The biogenesis of theTabernanthe iboga alkaloids

Zusammenfassung Die vorliegende Arbeit schlägt eine Biogenese der Tabernanthe-Alkaloide vor, die von einem -Kondensationsprodukt von Tryptophan mit 3,4-Dioxyphenylalanin ausgeht. Der siebengliedrige Ring C dieser Alkaloide entsteht durch Ringöffnung und erneute Ringschliessung eines Oxydationsproduktes. Weitere Stufen umfassen eine Mannich-Kondensation, eine Reduktion und einen Ringschluss zu einer Hydroxycarboxyverbindung, aus der durch einfache Reaktionen Voacangin und Ibogain abgeleitet werden können.

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The Alkaloids ofTabernanthe Iboga, Part V.     

Correlation of anthothecol and hirtin

Summary Hirtin (3) and anthothecol (2) have been correlated by conversion of each to the derivative (10).     

Large-scale sequencing of human influenza reveals the dynamic nature of viral genome evolution

Influenza viruses are remarkably adept at surviving in the human population over a long timescale. The human influenza A virus continues to thrive even among populations with widespread access to vaccines, and continues to be a major cause of morbidity and mortality. The virus mutates from year to year, making the existing vaccines ineffective on a regular basis, and requiring that new strains be chosen for a new vaccine. Less-frequent major changes, known as antigenic shift, create new strains against which the human population has little protective immunity, thereby causing worldwide pandemics. The most recent pandemics include the 1918 'Spanish' flu, one of the most deadly outbreaks in recorded history, which killed 30-50 million people worldwide, the 1957 'Asian' flu, and the 1968 'Hong Kong' flu. Motivated by the need for a better understanding of influenza evolution, we have developed flexible protocols that make it possible to apply large-scale sequencing techniques to the highly variable influenza genome. Here we report the results of sequencing 209 complete genomes of the human influenza A virus, encompassing a total of 2,821,103 nucleotides. In addition to increasing markedly the number of publicly available, complete influenza virus genomes, we have discovered several anomalies in these first 209 genomes that demonstrate the dynamic nature of influenza transmission and evolution. This new, large-scale sequencing effort promises to provide a more comprehensive picture of the evolution of influenza viruses and of their pattern of transmission through human and animal populations. All data from this project are being deposited, without delay, in public archives.     

Insulin disrupts beta-adrenergic signalling to protein kinase A in adipocytes

Hormones mobilize intracellular second messengers and initiate signalling cascades involving protein kinases and phosphatases, which are often spatially compartmentalized by anchoring proteins to increase signalling specificity. These scaffold proteins may themselves be modulated by hormones. In adipocytes, stimulation of beta-adrenergic receptors increases cyclic AMP levels and activates protein kinase A (PKA), which stimulates lipolysis by phosphorylating hormone-sensitive lipase and perilipin. Acute insulin treatment activates phosphodiesterase 3B, reduces cAMP levels and quenches beta-adrenergic receptor signalling. In contrast, chronic hyperinsulinaemic conditions (typical of type 2 diabetes) enhance beta-adrenergic receptor-mediated cAMP production. This amplification of cAMP signalling is paradoxical because it should enhance lipolysis, the opposite of the known short-term effect of hyperinsulinaemia. Here we show that in adipocytes, chronically high insulin levels inhibit beta-adrenergic receptors (but not other cAMP-elevating stimuli) from activating PKA. We measured this using an improved fluorescent reporter and by phosphorylation of endogenous cAMP-response-element binding protein (CREB). Disruption of PKA scaffolding mimics the interference of insulin with beta-adrenergic receptor signalling. Chronically high insulin levels may disrupt the close apposition of beta-adrenergic receptors and PKA, identifying a new mechanism for crosstalk between heterologous signal transduction pathways.     

DNA sequence and analysis of human chromosome 18

Chromosome 18 appears to have the lowest gene density of any human chromosome and is one of only three chromosomes for which trisomic individuals survive to term. There are also a number of genetic disorders stemming from chromosome 18 trisomy and aneuploidy. Here we report the finished sequence and gene annotation of human chromosome 18, which will allow a better understanding of the normal and disease biology of this chromosome. Despite the low density of protein-coding genes on chromosome 18, we find that the proportion of non-protein-coding sequences evolutionarily conserved among mammals is close to the genome-wide average. Extending this analysis to the entire human genome, we find that the density of conserved non-protein-coding sequences is largely uncorrelated with gene density. This has important implications for the nature and roles of non-protein-coding sequence elements.     

Identification of large ancient duplications associated with human gene deserts

We identified 15 regions of >1 Mb in the human genome composed of large ancient local duplications corresponding to gene deserts. We detected these intrachromosomal duplications in mouse and dog but not in chicken; they present as patches of similarity as low as 60%. These findings suggest that some human gene deserts originated from duplications of segments lacking genes in a mammalian common ancestor.     

Organization of genetic variation in individuals of arbuscular mycorrhizal fungi

Arbuscular mycorrhizal (AM) fungi (Glomeromycota) are thought to be the oldest group of asexual multicellular organisms. They colonize the roots of most land plants, where they facilitate mineral uptake from the soil in exchange for plant-assimilated carbon. Cells of AM fungi contain hundreds of nuclei. Unusual polymorphism of ribosomal DNA observed in individual spores of AM fungi inspired a hypothesis that heterokaryosis--that is, the coexistence of many dissimilar nuclei in cells--occurs throughout the AM fungal life history. Here we report a genetic approach to test the hypothesis of heterokaryosis in AM fungi. Our study of the transmission of polymorphic genetic markers in natural isolates of Glomus etunicatum, coupled with direct amplification of rDNA from microdissected nuclei by polymerase chain reaction, supports the alternative hypothesis of homokaryosis, in which nuclei populating AM fungal individuals are genetically uniform. Intrasporal rDNA polymorphism contained in each nucleus signals a relaxation of concerted evolution, a recombination-driven process that is responsible for homogenizing rDNA repeats. Polyploid organization of glomeromycotan genomes could accommodate intranuclear rDNA polymorphism and buffer these apparently asexual organisms against the effects of accumulating mutations.