An endogenous tumour-promoting ligand of the human aryl hydrocarbon receptor

Activation of the aryl hydrocarbon receptor (AHR) by environmental xenobiotic toxic chemicals, for instance 2,3,7,8-tetrachlorodibenzo-p-dioxin (dioxin), has been implicated in a variety of cellular processes such as embryogenesis, transformation, tumorigenesis and inflammation. But the identity of an endogenous ligand activating the AHR under physiological conditions in the absence of environmental toxic chemicals is still unknown. Here we identify the tryptophan (Trp) catabolite kynurenine (Kyn) as an endogenous ligand of the human AHR that is constitutively generated by human tumour cells via tryptophan-2,3-dioxygenase (TDO), a liver- and neuron-derived Trp-degrading enzyme not yet implicated in cancer biology. TDO-derived Kyn suppresses antitumour immune responses and promotes tumour-cell survival and motility through the AHR in an autocrine/paracrine fashion. The TDO-AHR pathway is active in human brain tumours and is associated with malignant progression and poor survival. Because Kyn is produced during cancer progression and inflammation in the local microenvironment in amounts sufficient for activating the human AHR, these results provide evidence for a previously unidentified pathophysiological function of the AHR with profound implications for cancer and immune biology.     

High plant diversity is needed to maintain ecosystem services

Biodiversity is rapidly declining worldwide, and there is consensus that this can decrease ecosystem functioning and services. It remains unclear, though, whether few or many of the species in an ecosystem are needed to sustain the provisioning of ecosystem services. It has been hypothesized that most species would promote ecosystem services if many times, places, functions and environmental changes were considered; however, no previous study has considered all of these factors together. Here we show that 84% of the 147 grassland plant species studied in 17 biodiversity experiments promoted ecosystem functioning at least once. Different species promoted ecosystem functioning during different years, at different places, for different functions and under different environmental change scenarios. Furthermore, the species needed to provide one function during multiple years were not the same as those needed to provide multiple functions within one year. Our results indicate that even more species will be needed to maintain ecosystem functioning and services than previously suggested by studies that have either (1) considered only the number of species needed to promote one function under one set of environmental conditions, or (2) separately considered the importance of biodiversity for providing ecosystem functioning across multiple years, places, functions or environmental change scenarios. Therefore, although species may appear functionally redundant when one function is considered under one set of environmental conditions, many species are needed to maintain multiple functions at multiple times and places in a changing world.     

A gene expression map of human chromosome 21 orthologues in the mouse

The DNA sequence of human chromosome 21 (HSA21) has opened the route for a systematic molecular characterization of all of its genes. Trisomy 21 is associated with Down's syndrome, the most common genetic cause of mental retardation in humans. The phenotype includes various organ dysmorphies, stereotypic craniofacial anomalies and brain malformations. Molecular analysis of congenital aneuploidies poses a particular challenge because the aneuploid region contains many protein-coding genes whose function is unknown. One essential step towards understanding their function is to analyse mRNA expression patterns at key stages of organism development. Seminal works in flies, frogs and mice showed that genes whose expression is restricted spatially and/or temporally are often linked with specific ontogenic processes. Here we describe expression profiles of mouse orthologues to HSA21 genes by a combination of large-scale mRNA in situ hybridization at critical stages of embryonic and brain development and in silico (computed) mining of expressed sequence tags. This chromosome-scale expression annotation associates many of the genes tested with a potential biological role and suggests candidates for the pathogenesis of Down's syndrome.     

New directions in the chemistry of natural products: The organic chemist as a pathfinder for biochemistry and medicine

Zusammenfassung Im Rückblick und Ausblick wird anhand einiger ausgewählter Arbeiten aus dem Laboratorium des Verfassers gezeigt, wie die Ziele und Methodologie der modernen Naturstoff-Forschung sich im Laufe der letzten 20 Jahre geändert haben. Noch immer kommen die unerwartetsten Anregungen für ungewöhnliche Strukturen aus der Natur, so zum Beispiel die neuen Tier-AlkaloideHistrionicotoxin und seine Begleiter, die an einem Spiro-cyclohexyl-piperidin-Skelett, Azetylen- und Allen-Seitenketten enthalten. Mehr noch als die Struktur interessiert beimBatrachotoxin die selektive Wirkung auf den passiven Transport von Natrium-Ionen durch Membranen elektrogener Gewebe, ein Effekt, der durchTetrodotoxin reversibel aufgehoben werden kann. Heute zählt man auch die Eiweiss-Stoffe zu den wichtigen Naturprodukten. Ihre Erforschung wurde durch die Einführung selektiver Spaltungsmethoden ermöglicht und erleichtert, was am Beispiel desImmunoglobulins und desKollagens gezeigt wird. Diese Spaltungsmethoden beruhen auf der Ausnutzung benachbarter Gruppen-Effekte, die weiterhin auch als Basis zum Ausbau von Enzym-Modellen dienen. Die Beschäftigung mit der Chemie der Überträgersubstanzen der Nervenfortleitung, wie Dopamin und Noradrenalin, führte zur Auffindung von6-Hydroxydopamin, das zum ersten Mal selektiv «chemische Sympathektomie» erlaubt. In der physiologischen Inaktivierung dieser Nervenhormone spielt dieBrenzkatechin O-Methyltransferase eine grosse Rolle im Stoffwechsel, der man durch Reindarstellung und Beschreibung des Enzyms näherzukommen versucht. Im Stoffwechsel von aromatischen Substraten bedeutet die ersteIsolierung eines Arenoxyds einen wichtigen Fortschritt. Ein derart labiles Stoffwechselprodukt spielt in der langfristigen Toxikologie aromatischer Arzneimittel und in der Ätiologie von Krebs durch cancerogene Kohlenwasserstoffe eine Rolle. Zum Studium von Oxydationsmechanismen mikrosomaler oder Modell-Hydroxylierungen wird als Kriterium mehr und mehr die sogenannteNIH-Verschiebung herangezogen.

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13. Paul Karrer Lecture, presented 30 June 1971, in the Aula of the University of Zurich. German title: Neue Ziele in der Naturstoffchemie: Der organische Chemiker als Wegbereiter der Biochemie und Medizin.     

Neuronal circuitry mechanism regulating adult quiescent neural stem-cell fate decision

Adult neurogenesis arises from neural stem cells within specialized niches. Neuronal activity and experience, presumably acting on this local niche, regulate multiple stages of adult neurogenesis, from neural progenitor proliferation to new neuron maturation, synaptic integration and survival. It is unknown whether local neuronal circuitry has a direct impact on adult neural stem cells. Here we show that, in the adult mouse hippocampus, nestin-expressing radial glia-like quiescent neural stem cells (RGLs) respond tonically to the neurotransmitter γ-aminobutyric acid (GABA) by means of γ2-subunit-containing GABAA receptors. Clonal analysis of individual RGLs revealed a rapid exit from quiescence and enhanced symmetrical self-renewal after conditional deletion of γ2. RGLs are in close proximity to terminals expressing 67-kDa glutamic acid decarboxylase (GAD67) of parvalbumin-expressing (PV+) interneurons and respond tonically to GABA released from these neurons. Functionally, optogenetic control of the activity of dentate PV+ interneurons, but not that of somatostatin-expressing or vasoactive intestinal polypeptide (VIP)-expressing interneurons, can dictate the RGL choice between quiescence and activation. Furthermore, PV+ interneuron activation restores RGL quiescence after social isolation, an experience that induces RGL activation and symmetrical division. Our study identifies a niche cell–signal–receptor trio and a local circuitry mechanism that control the activation and self-renewal mode of quiescent adult neural stem cells in response to neuronal activity and experience.     

Turning points in the evolution of peroxidase–catalase superfamily: molecular phylogeny of hybrid heme peroxidases

Heme peroxidases and catalases are key enzymes of hydrogen peroxide metabolism and signaling. Here, the reconstruction of the molecular evolution of the peroxidase–catalase superfamily (annotated in pfam as PF00141) based on experimentally verified as well as numerous newly available genomic sequences is presented. The robust phylogenetic tree of this large enzyme superfamily was obtained from 490 full-length protein sequences. Besides already well-known families of heme b peroxidases arranged in three main structural classes, completely new (hybrid type) peroxidase families are described being located at the border of these classes as well as forming (so far missing) links between them. Hybrid-type A peroxidases represent a minor eukaryotic subfamily from Excavates, Stramenopiles and Rhizaria sharing enzymatic and structural features of ascorbate and cytochrome c peroxidases. Hybrid-type B peroxidases are shown to be spread exclusively among various fungi and evolved in parallel with peroxidases in land plants. In some ascomycetous hybrid-type B peroxidases, the peroxidase domain is fused to a carbohydrate binding (WSC) domain. Both here described hybrid-type peroxidase families represent important turning points in the complex evolution of the whole peroxidase–catalase superfamily. We present and discuss their phylogeny, sequence signatures and putative biological function.