jason young

We present the discovery of seven quasars at z>5.7, selected from ~2000 deg^2 of multicolor imaging data of the Sloan Digital Sky Survey (SDSS). The new quasars have redshifts z from 5.79 to 6.13. Five are selected as part of a complete flux-limited sample in the SDSS Northern Galactic Cap; two have larger photometric errors and are not part of the complete sample. One of the new quasars, SDSS J1335+3533 (z=5.93), exhibits no emission lines; the 3-sigma limit on the rest-frame equivalent width of Ly alpha+NV line is 5 A. It is the highest redshift lineless quasar known, and could be a gravitational lensed galaxy, a BL Lac object or a new type of quasar. Two new z>6 quasars, SDSS 1250+3130 (z=6.13) and SDSS J1137+3549 (z=6.01), show deep Gunn-Peterson absorption gaps in Ly alpha. These gaps are narrower the complete Gunn-Peterson absorption troughs observed among quasars at z>6.2 and do not have complete Ly beta absorption.

With the emergence of genome-wide expression profiling data sets, the guilt by association (GBA) principle has been a cornerstone for deriving gene functional interpretations in silico. Given the limited success of traditional methods for producing clusters of genes with great amounts of functional similarity, new data-mining algorithms are required to fully exploit the potential of high-throughput genomic approaches. Ontology-based pattern identification (OPI) is a novel data-mining algorithm that systematically identifies expression patterns that best represent existing knowledge of gene function. Instead of relying on a universal threshold of expression similarity to define functionally related groups of genes, OPI finds the optimal analysis settings that yield gene expression patterns and gene lists that best predict gene function using the principle of GBA. We applied OPI to a publicly available gene expression data set on the life cycle of the malarial parasite Plasmodium falciparum and systematically annotated genes for 320 functional categories based on current Gene Ontology annotations. An ontology-based hierarchical tree of the 320 categories provided a systems-wide biological view of this important malarial parasite.

In this review, we bring together some of the approaches toward understanding the cellular and molecular biology of Plasmodium species and their interaction with their host red blood cells. Considerable impetus has come from the development of new methods of molecular genetics and bioinformatics, and it is important to evaluate the wealth of these novel data in the context of basic cell biology. We describe how these approaches are gaining valuable insights into the parasite–host cell interaction, including (1) the multistep process of red blood cell invasion by the merozoite; (2) the mechanisms by which the intracellular parasite feeds on the red blood cell and exports parasite proteins to modify its cytoadherent properties; (3) the modulation of the cell cycle by sensing the environmental tryptophan-related molecules; (4) the mechanism used to survive in a low Ca2+ concentration inside red blood cells; (5) the activation of signal transduction machinery and the regulation of intracellular calcium; (6) transfection technology; and (7) transcriptional regulation and genome-wide mRNA studies in Plasmodium falciparum.

The sexual stages of malarial parasites are essential for the mosquito transmission of the disease and therefore are the focus of transmission-blocking drug and vaccine development. In order to better understand genes important to the sexual development process, the transcriptomes of high-purity stage I–V Plasmodium falciparum gametocytes were comprehensively profiled using a full-genome high-density oligonucleotide microarray. The interpretation of this transcriptional data was aided by applying a novel knowledge-based data-mining algorithm termed ontology-based pattern identification (OPI) using current information regarding known sexual stage genes as a guide. This analysis resulted in the identification of a sexual development cluster containing 246 genes, of which ∼75% were hypothetical, exhibiting highly-correlated, gametocyte-specific expression patterns. Inspection of the upstream promoter regions of these 246 genes revealed putative cis-regulatory elements for sexual development transcriptional control mechanisms. Furthermore, OPI analysis was extended using current annotations provided by the Gene Ontology Consortium to identify 380 statistically significant clusters containing genes with expression patterns characteristic of various biological processes, cellular components, and molecular functions. Collectively, these results, available as part of a web-accessible OPI database (http://carrier.gnf.org/publications/Gametocyte), shed light on the components of molecular mechanisms underlying parasite sexual development and other areas of malarial parasite biology.

p23 is a regulatory co-chaperone of heat shock protein (Hsp) 90, but can also act as a general molecular chaperone by itself. Using novel point mutations of p23 that disrupt its interaction with Hsp90 we found its co-chaperone function to be required for its inhibitory effect on glucocorticoid receptor (GR). The C-terminal region of p23, which is required for its chaperone activity, is dispensable for inhibition of GR. Importantly, similar results were obtained with a constitutively active GR. Thus, the action of p23 on the nuclear stage of GR regulation requires its Hsp90 co-chaperone function, but not its chaperone activity.

DegS, the periplasmic stress sensor, becomes activated when its PDZ domain recognizes the improperly exposed C-terminal sequences of outer membrane porins. This interaction relieves the inhibition of the neighboring protease domain of DegS, triggering a proteolysis cascade that leads to the σE-driven expression of periplasmic chaperones.

Hsp90 is an abundant and constitutively expressed stress protein and molecular chaperone. Here we dissected human hsp90 into three major domains to identify the putative chaperone site at which hsp90 binds unfolded polypeptide. Surprisingly, both the N-terminal and the C-terminal domain of hsp90 prevent the aggregation of denatured polypeptides. The chaperone activity of the N-domain is inhibited by geldanamycin, a specific inhibitor of hsp90-mediated protein refolding. While both domains suppress protein aggregation, only the C-domain binds an antigenic peptide derived from VSV G. Based on these results, hsp90 may be the first chaperone to contain two independent chaperone sites with differential specificity.

The role of cytosolic factors in protein targeting to mitochondria is poorly understood. Here, we show that in mammals, the cytosolic chaperones Hsp90 and Hsp70 dock onto a specialized TPR domain in the import receptor Tom70 at the outer mitochondrial membrane. This interaction serves to deliver a set of preproteins to the receptor for subsequent membrane translocation dependent on the Hsp90 ATPase. Disruption of the chaperone/Tom70 recognition inhibits the import of these preproteins into mitochondria. In yeast, Hsp70 rather than Hsp90 is used in import, and Hsp70 docking is required for the formation of a productive preprotein/Tom70 complex. We outline a novel mechanism in which chaperones are recruited for a specific targeting event by a membrane-bound receptor.

Cisplatin is an antineoplastic drug that binds to DNA, thereby inhibiting cell division and tumor growth. Cisplatin may also disrupt the function of some proteins, including heat shock protein 90 (Hsp90). We report that cisplatin dose-dependently inhibited transcriptional activity of the androgen receptor and the glucocorticoid receptor (GR) in transient reporter assays. A truncated, hormone-independent GR was only partially inhibited at significantly higher doses of cisplatin. Cisplatin treatment of neuroblastoma cells led to an immediate inhibition of hormone binding by GR, followed by proteasome-dependent degradation of the receptor. Other Hsp90-regulated proteins, i.e. the phosphokinases raf-1, lck, and c-src, were not affected, indicating a specific functional interference of cisplatin with the steroid receptors GR and androgen receptor. Cisplatin did not elicit a stress response, in contrast to geldanamycin. Immunoprecipitation revealed that cisplatin disrupts binding of GR to Hsp90. Moreover, cisplatin-treated Hsp90 was unable to associate with untreated ligand binding domain of GR. Reticulocyte lysate was able to restore hormone binding of GR in vitro, but not when the lysate was pretreated with geldanamycin. Our data reveal that cisplatin influences steroid receptors also independently of its DNA-mediated effects and, thus, suggest a novel modes of action for this cytostatic drug.

Cells are faced with the task of folding thousands of different polypeptides into a wide range of conformations. For many proteins, the folding process requires the action of molecular chaperones. In the cytosol of prokaryotic and eukaryotic cells, molecular chaperones of different structural classes form a network of pathways that can handle substrate polypeptides from the point of initial synthesis on ribosomes to the final stages of folding.

DegS, the periplasmic stress sensor, becomes activated when its PDZ domain recognizes the improperly exposed C-terminal sequences of outer membrane porins. This interaction relieves the inhibition of the neighboring protease domain of DegS, triggering a proteolysis cascade that leads to the sigma(E)-driven expression of periplasmic chaperones.

ABSTRACT Geographers have argued that the emergence of the geospatial web, or geoweb, represents a radical shift away from the state's monopolization of geospatial technologies. Like the public participation geographic information systems (PPGIS) movement before it, the geoweb research agenda has emphasized a desire for empowerment and participatory democracy. However, this research agenda has also inherited a conceptualization of power that emphasizes the linkages between empowerment and public visibility, and this paper argues that this inheritance opens potentially sensitive geoweb data to exploitation. Geographers therefore have an important role to play in emphasizing the need to explore ways of harnessing the power of the geoweb for marginalized communities while nonetheless maintaining those communities' privacy. This paper uses work with the Maijuna indigenous people of Peru as a case study to begin a discussion about how the political goals of disempowered people may be best obtained through both public and private uses of the geoweb.

An important potential benefit of a jurisdiction developing an upper-level traffic safety policy statement, such as a strategic highway safety plan (SHSP) or a traffic safety action plan, is the creation of a manageable number of focus areas, known as emphasis areas. The responsible agencies in the jurisdiction can then direct their finite resources in a systematic and strategic way designed to maximize the effort to reduce the number and severity of roadway collisions. In the United States, the federal government through AASHTO has suggested 22 potential emphasis areas. In Canada, CCMTA's 10 potential emphasis areas have been listed for consideration. This study reviewed the SHSP and traffic safety action plan of 53 jurisdictions in North America, and conducted descriptive data analyses to clarify the issues that currently affect the selection and prioritization process of jurisdiction-specific emphasis areas. We found that the current process relies heavily on high-level collision data analysis and communication among the SHSP stakeholders, but may not be the most efficient and effective way of selecting and prioritizing the emphasis areas and allocating safety improvement resources. This study then formulated a formal collision diagnosis test, known as the beta-binomial test, to clarify and illuminate the selection and the prioritization of jurisdiction-specific emphasis areas. We developed numerical examples to demonstrate how engineers can apply the proposed diagnosis test to improve the selection and prioritization of individual jurisdictions' emphasis areas.