The genome of the choanoflagellate Monosiga brevicollis and the origin of metazoans

Choanoflagellates are the closest known relatives of metazoans. To discover potential molecular mechanisms underlying the evolution of metazoan multicellularity, we sequenced and analysed the genome of the unicellular choanoflagellate Monosiga brevicollis. The genome contains approximately 9,200 intron-rich genes, including a number that encode cell adhesion and signalling protein domains that are otherwise restricted to metazoans. Here we show that the physical linkages among protein domains often differ between M. brevicollis and metazoans, suggesting that abundant domain shuffling followed the separation of the choanoflagellate and metazoan lineages. The completion of the M. brevicollis genome allows us to reconstruct with increasing resolution the genomic changes that accompanied the origin of metazoans.     

Structure of the sulphiredoxin-peroxiredoxin complex reveals an essential repair embrace

Typical 2-Cys peroxiredoxins (Prxs) have an important role in regulating hydrogen peroxide-mediated cell signalling. In this process, Prxs can become inactivated through the hyperoxidation of an active site Cys residue to Cys sulphinic acid. The unique repair of this moiety by sulphiredoxin (Srx) restores peroxidase activity and terminates the signal. The hyperoxidized form of Prx exists as a stable decameric structure with each active site buried. Therefore, it is unclear how Srx can access the sulphinic acid moiety. Here we present the 2.6 A crystal structure of the human Srx-PrxI complex. This complex reveals the complete unfolding of the carboxy terminus of Prx, and its unexpected packing onto the backside of Srx away from the Srx active site. Binding studies and activity analyses of site-directed mutants at this interface show that the interaction is required for repair to occur. Moreover, rearrangements in the Prx active site lead to a juxtaposition of the Prx Gly-Gly-Leu-Gly and Srx ATP-binding motifs, providing a structural basis for the first step of the catalytic mechanism. The results also suggest that the observed interactions may represent a common mode for other proteins to bind to Prxs.     

Antipredator defence mechanism in the amphidromous shrimp Xiphocaris elongata (Decapoda: Xiphocarididae): rostrum length

Predators may affect prey through inducible defences that can alter prey phenotype. The shrimp Xiphocaris elongata exhibits a short rostrum (SR) in the absence of fish predators and a long rostrum (LR) in their presence. The long rostrum in X. elongata is inducible by the predatory fish Agonostomus monticola (mountain mullet). Our objective was to test whether the long rostrum is an effective antipredator defence against A. monticola in different stages of predator–prey interactions (i.e. choice, attacks, bites, rejections, handling time and survival). We conducted behavioural experiments in fish tanks in which we fed A. monticola simultaneously with (1) one LR shrimp and one SR shrimp, or (2) one LR shrimp and one shrimp which originally had a long rostrum but whose rostrum was cut (LR[S]). We scored the fish behaviours in terms of choice, unsuccessful attacks, bites, rejections and handling time. We also conducted mortality experiments in closed artificial pools in which we exposed (1) 10 LR and 10 SR shrimp or (2) 10 LR and 10 LR[S] shrimp to A. monticola, and quantified shrimp survival after 24 h. In the trials with LR and SR shrimp, A. monticola tended to attack SR shrimp first. LR shrimp were unsuccessfully attacked, bitten and rejected more than SR individuals. Handling time was higher for LR shrimp. The mortality experiments show higher survival of LR shrimp. In the trials with LR and LR[S] shrimp, A. monticola tended to attack LR[S] shrimp first. Unsuccessful attacks were similar for LR and LR[S]. There were more bites and rejections and longer handling time for LR shrimp. Survival was similar for LR and LR[S] shrimp in the mortality experiments. This study provides evidence in support of the hypothesis that the long rostrum in X. elongata is an effective antipredator defence against A. monticola by conferring benefits in most stages of the predator–prey interactions.     

Hsp90 as a capacitor of phenotypic variation

Heat-shock protein 90 (Hsp90) chaperones the maturation of many regulatory proteins and, in the fruitfly Drosophila melanogaster, buffers genetic variation in morphogenetic pathways. Levels and patterns of genetic variation differ greatly between obligatorily outbreeding species such as fruitflies and self-fertilizing species such as the plant Arabidopsis thaliana. Also, plant development is more plastic, being coupled to environmental cues. Here we report that, in Arabidopsis accessions and recombinant inbred lines, reducing Hsp90 function produces an array of morphological phenotypes, which are dependent on underlying genetic variation. The strength and breadth of Hsp90's effects on the buffering and release of genetic variation suggests it may have an impact on evolutionary processes. We also show that Hsp90 influences morphogenetic responses to environmental cues and buffers normal development from destabilizing effects of stochastic processes. Manipulating Hsp90's buffering capacity offers a tool for harnessing cryptic genetic variation and for elucidating the interplay between genotypes, environments and stochastic events in the determination of phenotype.     

Selective killing of cancer cells by a small molecule targeting the stress response to ROS

Malignant transformation, driven by gain-of-function mutations in oncogenes and loss-of-function mutations in tumour suppressor genes, results in cell deregulation that is frequently associated with enhanced cellular stress (for example, oxidative, replicative, metabolic and proteotoxic stress, and DNA damage). Adaptation to this stress phenotype is required for cancer cells to survive, and consequently cancer cells may become dependent upon non-oncogenes that do not ordinarily perform such a vital function in normal cells. Thus, targeting these non-oncogene dependencies in the context of a transformed genotype may result in a synthetic lethal interaction and the selective death of cancer cells. Here we used a cell-based small-molecule screening and quantitative proteomics approach that resulted in the unbiased identification of a small molecule that selectively kills cancer cells but not normal cells. Piperlongumine increases the level of reactive oxygen species (ROS) and apoptotic cell death in both cancer cells and normal cells engineered to have a cancer genotype, irrespective of p53 status, but it has little effect on either rapidly or slowly dividing primary normal cells. Significant antitumour effects are observed in piperlongumine-treated mouse xenograft tumour models, with no apparent toxicity in normal mice. Moreover, piperlongumine potently inhibits the growth of spontaneously formed malignant breast tumours and their associated metastases in mice. Our results demonstrate the ability of a small molecule to induce apoptosis selectively in cells that have a cancer genotype, by targeting a non-oncogene co-dependency acquired through the expression of the cancer genotype in response to transformation-induced oxidative stress.     

Rapid induction of neutrophil-endothelial adhesion by endothelial complement fixation

The adhesion of neutrophils to vascular endothelium is an early event in their recruitment into acute inflammatory lesions. In evaluating potential neutrophil-endothelial adhesive mechanisms in acute inflammation, important considerations are that adhesion in vivo may occur very rapidly following injury and that the specificity of the reaction resides in altered endothelium. That is, neutrophils adhere only to altered endothelium adjacent to an inflammatory focus, rather than at random as would be expected if activation of neutrophils were the initiator of adhesion. We have explored a possible bridging role for complement in causing early neutrophil-endothelial cell adhesion. The complement system is involved in inflammatory processes, is capable of rapid amplification, and endothelial complement fixation at sites of inflammation could generate an endothelium-restricted signal for neutrophil adhesion. We have now developed a model in which this can be investigated without complicating factors such as immunoglobulin deposition, by constructing a novel molecule, a hybrid of the endothelial binding lectin Ulex europaeus I and of the complement activator cobra venom factor. This molecule has the capacity to cause fixation of complement on human umbilical vein endothelial cells. We show that complement fixation is a potent and rapid stimulus for neutrophil adhesion. Neutrophil adhesion requires only endothelial deposition of C3, and is mediated through the type 3 complement receptor.     

Die Farbstoffe der Blattläuse(Aphididae)

Summary Many dark-coloured species ofAphididae contain a colouring matter (protoaphin) of unusual structure in the haemolymph. After death of the insect this undergoes a remarkable series of changes by enzymic action yielding successively the pigments xanthoaphin, chrysoaphin and erythroaphin. Recent investigations leading to the complete structural elucidation of all these pigments is described.

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ViertePaul-Karrer-Vorlesung von Lord A. R. Todd F. R. S., gehalten an der Universität Zürich am 4, Juli 1962.     

A technique for successful 20 h kidney storage at 4°C

Zusammenfassung Es gelingt die normale Nierenfunktion des 20 h bei 4°C tiefgekühlten Organs durch Perfusion mit Novocain und Reomacrodex von 40°C wieder herzustellen.