An epi-allelic series of p53 hypomorphs created by stable RNAi produces distinct tumor phenotypes in vivo

The application of RNA interference (RNAi) to mammalian systems has the potential to revolutionize genetics and produce novel therapies. Here we investigate whether RNAi applied to a well-characterized gene can stably suppress gene expression in hematopoietic stem cells and produce detectable phenotypes in mice. Deletion of the Trp53 tumor suppressor gene greatly accelerates Myc-induced lymphomagenesis, resulting in highly disseminated disease. To determine whether RNAi suppression of Trp53 could produce a similar phenotype, we introduced several Trp53 short hairpin RNAs (shRNAs) into hematopoietic stem cells derived from E(mu)-Myc transgenic mice, and monitored tumor onset and overall pathology in lethally irradiated recipients. Different Trp53 shRNAs produced distinct phenotypes in vivo, ranging from benign lymphoid hyperplasias to highly disseminated lymphomas that paralleled Trp53-/- lymphomagenesis in the E(mu)-Myc mouse. In all cases, the severity and type of disease correlated with the extent to which specific shRNAs inhibited p53 activity. Therefore, RNAi can stably suppress gene expression in stem cells and reconstituted organs derived from those cells. In addition, intrinsic differences between individual shRNA expression vectors targeting the same gene can be used to create an 'epi-allelic series' for dissecting gene function in vivo.     

The Widespread Colonization Island of Actinobacillus actinomycetemcomitans

Genomic islands, such as pathogenicity islands, contribute to the evolution and diversification of microbial life. Here we report on the Widespread Colonization Island, which encompasses the tad (tight adherence) locus for colonization of surfaces and biofilm formation by the human pathogen Actinobacillus actinomycetemcomitans. At least 12 of the 14 genes at the tad locus are required for tenacious biofilm formation and synthesis of bundled Flp pili (fibrils) that mediate adherence. The pilin subunit, Flp1, remains inside the cell in tad-locus mutants, indicating that these genes encode a secretion system for export and assembly of fibrils. We found tad-related regions in a wide variety of Bacterial and Archaeal species, and their sequence characteristics indicate possible horizontal transfer. To test the hypothesis of horizontal transfer, we compared the phylogeny of the tad locus to a robust organismal phylogeny using statistical tests of congruence and tree reconciliation techniques. Our analysis strongly supports a complex history of gene shuffling by recombination and multiple horizontal transfers, duplications and losses. We present evidence for a specific horizontal transfer event leading to the establishment of this region as a determinant of disease.     

A gravitationally lensed quasar with quadruple images separated by 14.62 arcseconds

Gravitational lensing is a powerful tool for the study of the distribution of dark matter in the Universe. The cold-dark-matter model of the formation of large-scale structures (that is, clusters of galaxies and even larger assemblies) predicts the existence of quasars gravitationally lensed by concentrations of dark matter so massive that the quasar images would be split by over 7 arcsec. Numerous searches for large-separation lensed quasars have, however, been unsuccessful. All of the roughly 70 lensed quasars known, including the first lensed quasar discovered, have smaller separations that can be explained in terms of galaxy-scale concentrations of baryonic matter. Although gravitationally lensed galaxies with large separations are known, quasars are more useful cosmological probes because of the simplicity of the resulting lens systems. Here we report the discovery of a lensed quasar, SDSS J1004 + 4112, which has a maximum separation between the components of 14.62 arcsec. Such a large separation means that the lensing object must be dominated by dark matter. Our results are fully consistent with theoretical expectations based on the cold-dark-matter model.     

Osteoclast differentiation and activation

Osteoclasts are specialized cells derived from the monocyte/macrophage haematopoietic lineage that develop and adhere to bone matrix, then secrete acid and lytic enzymes that degrade it in a specialized, extracellular compartment. Discovery of the RANK signalling pathway in the osteoclast has provided insight into the mechanisms of osteoclastogenesis and activation of bone resorption, and how hormonal signals impact bone structure and mass. Further study of this pathway is providing the molecular basis for developing therapeutics to treat osteoporosis and other diseases of bone loss.     

Temperature-related behavior of some migrant birds in the desert

Behavior of migrant birds in relation to temperature was studied and compared to that of resident species in the northern Mojave Desert. Migrants reduced foraging intensity above 30 C, but resident species showed no striking decrease in intensity of foraging at temperatures up to 35 C. Migrant species shifted activities to shaded microhabitats at temperatures between 20 and 30 C; the resident Verdin showed a similar shift at 35 C. Most migrants decreased the amount of time spent foraging at temperatures above 30; Verdins showed a similar but stronger response to temperatures about 30 C. Significant reductions in the use of hovering and hawking maneuvers were found among migrants at temperatures above 30 C. Migrants showed similar types of behavioral adjustments to temperatures as did resident desert species, but they responded earlier in the daily temperature cycle. Desert birds appear to correlate their daily activity strongly with temperature, but nondesert species may respond either to temperature or time of day.     

Insulin-like growth factor-II gene expression in Wilms' tumour and embryonic tissues

Wilms' tumour (nephroblastoma) is an embryonal neoplasm occurring in hereditary and spontaneous forms. Both types show rearrangements of the short arm of chromosome 11. The germ line of children with the rare inherited triad of aniridia, genito-urinary abnormality and mental retardation carry a chromosome 11 that has a deletion in its short arm (band 11p13) and these children are at increased risk of developing Wilms' tumour. Neonates with the Beckwith-Wiedemann syndrome, in which there may be duplication of the 11p13-11p15 region, are similarly predisposed. In the spontaneous form of the tumour a deletion of the 11p14 band in tumour cells, but not in normal cells, has been reported, and the development of homozygosity for recessive mutations in the 11p region is implicated in the aetiology of Wilms' tumour. In view of these chromosomal rearrangements and because Wilms' tumour is histologically indistinguishable from the early stages of kidney development, we have now examined the expression of genes localized to 11p in Wilms' tumour and human embryonic tissue. In 12 sporadic tumours examined, the expression of the gene coding for insulin-like growth factor-II (IGF-II), localized to the 11p15 region, was markedly increased relative to adult tissues, but was comparable to the level of expression in several fetal tissues including kidney, liver, adrenals and striated muscle. This may reflect the stage of tumour differentiation, but could also contribute to the malignant process, as IGF-II is an embryonal mitogen.     

Late Quaternary arthropods from the Colorado Plateau, Arizona and Utah

Late Quaternary-age arthropods were recovered from dry cave deposits and packrat middens located in the Grand Canyon, Canyonlands, and Glen Canyon region of the Colorado Plateau. This Quaternary data resource has not been analyzed before from the Colorado Plateau national parks. Radiocarbon dates on the various deposits containing arthropods range from 1510 to 30,660 yr B.P. The fossil assemblages yielded 57 identified taxa of insects, arachnids, and millipedes, including 15 taxa taken to the species level. The information from the fossil insect record of the Colorado Plateau is not yet sufficiently detailed to permit precise paleoenvironmental reconstructions. However, preliminary conclusions suggest a cooler, moister climatic regime during the late Wisconsin glacial and a mosaic of vegetation types, such as grassland and shrubby communities, unlike the present vegetation at the localities.     

Gordon Pask's Conversation Theory: A Domain Independent Constructivist Model of Human Knowing

Although it is conceded (as argued by many)that distinct knowledge domains do presentparticular problems of coming to know, in thispaper it is argued that it is possible (anduseful) to construct a domain independent modelof the processes of coming to know, one inwhich observers share understandings and do soin agreed ways. The model in question is partof the conversation theory (CT) of Gordon Pask. CT, as a theory of theory construction andcommunication, has particular relevance forfoundational issues in science and scienceeducation. CT explicitly propounds a ``radicalconstructivist' (RC) epistemology. A briefaccount is given of the main tenets of RC andCT's place in that tradition and the traditionsof cybernetics. The paper presents a briefnon-technical account of the main concepts ofCT including elaborations by Laurillard andHarri-Augstein and Thomas. As part of CT, Pask also elaborated a methodology – knowledgeand task analysis – for analysing the structureof different knowledge domains; thismethodology is sketched in outline.