Exome sequencing identifies MAX mutations as a cause of hereditary pheochromocytoma

Hereditary pheochromocytoma (PCC) is often caused by germline mutations in one of nine susceptibility genes described to date, but there are familial cases without mutations in these known genes. We sequenced the exomes of three unrelated individuals with hereditary PCC (cases) and identified mutations in MAX, the MYC associated factor X gene. Absence of MAX protein in the tumors and loss of heterozygosity caused by uniparental disomy supported the involvement of MAX alterations in the disease. A follow-up study of a selected series of 59 cases with PCC identified five additional MAX mutations and suggested an association with malignant outcome and preferential paternal transmission of MAX mutations. The involvement of the MYC-MAX-MXD1 network in the development and progression of neural crest cell tumors is further supported by the lack of functional MAX in rat PCC (PC12) cells and by the amplification of MYCN in neuroblastoma and suggests that loss of MAX function is correlated with metastatic potential.     

Bifidobacteria and the infant gut: an example of co-evolution and natural selection

Throughout the human life, the gut microbiota interacts with us in a number of different ways, thereby influencing our health status. The acquisition of such an interactive gut microbiota commences at birth. Medical and environmental factors including diet, antibiotic exposure and mode of delivery are major factors that shape the composition of the microbial communities in the infant gut. Among the most abundant members of the infant microbiota are species belonging to the Bifidobacterium genus, which are believed to confer beneficial effects upon their host. Bifidobacteria may be acquired directly from the mother by vertical transmission and their persistence in the infant gut is associated with their saccharolytic activity toward glycans that are abundant in the infant gut. Here, we discuss the establishment of the infant gut microbiota and the contribution of bifidobacteria to this early life microbial consortium.     

Reinforcement with naloxone of N-n-propylnorapomorphine (NPA) capability for stimulating male rat copulatory behavior

Summary Naloxone at a dose of 2 mg·kg^–1, which per se did not significantly alter the copulatory pattern of sexually active adult male rats, did significantly reduce the intromission frequency as well as latency to ejaculation when administered before a low and inactive dose of N-n-propylnorapomorphine (0.5 g·kg^–1).     

The origins and uses of mouse outbred stocks

Outbred mouse stocks, often used in genetics, toxicology and pharmacology research, have been generated in rather haphazard ways. Understanding the characteristics of these stocks and their advantages and disadvantages is important for experimental design. In many studies these mice are used inappropriately, wasting animals' lives and resources on suboptimal experiments. Recently, however, researchers from the field of complex trait analysis have capitalized on the genetics of outbred stocks to refine the identification of quantitative trait loci. Here we assess the most widely used outbred stocks of mice and present guidelines for their use.     

Geological record of fluid flow and seismogenesis along an erosive subducting plate boundary

Tectonic erosion of the overriding plate by the downgoing slab is believed to occur at half the Earth's subduction zones. In situ investigation of the geological processes at active erosive margins is extremely difficult owing to the deep marine environment and the net loss of forearc crust to deeper levels in the subduction zone. Until now, a fossil erosive subduction channel-the shear zone marking the plate boundary-has not been recognized in the field, so that seismic observations have provided the only information on plate boundary processes at erosive margins. Here we show that a fossil erosive margin is preserved in the Northern Apennines of Italy. It formed during the Tertiary transition from oceanic subduction to continental collision, and was preserved by the late deactivation and fossilization of the plate boundary. The outcropping erosive subduction channel is approximately 500 m thick. It is representative of the first 5 km of depth, with its deeper portions reaching approximately 150 degrees C. The fossil zone records several surprises. Two décollements were simultaneously active at the top and base of the subduction channel. Both deeper basal erosion and near-surface frontal erosion occurred. At shallow depths extension was a key deformation component within this erosive convergent plate boundary, and slip occurred without an observable fluid pressure cycle. At depths greater than about 3 km a fluid cycle is clearly shown by the development of veins and the alternation of fast (co-seismic) and slow (inter-seismic) slip. In the deepest portions of the outcropping subduction channel, extension is finally overprinted by compressional structures. In modern subduction zones the onset of seismic activity is believed to occur at approximately 150 degrees C, but in the fossil channel the onset occurred at cooler palaeo-temperatures.     

Genetic evidence that FGFs have an instructive role in limb proximal-distal patterning

Half a century ago, the apical ectodermal ridge (AER) at the distal tip of the tetrapod limb bud was shown to produce signals necessary for development along the proximal-distal (P-D) axis, but how these signals influence limb patterning is still much debated. Fibroblast growth factor (FGF) gene family members are key AER-derived signals, with Fgf4, Fgf8, Fgf9 and Fgf17 expressed specifically in the mouse AER. Here we demonstrate that mouse limbs lacking Fgf4, Fgf9 and Fgf17 have normal skeletal pattern, indicating that Fgf8 is sufficient among AER-FGFs to sustain normal limb formation. Inactivation of Fgf8 alone causes a mild skeletal phenotype; however, when we also removed different combinations of the other AER-FGF genes, we obtained unexpected skeletal phenotypes of increasing severity, reflecting the contribution that each FGF can make to the total AER-FGF signal. Analysis of the compound mutant limb buds revealed that, in addition to sustaining cell survival, AER-FGFs regulate P-D-patterning gene expression during early limb bud development, providing genetic evidence that AER-FGFs function to specify a distal domain and challenging the long-standing hypothesis that AER-FGF signalling is permissive rather than instructive for limb patterning. We discuss how a two-signal model for P-D patterning can be integrated with the concept of early specification to explain the genetic data presented here.     

Episodic fresh surface waters in the Eocene Arctic Ocean

It has been suggested, on the basis of modern hydrology and fully coupled palaeoclimate simulations, that the warm greenhouse conditions that characterized the early Palaeogene period (55-45 Myr ago) probably induced an intensified hydrological cycle with precipitation exceeding evaporation at high latitudes. Little field evidence, however, has been available to constrain oceanic conditions in the Arctic during this period. Here we analyse Palaeogene sediments obtained during the Arctic Coring Expedition, showing that large quantities of the free-floating fern Azolla grew and reproduced in the Arctic Ocean by the onset of the middle Eocene epoch (approximately 50 Myr ago). The Azolla and accompanying abundant freshwater organic and siliceous microfossils indicate an episodic freshening of Arctic surface waters during an approximately 800,000-year interval. The abundant remains of Azolla that characterize basal middle Eocene marine deposits of all Nordic seas probably represent transported assemblages resulting from freshwater spills from the Arctic Ocean that reached as far south as the North Sea. The termination of the Azolla phase in the Arctic coincides with a local sea surface temperature rise from approximately 10 degrees C to 13 degrees C, pointing to simultaneous increases in salt and heat supply owing to the influx of waters from adjacent oceans. We suggest that onset and termination of the Azolla phase depended on the degree of oceanic exchange between Arctic Ocean and adjacent seas.     

Mapping and sequencing of structural variation from eight human genomes

Genetic variation among individual humans occurs on many different scales, ranging from gross alterations in the human karyotype to single nucleotide changes. Here we explore variation on an intermediate scale--particularly insertions, deletions and inversions affecting from a few thousand to a few million base pairs. We employed a clone-based method to interrogate this intermediate structural variation in eight individuals of diverse geographic ancestry. Our analysis provides a comprehensive overview of the normal pattern of structural variation present in these genomes, refining the location of 1,695 structural variants. We find that 50% were seen in more than one individual and that nearly half lay outside regions of the genome previously described as structurally variant. We discover 525 new insertion sequences that are not present in the human reference genome and show that many of these are variable in copy number between individuals. Complete sequencing of 261 structural variants reveals considerable locus complexity and provides insights into the different mutational processes that have shaped the human genome. These data provide the first high-resolution sequence map of human structural variation--a standard for genotyping platforms and a prelude to future individual genome sequencing projects.     

人工神经网络在苏州空气污染预报中的应用

人工神经网络在预测预报领域的应用越来越广泛。简单介绍了BP神经网络的基本原理,较详细地回顾了国内BP神经网络在空气污染预报领域的研究应用情况,并建立了苏州市区SO2浓度预报的BP神经网络,预报结果表明:该模型具有简便、快速、准确的优点,可推广用于其它空气污染物的预报。