Common variants near TARDBP and EGR2 are associated with susceptibility to Ewing sarcoma

Ewing sarcoma, a pediatric tumor characterized by EWSR1-ETS fusions, is predominantly observed in populations of European ancestry. We performed a genome-wide association study (GWAS) of 401 French individuals with Ewing sarcoma, 684 unaffected French individuals and 3,668 unaffected individuals of European descent and living in the United States. We identified candidate risk loci at 1p36.22, 10q21 and 15q15. We replicated these loci in two independent sets of cases and controls. Joint analysis identified associations with rs9430161 (P = 1.4 × 10(-20); odds ratio (OR) = 2.2) located 25 kb upstream of TARDBP, rs224278 (P = 4.0 × 10(-17); OR = 1.7) located 5 kb upstream of EGR2 and, to a lesser extent, rs4924410 at 15q15 (P = 6.6 × 10(-9); OR = 1.5). The major risk haplotypes were less prevalent in Africans, suggesting that these loci could contribute to geographical differences in Ewing sarcoma incidence. TARDBP shares structural similarities with EWSR1 and FUS, which encode RNA binding proteins, and EGR2 is a target gene of EWSR1-ETS. Variants at these loci were associated with expression levels of TARDBP, ADO (encoding cysteamine dioxygenase) and EGR2.     

Small molecule activators of SIRT1 as therapeutics for the treatment of type 2 diabetes

Calorie restriction extends lifespan and produces a metabolic profile desirable for treating diseases of ageing such as type 2 diabetes. SIRT1, an NAD+-dependent deacetylase, is a principal modulator of pathways downstream of calorie restriction that produce beneficial effects on glucose homeostasis and insulin sensitivity. Resveratrol, a polyphenolic SIRT1 activator, mimics the anti-ageing effects of calorie restriction in lower organisms and in mice fed a high-fat diet ameliorates insulin resistance, increases mitochondrial content, and prolongs survival. Here we describe the identification and characterization of small molecule activators of SIRT1 that are structurally unrelated to, and 1,000-fold more potent than, resveratrol. These compounds bind to the SIRT1 enzyme-peptide substrate complex at an allosteric site amino-terminal to the catalytic domain and lower the Michaelis constant for acetylated substrates. In diet-induced obese and genetically obese mice, these compounds improve insulin sensitivity, lower plasma glucose, and increase mitochondrial capacity. In Zucker fa/fa rats, hyperinsulinaemic-euglycaemic clamp studies demonstrate that SIRT1 activators improve whole-body glucose homeostasis and insulin sensitivity in adipose tissue, skeletal muscle and liver. Thus, SIRT1 activation is a promising new therapeutic approach for treating diseases of ageing such as type 2 diabetes.     

Acquisition of a multifunctional IgA+ plasma cell phenotype in the gut

The largest mucosal surface in the body is in the gastrointestinal tract, a location that is heavily colonized by microbes that are normally harmless. A key mechanism required for maintaining a homeostatic balance between this microbial burden and the lymphocytes that densely populate the gastrointestinal tract is the production and transepithelial transport of poly-reactive IgA (ref. 1). Within the mucosal tissues, B cells respond to cytokines, sometimes in the absence of T-cell help, undergo class switch recombination of their immunoglobulin receptor to IgA, and differentiate to become plasma cells. However, IgA-secreting plasma cells probably have additional attributes that are needed for coping with the tremendous bacterial load in the gastrointestinal tract. Here we report that mouse IgA(+) plasma cells also produce the antimicrobial mediators tumour-necrosis factor-α (TNF-α) and inducible nitric oxide synthase (iNOS), and express many molecules that are commonly associated with monocyte/granulocytic cell types. The development of iNOS-producing IgA(+) plasma cells can be recapitulated in vitro in the presence of gut stroma, and the acquisition of this multifunctional phenotype in vivo and in vitro relies on microbial co-stimulation. Deletion of TNF-α and iNOS in B-lineage cells resulted in a reduction in IgA production, altered diversification of the gut microbiota and poor clearance of a gut-tropic pathogen. These findings reveal a novel adaptation to maintaining homeostasis in the gut, and extend the repertoire of protective responses exhibited by some B-lineage cells.     

Mathematical Arguments in Context

Except in very poor mathematical contexts, mathematical arguments do not stand in isolation of other mathematical arguments. Rather, they form trains of formal and informal arguments, adding up to interconnected theorems, theories and eventually entire fields. This paper critically comments on some common views on the relation between formal and informal mathematical arguments, most particularly applications of Toulmin’s argumentation model, and launches a number of alternative ideas of presentation inviting the contextualization of pieces of mathematical reasoning within encompassing bodies of explicit and implicit, formal and informal background knowledge.     

How Sweet It Is: Sugar,Science, and the State

Americans import large amounts of sugar, levy a stiff tariff on it, and base this tariff on the saccharine content of each sample, and thus the assessment of sugar quality for tax purposes was enormously important. It was also among the most difficult challenges of a scientific or technical nature facing the federal government in the nineteenth century, and the issues it raised would often recur as science-based quality control became an essential feature of industry.     

The correspondence between James Hutton (1726–1797) and James Watt (1736–1819) with two letters from Hutton to George Clerk-Maxwell (1715–1784): Part I

In the collection of Watt's papers at Doldowlod, home of Lord Gibson-Watt, there are seven previously unpublished letters from James Hutton to James Watt, and four letters from Watt to Hutton, also unpublished. The letters were written between 1774 and 1795. Very little of Hutton's other correspondence survives, so these letters add significantly to our knowledge. The earliest letters, together with two letters to George Clerk-Maxwell (in the Scottish Record Office), describe geological tours that Hutton made through Wales, the Midlands, and the south-west of England in 1774. The correspondence after 1774, which will appear in a later edition of Annals of Science, reveals Watt's expertise in geology, and also discusses meteorology, varnish making, Symington's steam engines, the first experiments with steam navigation, pneumatic medicine, and other topics.     

Schrödinger and Dirac equations for the hydrogen atom, and Laguerre polynomials

It is usually claimed that the Laguerre polynomials were popularized by Schrödinger when creating wave mechanics; however, we show that he did not immediately identify them in studying the hydrogen atom. In the case of relativistic Dirac equations for an electron in a Coulomb field, Dirac gave only approximations, Gordon and Darwin gave exact solutions, and Pidduck first explicitly and elegantly introduced the Laguerre polynomials, an approach neglected by most modern treatises and articles. That Laguerre polynomials were not very popular before their use in quantum mechanics, probably because they had been little used in classical mathematical physics, is confirmed by the fact that, as we show, they had been rediscovered independently several times during the nineteenth century, in published or unpublished studies of Abel, Murphy, Chebyshev, and Laguerre.     

Le molybdène en biologie

Zusammenfassung Durch seine Beteiligung an der Reduktion der Nitrate und an der Aufnahme von Stickstoff, spielt das Molybdän eine erhebliche Rolle im Cyclus dieses Elements. Aus diesem Grunde ist es nützlich, diejenigen Stoffwechselprozesse zu kennen, an denen das Molybdän entscheidend beteiligt ist. Es ist das Ziel dieser Übersicht, einen zusammenfassenden Einblick in den Stand unserer Kenntnisse auf dem Gebiet dieses Oligoelements zu geben; eine chronologische Betrachtung erlaubt uns, zuerst diejenigen biochemischen Vorgänge zu betrachten, für die seine Einwirkung als gesichert gilt.Die Gesamtheit der Arbeiten über die Nitratreduktion lassen darauf schliessen, dass das Molybdän spezifisch zur Funktion der Nitratreduktase gehört. Indem es integraler Bestandteil der aus Mikroorganismen und höheren Pflanzen extrahierten Nitratreduktase ist, kommt ihm eine Rolle im Elektronentransport, welcher von den Nitraten zu den Nitriten führt, zu. Es handelt sich hier um die erste Stufe der Reaktionen, die zur Ammoniakbildung führen.Man weiss schon lange, dass Molybdän zur Bindung des Luftstickstoffs benötigt wird. Unsere Kenntnisse über eine spezifische Beteiligung des Elements an diesem Vorgang verdankt man jedoch neueren Arbeiten, vor allem jenen, welche die Bindung von Stickstoff in zellfreien Extrakten zum Gegenstand haben. Diese Ergebnisse werden im Lichte der neuern Theorien über den Mechanismus der Stickstoffbindung besprochen.Abschliessend werden einige andere Reaktionen des pflanzlichen und tierischen Stoffwechsels betrachtet, an denen das Molybdän Anteil hat.     

L'optique balistique newtonienne à l'épreuve des satellites de Jupiter

Sans résumé Présenté par Alan E.Shapiro