bonferroni 5% limit.</p

Major haplotype pairs observed across chromosome 13 as defined by GWAS significant SNP.

1<p>Phased haplotypes are composed of the top SNP identified in each GWAS where genome-wide significance was reached and estimated from the total population frequency.</p>2<p>Haplotype pairs observed at frequencies less than 10% in a sample set have been collapsed.</p

The genetic signature of within breed sub-type on chromosome 13.

<p>Individuals representing the extremes of physical appearance (Meatmouth, heavily wrinkled thickened skin, <i>n</i> = 123; Bonemouth, few wrinkles left into adulthood, <i>n</i> = 33) were compared. <b>A</b>. Pairwise <i>F</i>_ST was calculated between the two groups for 126,206 SNP and plotted in chromosomal order. Smoothed values in bins of 100 SNP are superimposed to better illustrate the peak of association (red line). <b>B</b>. A zoomed view of a subset of the genes from the chromosome region in relation to the peak of <i>F</i>_ST (based on most divergent SNP and a 5% threshold, red box). <b>C</b>. The plot of a mixed model association test for breed subtype. The top genome-wide significant SNP (13∶23180227, <i>p_MM</i> = 2.63×10⁻⁹) has been highlighted with an open circle and linkage disequilibrium (<i>r²</i>) between this marker and the others in the region are coloured according to strength. A genome wide significant threshold (red dotted line) has been defined using an analysis specific Bonferroni 5% limit.</p

A novel locus on chromosome 14 is associated with Shar-Pei amyloidosis. A

<p>. The genome wide association study of amyloidosis positive (<i>n</i> = 37) and negative (<i>n</i> = 14) individuals revealed a signal of association on chromosome 14 (14∶54948811, <i>p_MM</i> = 4.34×10⁻⁶) which was of slightly reduced strength to that observed on chromosome 13 (13∶27371905, <i>p_MM</i> = 3.0×10⁻⁶). <b>B</b>. A zoomed view of a subset of the genes across the chromosome 14 disease associated region, <b>C</b>. This region encompasses two peaks in moderate LD (<i>r²</i> = 0.6) as indicated by heat colouring. A genome wide significant threshold (red dotted line) has been defined using as Bonferroni 5%. <b>D</b>. The scaled plots of genes demonstrating differential expression between amyloidosis negative (<i>n</i> = 7) and positive (<i>n</i> = 7) kidney biopsies. Samples are shown in the same order for each gene and also in order of phased H14 haplotypes (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0075242#pone.0075242.s005" target="_blank">Table S3</a>). Each sample registered expression, although in some cases it was negligible. p-values 0.05>0.01, *>**.</p