Enzymatic capture of an extrahelical thymine in the search for uracil in DNA

The enzyme uracil DNA glycosylase (UNG) excises unwanted uracil bases in the genome using an extrahelical base recognition mechanism. Efficient removal of uracil is essential for prevention of C-to-T transition mutations arising from cytosine deamination, cytotoxic U*A pairs arising from incorporation of dUTP in DNA, and for increasing immunoglobulin gene diversity during the acquired immune response. A central event in all of these UNG-mediated processes is the singling out of rare U*A or U*G base pairs in a background of approximately 10(9) T*A or C*G base pairs in the human genome. Here we establish for the human and Escherichia coli enzymes that discrimination of thymine and uracil is initiated by thermally induced opening of T*A and U*A base pairs and not by active participation of the enzyme. Thus, base-pair dynamics has a critical role in the genome-wide search for uracil, and may be involved in initial damage recognition by other DNA repair glycosylases.     

Natural history and evolutionary principles of gene duplication in fungi

Gene duplication and loss is a powerful source of functional innovation. However, the general principles that govern this process are still largely unknown. With the growing number of sequenced genomes, it is now possible to examine these events in a comprehensive and unbiased manner. Here, we develop a procedure that resolves the evolutionary history of all genes in a large group of species. We apply our procedure to seventeen fungal genomes to create a genome-wide catalogue of gene trees that determine precise orthology and paralogy relations across these species. We show that gene duplication and loss is highly constrained by the functional properties and interacting partners of genes. In particular, stress-related genes exhibit many duplications and losses, whereas growth-related genes show selection against such changes. Whole-genome duplication circumvents this constraint and relaxes the dichotomy, resulting in an expanded functional scope of gene duplication. By characterizing the functional fate of duplicate genes we show that duplicated genes rarely diverge with respect to biochemical function, but typically diverge with respect to regulatory control. Surprisingly, paralogous modules of genes rarely arise, even after whole-genome duplication. Rather, gene duplication may drive the modularization of functional networks through specialization, thereby disentangling cellular systems.     

The signature of hot hydrogen in the atmosphere of the extrasolar planet HD 209458b

About ten per cent of the known extrasolar planets are gas giants that orbit very close to their parent stars. The atmospheres of these 'hot Jupiters' are heated by the immense stellar irradiation. In the case of the planet HD 209458b, this energy deposition results in a hydrodynamic state in the upper atmosphere, allowing for sizeable expansion and escape of neutral hydrogen gas. HD 209458b was the first extrasolar planet discovered that transits in front of its parent star. The size of the planet can be measured using the total optical obscuration of the stellar disk during an observed transit, and the structure and composition of the planetary atmosphere can be studied using additional planetary absorption signatures in the stellar spectrum. Here we report the detection of absorption by hot hydrogen in the atmosphere of HD 209458b. Previously, the lower atmosphere and the full extended upper atmosphere of HD 209458b have been observed, whereas here we probe a layer where the escaping gas forms in the upper atmosphere of HD 209458b.     

Ebola virus entry requires the cholesterol transporter Niemann-Pick C1

Infections by the Ebola and Marburg filoviruses cause a rapidly fatal haemorrhagic fever in humans for which no approved antivirals are available. Filovirus entry is mediated by the viral spike glycoprotein (GP), which attaches viral particles to the cell surface, delivers them to endosomes and catalyses fusion between viral and endosomal membranes. Additional host factors in the endosomal compartment are probably required for viral membrane fusion; however, despite considerable efforts, these critical host factors have defied molecular identification. Here we describe a genome-wide haploid genetic screen in human cells to identify host factors required for Ebola virus entry. Our screen uncovered 67 mutations disrupting all six members of the homotypic fusion and vacuole protein-sorting (HOPS) multisubunit tethering complex, which is involved in the fusion of endosomes to lysosomes, and 39 independent mutations that disrupt the endo/lysosomal cholesterol transporter protein Niemann-Pick C1 (NPC1). Cells defective for the HOPS complex or NPC1 function, including primary fibroblasts derived from human Niemann-Pick type C1 disease patients, are resistant to infection by Ebola virus and Marburg virus, but remain fully susceptible to a suite of unrelated viruses. We show that membrane fusion mediated by filovirus glycoproteins and viral escape from the vesicular compartment require the NPC1 protein, independent of its known function in cholesterol transport. Our findings uncover unique features of the entry pathway used by filoviruses and indicate potential antiviral strategies to combat these deadly agents.     

Autophagy in immunity and inflammation

Autophagy is an essential, homeostatic process by which cells break down their own components. Perhaps the most primordial function of this lysosomal degradation pathway is adaptation to nutrient deprivation. However, in complex multicellular organisms, the core molecular machinery of autophagy - the 'autophagy proteins' - orchestrates diverse aspects of cellular and organismal responses to other dangerous stimuli such as infection. Recent developments reveal a crucial role for the autophagy pathway and proteins in immunity and inflammation. They balance the beneficial and detrimental effects of immunity and inflammation, and thereby may protect against infectious, autoimmune and inflammatory diseases.     

A bibliographical study of the introduction of Lavoisier's Traité élémentaire de chimie into Great Britain and America

As the most famous woman scientist of the twentieth century, there has been no shortage of books and articles on the life and career of Marie Curie (1867–1934). Her role as a director of a laboratory-based research school in the new scientific field of radioactivity, a field which embraced both chemistry and physics, however, has never been examined. In recent years, there has been a growing interest in the question of research schools, and Morrell, Ravetz, Geison, and Klosterman, amongst others, have written on this subject. Using, in part, the methodology of Morrell, this paper investigates the role of Marie Curie as a school director in the Paris Faculty in the years 1907–14, examining the work and characteristics of her school and assessing her effectiveness as a director.     

Reconsidering the dynamics of reason: Response to Ferrari,Mormann, Nordmann,and Uebel

I address the points raised by the four commentators by indicating how I have been thinking about extending and expanding my perspective since Dynamics of Reason (2001). This involves reinterpreting the Kantian distinction between understanding and sensibility, and thereby rethinking the relativized a priori. I connect these ideas with experimental contexts and technology, as well as with the wider culture context. I suggest implications for the relationships among science, democracy, and religion—and eventually reconceptualizing Kant’s original Enlightenment project.