Meta-analyses identify 13 loci associated with age at menopause and highlight DNA repair and immune pathways

To newly identify loci for age at natural menopause, we carried out a meta-analysis of 22 genome-wide association studies (GWAS) in 38,968 women of European descent, with replication in up to 14,435 women. In addition to four known loci, we identified 13 loci newly associated with age at natural menopause (at P < 5 × 10(-8)). Candidate genes located at these newly associated loci include genes implicated in DNA repair (EXO1, HELQ, UIMC1, FAM175A, FANCI, TLK1, POLG and PRIM1) and immune function (IL11, NLRP11 and PRRC2A (also known as BAT2)). Gene-set enrichment pathway analyses using the full GWAS data set identified exoDNase, NF-κB signaling and mitochondrial dysfunction as biological processes related to timing of menopause.     

Cathepsin D and the catabolic degradation of proteoglycans in granulomatous tissue]

Incubated in vitro at 37 degrees C, granulation tissues release glycosaminoglycans into the incubation medium. Such release is inhibited if pepstatine is present in the medium. From this result, it can be inferred that the protien moiety of the proteioglycans is degraded by cathepsin D. Therefore a role of this enzyme in granulation tissues appears, especially in the late reparative phase.     

A history of the axiomatic formulation of probability from Borel to Kolmogorov: Part I

This paper, the first of two, traces the origins of the modern axiomatic formulation of Probability Theory, which was first given in definitive form by Kolmogorov in 1933. Even before that time, however, a sequence of developments, initiated by a landmark paper of E. Borel, were giving rise to problems, theorems, and reformulations that increasingly related probability to measure theory and, in particular, clarified the key role of countable additivity in Probability Theory.This paper describes the developments from Borel's work through F. Hausdorff's. The major accomplishments of the period were Borel's Zero-One Law (also known as the Borel-Cantelli Lemmas), his Strong Law of Large Numbers, and his Continued Fraction Theorem. What is new is a detailed analysis of Borel's original proofs, from which we try to account for the roots (psychological as well as mathematical) of the many flaws and inadequacies in Borel's reasoning. We also document the increasing realization of the link between the theories of measure and of probability in the period from G. Faber to F. Hausdorff. We indicate the misleading emphasis given to independence as a basic concept by Borel and his equally unfortunate association of a Heine-Borel lemma with countable additivity. Also original is the (possible) genesis we propose for each of the two examples chosen by Borel to exhibit his new theory; in each case we cite a now neglected precursor of Borel, one of them surely known to Borel, the other, probably so. The brief sketch of instances of the Cantelli lemma before Cantelli's publication is also original.We describe the interesting polemic between F. Bernstein and Borel concerning the Continued Fraction Theorem, which serves as a rare instance of a contemporary criticism of Borel's reasoning. We also discuss Hausdorff's proof of Borel's Strong Law (which seems to be the first valid proof of the theorem along the lines sketched by Borel).In retrospect, one may ask why problems of geometric (or continuous) probability did not give rise to the (Kolmogorov) view of probability as a form of measure, rather than the study of repeated independent trials, which was Borel's approach. This paper shows that questions of geometric probability were always the essential guide to the early development of the theory, despite the contrary viewpoint exhibited by Borel's preferred interpretation of his own results.     

The draft genome of the transgenic tropical fruit tree papaya (Carica papaya Linnaeus)

Papaya, a fruit crop cultivated in tropical and subtropical regions, is known for its nutritional benefits and medicinal applications. Here we report a 3x draft genome sequence of 'SunUp' papaya, the first commercial virus-resistant transgenic fruit tree to be sequenced. The papaya genome is three times the size of the Arabidopsis genome, but contains fewer genes, including significantly fewer disease-resistance gene analogues. Comparison of the five sequenced genomes suggests a minimal angiosperm gene set of 13,311. A lack of recent genome duplication, atypical of other angiosperm genomes sequenced so far, may account for the smaller papaya gene number in most functional groups. Nonetheless, striking amplifications in gene number within particular functional groups suggest roles in the evolution of tree-like habit, deposition and remobilization of starch reserves, attraction of seed dispersal agents, and adaptation to tropical daylengths. Transgenesis at three locations is closely associated with chloroplast insertions into the nuclear genome, and with topoisomerase I recognition sites. Papaya offers numerous advantages as a system for fruit-tree functional genomics, and this draft genome sequence provides the foundation for revealing the basis of Carica's distinguishing morpho-physiological, medicinal and nutritional properties.     

NLRX1 is a regulator of mitochondrial antiviral immunity

The RIG-like helicase (RLH) family of intracellular receptors detect viral nucleic acid and signal through the mitochondrial antiviral signalling adaptor MAVS (also known as Cardif, VISA and IPS-1) during a viral infection. MAVS activation leads to the rapid production of antiviral cytokines, including type 1 interferons. Although MAVS is vital to antiviral immunity, its regulation from within the mitochondria remains unknown. Here we describe human NLRX1, a highly conserved nucleotide-binding domain (NBD)- and leucine-rich-repeat (LRR)-containing family member (known as NLR) that localizes to the mitochondrial outer membrane and interacts with MAVS. Expression of NLRX1 results in the potent inhibition of RLH- and MAVS-mediated interferon-beta promoter activity and in the disruption of virus-induced RLH-MAVS interactions. Depletion of NLRX1 with small interference RNA promotes virus-induced type I interferon production and decreases viral replication. This work identifies NLRX1 as a check against mitochondrial antiviral responses and represents an intersection of three ancient cellular processes: NLR signalling, intracellular virus detection and the use of mitochondria as a platform for anti-pathogen signalling. This represents a conceptual advance, in that NLRX1 is a modulator of pathogen-associated molecular pattern receptors rather than a receptor, and identifies a key therapeutic target for enhancing antiviral responses.