The role of test accuracy in predicting acceptance of genetic susceptibility testing for Alzheimer's disease

A survey questionnaire regarding perceptions of risk and genetic susceptibility to Alzheimer's disease (AD) was completed by 518 offspring of AD cases from families with multiple affected, ascertained as part of a genetic linkage study of late onset AD. The questionnaire focused on respondents' perceptions of their own risk for AD as well as on the properties of real and hypothetical susceptibility tests, including error rates for false-positive and false-negative test results. Our findings showed that about 20% of the sample would refuse a susceptibility test with zero error rates, about 40% would accept tests with very high error rates in both directions, and the remainder would exercise some discrimination. Acceptance of high test error rates was significantly associated with male gender, low education, and high perceived lifetime risk of AD. In a previous paper related to this work, we showed that physicians caring for these families exercised much more discrimination in judging the acceptability of genetic tests they would offer to these same respondents. The findings show that there is a pressing need to educate the public, particularly those with relatives affected by a complex disease, to expect standards of accuracy for genetic tests comparable to those that prevail in other diagnostic and prognostic testing efforts in the broad field of clinical medicine.     

Regulation of protein kinases; controlling activity through activation segment conformation

There are currently at least forty-six unique protein kinase crystal structures, twenty-four of which are available in an active state. Here we examine these structures using a structural bioinformatics approach to understand how the conformation of the activation segment controls kinase activity.     

Xenopus U3 snoRNA docks on pre-rRNA through a novel base-pairing interaction

U3 small nucleolar RNA (snoRNA) is essential for rRNA processing to form 18S ribosomal RNA (rRNA). Previously, it has been shown that nucleolin is needed to load U3 snoRNA on pre-rRNA. However, as documented here, this is not sufficient. We present data that base-pairing between the U3 hinges and the external transcribed spacer (ETS) is critical for functional alignment of U3 on its pre-rRNA substrate. Additionally, the interaction between the U3 hinges and the ETS is proposed to serve as an anchor to hold U3 on the pre-rRNA substrate, while box A at the 5' end of U3 snoRNA swivels from ETS contacts to 18S rRNA contacts. Compensatory base changes revealed base-pairing between the 3' hinge of U3 snoRNA and region E1 of the ETS in Xenopus pre-rRNA; this novel interaction is required for 18S rRNA production. In contrast, base-pairing between the 5' hinge of U3 snoRNA and region E2 of the ETS is auxiliary, unlike the case in yeast where it is required. Thus, higher and lower eukaryotes use different interactions for functional association of U3 with pre-rRNA. The U3 hinge sequence varies between species, but covariation in the ETS retains complementarity. This species-specific U3-pre-rRNA interaction offers a potential target for a new class of antibiotics to prevent ribosome biogenesis in eukaryotic pathogens.     

The gene ontology categorizer

The Gene Ontology Categorizer, developed jointly by the Los Alamos National Laboratory and Procter & Gamble Corp., provides a capability for the categorization task in the Gene Ontology (GO): given a list of genes of interest, what are the best nodes of the GO to summarize or categorize that list? The motivating question is from a drug discovery process, where after some gene expression analysis experiment, we wish to understand the overall effect of some cell treatment or condition by identifying 'where' in the GO the differentially expressed genes fall: 'clustered' together in one place? in two places? uniformly spread throughout the GO? 'high', or 'low'? In order to address this need, we view bio-ontologies more as combinatorially structured databases than facilities for logical inference, and draw on the discrete mathematics of finite partially ordered sets (posets) to develop data representation and algorithms appropriate for the GO. In doing so, we have laid the foundations for a general set of methods to address not just the categorization task, but also other tasks (e.g. distances in ontologies and ontology merger and exchange) in both the GO and other bio-ontologies (such as the Enzyme Commission database or the MEdical Subject Headings) cast as hierarchically structured taxonomic knowledge systems.     

S phase assembly of centromeric heterochromatin and cohesion

Accurate chromosome segregation in mitosis requires cohesion between sister centromeres mediated by heterochromatin. Although establishment of both silent heterochromatin and cohesion require passage through S phase, the mechanism was previously unknown. In our recent paper, we demonstrate that heterochromatin silencing and cohesion at the centromere rely on temporal activation of the conserved S phase protein kinase Hsk1-Dfp1. Hsk1-Dfp1 is needed for heterochromatin assembly downstream of Swi6 binding to chromatin; importantly, this activity is independent of the replication function of Hsk1-Dfp1. This defines a temporal connection between S phase, heterochromatin and cohesion that is independent of replication fork passage.     

"Emerging" parasitic infections in arctic ungulates

Important drivers for emergence of infectious disease in wildlifeinclude changes in the environment, shrinking habitats or concentrationof wildlife, and movement of people, animals, pathogens, orvectors. In this paper we present three case-studies of emergingparasitic infections and diseases in ungulates in the Canadiannorth. First we discuss climate warming as an important driverfor the emergence of disease associated with Umingmakstrongyluspallikuukensis, a nematode lungworm of muskoxen. Then we examinehow Protostrongylus stilesi, the sheep lungworm, emerged (orre-emerged) in muskoxen after re-introduction of this host intoits historical range made it sympatric with Dall's sheep. Finally,we consider Teladorsagia boreoarcticus, a newly described andcommon abomasal nematode of muskoxen that is emerging as a disease-causingparasite and may be an important regulator for muskox populationson Banks Island, Northwest Territories. These and other arctichost-parasite systems are exquisitely tuned and constrainedby a harsh and highly seasonal environment. The dynamics ofthese systems will be impacted by climate change and other ecologicaldisruptions. Baseline knowledge of parasite biodiversity andparasite and host ecology, together with predictive models andlong-term monitoring programs, are essential for anticipatingand detecting altered patterns of host range, geographic distribution,and the emergence of parasitic infections and diseases.