Induction of angiogenesis during the transition from hyperplasia to neoplasia

It is now well established that unrestricted growth of tumours is dependent upon angiogenesis. Previous studies on tumour growth, however, have not revealed when or how the transition to an angiogenic state occurs during early tumour development. The advent of transgenic mice carrying oncogenes that reproducibly elicit tumours of specific cell types is providing a new format for studying multi-step tumorigenesis. In one of these models, transgenic mice expressing an oncogene in the beta-cells of the pancreatic islets heritably recapitulate a progression from normality to hyperplasia to neoplasia. We report here that angiogenic activity first appears in a subset of hyperplastic islets before the onset of tumour formation. A novel in vitro assay confirms that hyperplasia per se does not obligate angiogenesis. Rather, a few hyperplastic islets become angiogenic in vitro at a time when such islets are neovascularized in vivo and at a frequency that correlates closely with subsequent tumour incidence. These findings suggest that induction of angiogenesis is an important step in carcinogenesis.     

Short-circuiting of the overturning circulation in the Antarctic Circumpolar Current

The oceanic overturning circulation has a central role in the Earth's climate system and in biogeochemical cycling, as it transports heat, carbon and nutrients around the globe and regulates their storage in the deep ocean. Mixing processes in the Antarctic Circumpolar Current are key to this circulation, because they control the rate at which water sinking at high latitudes returns to the surface in the Southern Ocean. Yet estimates of the rates of these processes and of the upwelling that they induce are poorly constrained by observations. Here we take advantage of a natural tracer-release experiment-an injection of mantle helium from hydrothermal vents into the Circumpolar Current near Drake Passage-to measure the rates of mixing and upwelling in the current's intermediate layers over a sector that spans nearly one-tenth of its circumpolar path. Dispersion of the tracer reveals rapid upwelling along density surfaces and intense mixing across density surfaces, both occurring at rates that are an order of magnitude greater than rates implicit in models of the average Southern Ocean overturning. These findings support the view that deep-water pathways along and across density surfaces intensify and intertwine as the Antarctic Circumpolar Current flows over complex ocean-floor topography, giving rise to a short circuit of the overturning circulation in these regions.     

基因工程为何必须坚持进行下去

今天的基因生物学充满了活力。它在有关细胞、酵母菌等单细胞生物以至复杂的人脑的生命科学中所占的份量与年俱增。这种奇妙的生物学热,在我最初踏人遗传学界时是完全无法想象的。1948年的生物学全是描述性的,处于科学标杆的最低部位,标杆的顶端是物理学。那时,爱因斯坦关于质．能互变的划时代理论已转化成为原子的巨大威力。如果不加约束的话,用它制成的武器完全可以摧毁人类文明的全部建筑物。因此,叙年代后期的物理学家们在因其使原子变成对社会有用之物而受人尊敬的同时,又担心他们发明的玩意儿一旦落入邪恶之手时,会干出何等蠢…     

Comprehensive analysis of the gene encoding filaggrin uncovers prevalent and rare mutations in ichthyosis vulgaris and atopic eczema

We recently reported two common filaggrin (FLG) null mutations that cause ichthyosis vulgaris and predispose to eczema and secondary allergic diseases. We show here that these common European mutations are ancestral variants carried on conserved haplotypes. To facilitate comprehensive analysis of other populations, we report a strategy for full sequencing of this large, highly repetitive gene, and we describe 15 variants, including seven that are prevalent. All the variants are either nonsense or frameshift mutations that, in representative cases, resulted in loss of filaggrin production in the epidermis. In an Irish case-control study, the five most common European mutations showed a strong association with moderate-to-severe childhood eczema (chi2 test: P = 2.12 x 10(-51); Fisher's exact test: heterozygote odds ratio (OR) = 7.44 (95% confidence interval (c.i.) = 4.9-11.3), and homozygote OR = 151 (95% c.i. = 20-1,136)). We found three additional rare null mutations in this case series, suggesting that the genetic architecture of filaggrin-related atopic dermatitis consists of both prevalent and rare risk alleles.     

The gene encoding R-spondin 4 (RSPO4), a secreted protein implicated in Wnt signaling, is mutated in inherited anonychia

Anonychia and hyponychia congenita (OMIM 206800) are rare autosomal recessive conditions in which the only presenting phenotype is the absence or severe hypoplasia of all fingernails and toenails. After determining linkage to chromosome 20p13, we identified homozygous or compound heterozygous mutations in the gene encoding R-spondin 4 (RSPO4), a secreted protein implicated in Wnt signaling, in eight affected families. Rspo4 expression was specifically localized to developing mouse nail mesenchyme at embryonic day 15.5, suggesting a crucial role in nail morphogenesis.     

The oxidation state of Hadean magmas and implications for early Earth's atmosphere

Magmatic outgassing of volatiles from Earth's interior probably played a critical part in determining the composition of the earliest atmosphere, more than 4,000 million years (Myr) ago. Given an elemental inventory of hydrogen, carbon, nitrogen, oxygen and sulphur, the identity of molecular species in gaseous volcanic emanations depends critically on the pressure (fugacity) of oxygen. Reduced melts having oxygen fugacities close to that defined by the iron-wüstite buffer would yield volatile species such as CH(4), H(2), H(2)S, NH(3) and CO, whereas melts close to the fayalite-magnetite-quartz buffer would be similar to present-day conditions and would be dominated by H(2)O, CO(2), SO(2) and N(2) (refs 1-4). Direct constraints on the oxidation state of terrestrial magmas before 3,850?Myr before present (that is, the Hadean eon) are tenuous because the rock record is sparse or absent. Samples from this earliest period of Earth's history are limited to igneous detrital zircons that pre-date the known rock record, with ages approaching ～4,400?Myr (refs 5-8). Here we report a redox-sensitive calibration to determine the oxidation state of Hadean magmatic melts that is based on the incorporation of cerium into zircon crystals. We find that the melts have average oxygen fugacities that are consistent with an oxidation state defined by the fayalite-magnetite-quartz buffer, similar to present-day conditions. Moreover, selected Hadean zircons (having chemical characteristics consistent with crystallization specifically from mantle-derived melts) suggest oxygen fugacities similar to those of Archaean and present-day mantle-derived lavas as early as ～4,350?Myr before present. These results suggest that outgassing of Earth's interior later than ～200?Myr into the history of Solar System formation would not have resulted in a reducing atmosphere.     

Stylet jaws of Chrysopetalidae (Annelida)

Micro-CT imaging elucidates jaw and pharynx structure in 14 nominal taxa belonging to Chrysopetalinae, Dysponetinae and Calamyzinae (Chrysopetalidae: Annelida). Systematic evaluation of chrysopetalid jaw form in each taxon is used to compare inter-generic relationships within and between each subfamily and with other polychaete families possessing lateral pairs of jaws. Jaw morphology proves diagnostic at all levels including agreement with current molecular phylogenetic analyses of the Chrysopetalidae. The greatest diversity of pharynx and jaw form, associated with sensory body characters, is found amongst taxa of the epibenthic Chrysopetalinae. It is hypothesized that the paired stylet jaws interlock to pierce prey tissue, and, in concert with a highly muscular pharynx, suck out prey fluids that pass down the internal groove of the stylets. Three generic groups are identified based on congruence of jaw form, and novel buccal structures are revealed in some taxa: a pharyngeal calcareous ‘ring’ and extensive pharyngeal glands. A continuum across free-living and facultative symbiont lifestyles is represented across all Chrysopetalinae. Dysponetinae comprises free-living, very small individuals that exhibit a meiofaunal lifestyle. All species possess one type of simple, tanned rod-like stylet jaws and certain simplified body structures. Calamyzinae species possess polyphyletic jaw forms and grades of radically simplified sensory morphologies. Free-living, bacteriovore calamyzins inhabit extreme chemosynthetic habitats and lack jaws, or possess modified jaws composed of an anterior platelet and posterior grooved jaw, present in the larvae and lost in the adult. New observations of an ectoparasitic Calamyzinae include details of a specialized mouth opening and stylet jaw present in a species that exhibits cryptic coloration, while grooved jaws are revealed for the first time in an obligate symbiont calamyzin. The grooved jaw form is considered a non-homoplasious synapomorphy that supports the monophyly of the family Chrysopetalidae.     

Combination forecasts of output growth in a seven‐country data set

This paper uses forecast combination methods to forecast output growth in a seven‐country quarterly economic data set covering 1959–1999, with up to 73 predictors per country. Although the forecasts based on individual predictors are unstable over time and across countries, and on average perform worse than an autoregressive benchmark, the combination forecasts often improve upon autoregressive forecasts. Despite the unstable performance of the constituent forecasts, the most successful combination forecasts, like the mean, are the least sensitive to the recent performance of the individual forecasts. While consistent with other evidence on the success of simple combination forecasts, this finding is difficult to explain using the theory of combination forecasting in a stationary environment. Copyright © 2004 John Wiley & Sons, Ltd.     

DNA sequencing of a cytogenetically normal acute myeloid leukaemia genome

Acute myeloid leukaemia is a highly malignant haematopoietic tumour that affects about 13,000 adults in the United States each year. The treatment of this disease has changed little in the past two decades, because most of the genetic events that initiate the disease remain undiscovered. Whole-genome sequencing is now possible at a reasonable cost and timeframe to use this approach for the unbiased discovery of tumour-specific somatic mutations that alter the protein-coding genes. Here we present the results obtained from sequencing a typical acute myeloid leukaemia genome, and its matched normal counterpart obtained from the same patient's skin. We discovered ten genes with acquired mutations; two were previously described mutations that are thought to contribute to tumour progression, and eight were new mutations present in virtually all tumour cells at presentation and relapse, the function of which is not yet known. Our study establishes whole-genome sequencing as an unbiased method for discovering cancer-initiating mutations in previously unidentified genes that may respond to targeted therapies.