Risk of severe asthma episodes predicted from fluctuation analysis of airway function

Asthma is an increasing health problem worldwide, but the long-term temporal pattern of clinical symptoms is not understood and predicting asthma episodes is not generally possible. We analyse the time series of peak expiratory flows, a standard measurement of airway function that has been assessed twice daily in a large asthmatic population during a long-term crossover clinical trial. Here we introduce an approach to predict the risk of worsening airflow obstruction by calculating the conditional probability that, given the current airway condition, a severe obstruction will occur within 30 days. We find that, compared with a placebo, a regular long-acting bronchodilator (salmeterol) that is widely used to improve asthma control decreases the risk of airway obstruction. Unexpectedly, however, a regular short-acting beta2-agonist bronchodilator (albuterol) increases this risk. Furthermore, we find that the time series of peak expiratory flows show long-range correlations that change significantly with disease severity, approaching a random process with increased variability in the most severe cases. Using a nonlinear stochastic model, we show that both the increased variability and the loss of correlations augment the risk of unstable airway function. The characterization of fluctuations in airway function provides a quantitative basis for objective risk prediction of asthma episodes and for evaluating the effectiveness of therapy.     

A 'periodic table' for protein structures

Current structural genomics programs aim systematically to determine the structures of all proteins coded in both human and other genomes, providing a complete picture of the number and variety of protein structures that exist. In the past, estimates have been made on the basis of the incomplete sample of structures currently known. These estimates have varied greatly (between 1,000 and 10,000; see for example refs 1 and 2), partly because of limited sample size but also owing to the difficulties of distinguishing one structure from another. This distinction is usually topological, based on the fold of the protein; however, in strict topological terms (neglecting to consider intra-chain cross-links), protein chains are open strings and hence are all identical. To avoid this trivial result, topologies are determined by considering secondary links in the form of intra-chain hydrogen bonds (secondary structure) and tertiary links formed by the packing of secondary structures. However, small additions to or loss of structure can make large changes to these perceived topologies and such subjective solutions are neither robust nor amenable to automation. Here I formalize both secondary and tertiary links to allow the rigorous and automatic definition of protein topology.     

Trends and random fluctuations in athletics

Improvements in the results of athletic competitions are often considered to stem from better training and equipment, but elements of chance are always present in athletics and these also contribute. Here we distinguish between these two effects by estimating the range into which athletic records would have fallen in the absence of systematic progress and then comparing this with actual performance results. We find that only 4 out of 22 disciplines have shown a systematic improvement, and that annual best results worldwide show saturation in some disciplines.     

Rauwolfia alkaloids XLVII isoreserpiline-ψ-indoxyl,its isolation,synthesis and structure

Zusammenfassung Isoreserpiline--indoxyl wurde ausRauwolfia vomitoria Afzel isoliert. Durch eine einfache Synthese, ausgehend von Reserpilin, wurde die Struktur dieses neuen Alkaloids bewiesen.     

Chemical structure of the morphogen differentiation inducing factor from Dictyostelium discoideum

Morphogens are signal molecules presumed to exist in embryos and to be involved in establishing the spatial pattern of cells during development. Differentiation inducing factor (DIF) has the properties of a morphogen required for producing the prestalk/prespore pattern in the aggregate formed by cells of the slime mould Dictyostelium in response to starvation. DIF-1, the major bioactive species after purification, has now been identified using a combined microchemical, spectroscopic and synthetic approach. The structure is defined as 1-(3,5-dichloro-2,6-dihydroxy-4-methoxyphenyl)-1-hexanone, and represents a new class of effector molecule. The availability of relatively large quantities of synthetic and isotopically labelled materials should now allow progress towards a detailed understanding of the pattern-forming processes in Dictyostelium development.     

Carotid occlusion and renal vein free fatty acids

Résumé L'occlusion de la carotide, l'épuisement du sodium du plasma et l'effet de la pression de perfusion rénale ont été utilisés pour étudier les niveaux d'acide gras non-estérifié dans la veine rénale. Dans la présente recherche, le système nerveux sympathique controlait la libération vers les reins de l'acide gras non-estérifié. Apparemment, l'épuisement du sodium n'affecte pas les niveaux normaux de repos de cet acide dans la veine rénale.

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A. W. Taylor is the recipient of a Research Associateship from the Department of National Health and Welfare, Ottawa.     

A role for ADP-ribosylation factor in nuclear vesicle dynamics.

Two distinct steps in nuclear envelope assembly can be assayed in vitro: the protein-mediated binding of nuclear-specific vesicles to chromatin, and the subsequent fusion of these vesicles to enclose the chromatin within a double nuclear membrane. Nuclear vesicle fusion, like fusion in the secretory pathway, requires ATP and cytosol and is inhibited by nonhydrolysable GTP analogues. The sensitivity of nuclear vesicle fusion to GTP-gamma S requires a GTP-dependent soluble factor, the properties of which are strikingly similar to a GTP-dependent Golgi binding factor (GGBF) that inhibits Golgi vesicle fusion in the presence of GTP-gamma S and belongs to the ADP-ribosylation factor (ARF) family of small GTPases. In the presence of GTP-gamma S, ARF proteins and alpha-, beta-, gamma-, delta-COP ('coatomer') subunits are associated with Golgi transport vesicles, but the exact roles of ARF proteins in secretion are not yet understood. We report here that purified ARF1 and GGBF have GTP-dependent soluble factor activity in the nuclear vesicle fusion assay. Our results show that the function of ARF is not limited to the Golgi apparatus, and indicate that there may be a link between the formation of nuclear vesicles during mitosis and proteins involved in secretion.