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.     

Charge self-regulation upon changing the oxidation state of transition metals in insulators

Transition-metal atoms embedded in an ionic or semiconducting crystal can exist in various oxidation states that have distinct signatures in X-ray photoemission spectroscopy and 'ionic radii' which vary with the oxidation state of the atom. These oxidation states are often tacitly associated with a physical ionization of the transition-metal atoms--that is, a literal transfer of charge to or from the atoms. Physical models have been founded on this charge-transfer paradigm, but first-principles quantum mechanical calculations show only negligible changes in the local transition-metal charge as the oxidation state is altered. Here we explain this peculiar tendency of transition-metal atoms to maintain a constant local charge under external perturbations in terms of an inherent, homeostasis-like negative feedback. We show that signatures of oxidation states and multivalence--such as X-ray photoemission core-level shifts, ionic radii and variations in local magnetization--that have often been interpreted as literal charge transfer are instead a consequence of the negative-feedback charge regulation.     

Super-chondritic Sm/Nd ratios in Mars, the Earth and the Moon

Small isotopic differences in the atomic abundance of neodymium-142 (142Nd) in silicate rocks represent the time-averaged effect of decay of formerly live samarium-146 (146Sm) and provide constraints on the timescales and mechanisms by which planetary mantles first differentiated. This chronology, however, assumes that the composition of the total planet is identical to that of primitive undifferentiated meteorites called chondrites. The difference in the 142Nd/144Nd ratio between chondrites and terrestrial samples may therefore indicate very early isolation (<30 Myr from the formation of the Solar System) of the upper mantle or a slightly non-chondritic bulk Earth composition. Here we present high-precision 142Nd data for 16 martian meteorites and show that Mars also has a non-chondritic composition. Meteorites belonging to the shergottite subgroup define a planetary isochron yielding an age of differentiation of 40 +/- 18 Myr for the martian mantle. This isochron does not pass through the chondritic reference value (100 x epsilon(142)Nd = -21 +/- 3; 147Sm/144Nd = 0.1966). The Earth, Moon and Mars all seem to have accreted in a portion of the inner Solar System with approximately 5 per cent higher Sm/Nd ratios than material accreted in the asteroid belt. Such chemical heterogeneities may have arisen from sorting of nebular solids or from impact erosion of crustal reservoirs in planetary precursors. The 143Nd composition of the primitive mantle so defined by 142Nd is strikingly similar to the putative endmember component 'FOZO' characterized by high 3He/4He ratios.     

Towards a proteome-scale map of the human protein-protein interaction network

Systematic mapping of protein-protein interactions, or 'interactome' mapping, was initiated in model organisms, starting with defined biological processes and then expanding to the scale of the proteome. Although far from complete, such maps have revealed global topological and dynamic features of interactome networks that relate to known biological properties, suggesting that a human interactome map will provide insight into development and disease mechanisms at a systems level. Here we describe an initial version of a proteome-scale map of human binary protein-protein interactions. Using a stringent, high-throughput yeast two-hybrid system, we tested pairwise interactions among the products of approximately 8,100 currently available Gateway-cloned open reading frames and detected approximately 2,800 interactions. This data set, called CCSB-HI1, has a verification rate of approximately 78% as revealed by an independent co-affinity purification assay, and correlates significantly with other biological attributes. The CCSB-HI1 data set increases by approximately 70% the set of available binary interactions within the tested space and reveals more than 300 new connections to over 100 disease-associated proteins. This work represents an important step towards a systematic and comprehensive human interactome project.     

购物中心大额购买者与小额购买者的行为差异:一项跨国和跨地区的比较研究

通过对在西安、美国和香港进行问卷调查所得数据的分析,研究了购物中心大额购买者与小额购买者之间在惠顾动机、惠顾行为和购买行为上的异同,得到三个适用性较强的结论:第一,大额购买者有较强的购买动机和较明确的购物计划,小额购买者的购买动机较弱,购物计划也比较模糊;第二,大额购买者是购买非食品类产品的主体,同时在食品购买方面也很重要,而小额购买者在购买食品方面十分重要;第三,在购买时,大额购买者比小额购买者更注重品牌.另外,还得到了一些只是在一定条件下适用的结论.最后讨论了研究结果的应用.     

“Continuity and change”: representing mass conservation in fluid mechanics

The evolution of the equation of mass conservation in fluid mechanics is studied. Following early hydraulic approximations, and progress by Daniel and Johann Bernoulli, its first expression as a partial differential equation was achieved by d’Alembert, and soon given definitive form by Euler. Later reworkings by Lagrange, Laplace, Poisson and others advanced the subject, but all based their derivations on the conserved mass of a moving fluid particle. Later, Duhamel and Thomson gave a simpler derivation, by considering mass flow into and out of a fixed portion of space. The later propagation of these derivations in nineteenth-century British textbooks and treatises is also examined, including Maxwell’s on the kinetic theory of gases.     

Increasing adult hippocampal neurogenesis is sufficient to improve pattern separation

Adult hippocampal neurogenesis is a unique form of neural circuit plasticity that results in the generation of new neurons in the dentate gyrus throughout life. Neurons that arise in adults (adult-born neurons) show heightened synaptic plasticity during their maturation and can account for up to ten per cent of the entire granule cell population. Moreover, levels of adult hippocampal neurogenesis are increased by interventions that are associated with beneficial effects on cognition and mood, such as learning, environmental enrichment, exercise and chronic treatment with antidepressants. Together, these properties of adult neurogenesis indicate that this process could be harnessed to improve hippocampal functions. However, despite a substantial number of studies demonstrating that adult-born neurons are necessary for mediating specific cognitive functions, as well as some of the behavioural effects of antidepressants, it is unknown whether an increase in adult hippocampal neurogenesis is sufficient to improve cognition and mood. Here we show that inducible genetic expansion of the population of adult-born neurons through enhancing their survival improves performance in a specific cognitive task in which two similar contexts need to be distinguished. Mice with increased adult hippocampal neurogenesis show normal object recognition, spatial learning, contextual fear conditioning and extinction learning but are more efficient in differentiating between overlapping contextual representations, which is indicative of enhanced pattern separation. Furthermore, stimulation of adult hippocampal neurogenesis, when combined with an intervention such as voluntary exercise, produces a robust increase in exploratory behaviour. However, increasing adult hippocampal neurogenesis alone does not produce a behavioural response like that induced by anxiolytic agents or antidepressants. Together, our findings suggest that strategies that are designed to increase adult hippocampal neurogenesis specifically, by targeting the cell death of adult-born neurons or by other mechanisms, may have therapeutic potential for reversing impairments in pattern separation and dentate gyrus dysfunction such as those seen during normal ageing.     

Evidence for mechanical coupling and strong Indian lower crust beneath southern Tibet

How surface deformation within mountain ranges relates to tectonic processes at depth is not well understood. The upper crust of the Tibetan Plateau is generally thought to be poorly coupled to the underthrusting Indian crust because of an intervening low-viscosity channel. Here, however, we show that the contrast in tectonic regime between primarily strike-slip faulting in northern Tibet and dominantly normal faulting in southern Tibet requires mechanical coupling between the upper crust of southern Tibet and the underthrusting Indian crust. Such coupling is inconsistent with the presence of active 'channel flow' beneath southern Tibet, and suggests that the Indian crust retains its strength as it underthrusts the plateau. These results shed new light on the debates regarding the mechanical properties of the continental lithosphere, and the deformation of Tibet.