A transforming mutation in the pleckstrin homology domain of AKT1 in cancer

Although AKT1 (v-akt murine thymoma viral oncogene homologue 1) kinase is a central member of possibly the most frequently activated proliferation and survival pathway in cancer, mutation of AKT1 has not been widely reported. Here we report the identification of a somatic mutation in human breast, colorectal and ovarian cancers that results in a glutamic acid to lysine substitution at amino acid 17 (E17K) in the lipid-binding pocket of AKT1. Lys 17 alters the electrostatic interactions of the pocket and forms new hydrogen bonds with a phosphoinositide ligand. This mutation activates AKT1 by means of pathological localization to the plasma membrane, stimulates downstream signalling, transforms cells and induces leukaemia in mice. This mechanism indicates a direct role of AKT1 in human cancer, and adds to the known genetic alterations that promote oncogenesis through the phosphatidylinositol-3-OH kinase/AKT pathway. Furthermore, the E17K substitution decreases the sensitivity to an allosteric kinase inhibitor, so this mutation may have important clinical utility for AKT drug development.     

Melanoma genome sequencing reveals frequent PREX2 mutations

Melanoma is notable for its metastatic propensity, lethality in the advanced setting and association with ultraviolet exposure early in life. To obtain a comprehensive genomic view of melanoma in humans, we sequenced the genomes of 25 metastatic melanomas and matched germline DNA. A wide range of point mutation rates was observed: lowest in melanomas whose primaries arose on non-ultraviolet-exposed hairless skin of the extremities (3 and 14 per megabase (Mb) of genome), intermediate in those originating from hair-bearing skin of the trunk (5-55 per Mb), and highest in a patient with a documented history of chronic sun exposure (111 per Mb). Analysis of whole-genome sequence data identified PREX2 (phosphatidylinositol-3,4,5-trisphosphate-dependent Rac exchange factor 2)--a PTEN-interacting protein and negative regulator of PTEN in breast cancer--as a significantly mutated gene with a mutation frequency of approximately 14% in an independent extension cohort of 107 human melanomas. PREX2 mutations are biologically relevant, as ectopic expression of mutant PREX2 accelerated tumour formation of immortalized human melanocytes in vivo. Thus, whole-genome sequencing of human melanoma tumours revealed genomic evidence of ultraviolet pathogenesis and discovered a new recurrently mutated gene in melanoma.     

Genomic and functional adaptation in surface ocean planktonic prokaryotes

The understanding of marine microbial ecology and metabolism has been hampered by the paucity of sequenced reference genomes. To this end, we report the sequencing of 137 diverse marine isolates collected from around the world. We analysed these sequences, along with previously published marine prokaryotic genomes, in the context of marine metagenomic data, to gain insights into the ecology of the surface ocean prokaryotic picoplankton (0.1-3.0?μm size range). The results suggest that the sequenced genomes define two microbial groups: one composed of only a few taxa that are nearly always abundant in picoplanktonic communities, and the other consisting of many microbial taxa that are rarely abundant. The genomic content of the second group suggests that these microbes are capable of slow growth and survival in energy-limited environments, and rapid growth in energy-rich environments. By contrast, the abundant and cosmopolitan picoplanktonic prokaryotes for which there is genomic representation have smaller genomes, are probably capable of only slow growth and seem to be relatively unable to sense or rapidly acclimate to energy-rich conditions. Their genomic features also lead us to propose that one method used to avoid predation by viruses and/or bacterivores is by means of slow growth and the maintenance of low biomass.     

Greenhouse gas mitigation can reduce sea-ice loss and increase polar bear persistence

On the basis of projected losses of their essential sea-ice habitats, a United States Geological Survey research team concluded in 2007 that two-thirds of the world's polar bears (Ursus maritimus) could disappear by mid-century if business-as-usual greenhouse gas emissions continue. That projection, however, did not consider the possible benefits of greenhouse gas mitigation. A key question is whether temperature increases lead to proportional losses of sea-ice habitat, or whether sea-ice cover crosses a tipping point and irreversibly collapses when temperature reaches a critical threshold. Such a tipping point would mean future greenhouse gas mitigation would confer no conservation benefits to polar bears. Here we show, using a general circulation model, that substantially more sea-ice habitat would be retained if greenhouse gas rise is mitigated. We also show, with Bayesian network model outcomes, that increased habitat retention under greenhouse gas mitigation means that polar bears could persist throughout the century in greater numbers and more areas than in the business-as-usual case. Our general circulation model outcomes did not reveal thresholds leading to irreversible loss of ice; instead, a linear relationship between global mean surface air temperature and sea-ice habitat substantiated the hypothesis that sea-ice thermodynamics can overcome albedo feedbacks proposed to cause sea-ice tipping points. Our outcomes indicate that rapid summer ice losses in models and observations represent increased volatility of a thinning sea-ice cover, rather than tipping-point behaviour. Mitigation-driven Bayesian network outcomes show that previously predicted declines in polar bear distribution and numbers are not unavoidable. Because polar bears are sentinels of the Arctic marine ecosystem and trends in their sea-ice habitats foreshadow future global changes, mitigating greenhouse gas emissions to improve polar bear status would have conservation benefits throughout and beyond the Arctic.     

A silicon neuron.

By combining neurophysiological principles with silicon engineering, we have produced an analog integrated circuit with the functional characteristics of real nerve cells. Because the physics underlying the conductivity of silicon devices and biological membranes is similar, the 'silicon neuron' is able to emulate efficiently the ion currents that cause nerve impulses and control the dynamics of their discharge. It operates in real-time and consumes little power, and many 'neurons' can be fabricated on a single silicon chip. The silicon neuron represents a step towards constructing artificial nervous systems that use more realistic principles of neuronal computation than do existing electronic neuronal networks.     

Selective responses of visual cortical cells do not depend on shunting inhibition

Theoretical analyses of the electrical behaviour of the highly branched processes of nerve cells has focused attention on the possibility that single cells perform complex logical operations rather than simply summing their synaptic inputs. In particular, it has been suggested that the orientation and direction selectivity of cells in the visual cortex results from the action of a nonlinear 'shunting' inhibition that emulates an AND-NOT logical operation. The characteristic biophysical feature of this proposed inhibitory mechanism is that it evokes a large and relatively sustained increase in the conductance of the neuronal membrane while leaving the membrane potential unaffected. This shunting mechanism contrasts with linear 'summative' inhibition in which conductance changes are less prominent, and inhibition is achieved by hyperpolarization of the membrane potential. In a direct experimental test of the hypothesis that the selectivity of visual cortical neurons depends on shunting inhibition we found no evidence for the large conductance changes predicted by the theory.     

The representation of three-way proximity data by single and multiple tree structure models

Models for the representation of proximity data (similarities/dissimilarities) can be categorized into one of three groups of models: continuous spatial models, discrete nonspatial models, and hybrid models (which combine aspects of both spatial and discrete models). Multidimensional scaling models and associated methods, used for thespatial representation of such proximity data, have been devised to accommodate two, three, and higher-way arrays. At least one model/method for overlapping (but generally non-hierarchical) clustering called INDCLUS (Carroll and Arabie 1983) has been devised for the case of three-way arrays of proximity data. Tree-fitting methods, used for thediscrete network representation of such proximity data, have only thus far been devised to handle two-way arrays. This paper develops a new methodology called INDTREES (for INdividual Differences in TREE Structures) for fitting various(discrete) tree structures to three-way proximity data. This individual differences generalization is one in which different individuals, for example, are assumed to base their judgments on the same family of trees, but are allowed to have different node heights and/or branch lengths.We initially present an introductory overview focussing on existing two-way models. The INDTREES model and algorithm are then described in detail. Monte Carlo results for the INDTREES fitting of four different three-way data sets are presented. In the application, a single ultrametric tree is fitted to three-way proximity data derived from intention-to-buy-data for various brands of over-the-counter pain relievers for relieving three common types of maladies. Finally, we briefly describe how the INDTREES procedure can be extended to accommodate hybrid modelling, as well as to handle other types of applications.     

The structure of O-methyllythrine hydrobromide

Zusammenfassung Die Struktur des O-Methyl-lythrinhydrobromids wurde r?ntgen-kristallographisch ermittelt. Durch den oxydativen Abbau wurde das Hydrobromid mit dem unsubstituierten Lythrin verknüpft. Die Massenspektren zeigten, dass eine Reihe von weiteren Lythraceae-Alkaloiden das gleiche Grundgerüst besitzen.