Low frequency of CHEK2 1100delC allele in Australian multiple-case breast cancer families : functional analysis in heterozygous individuals

A protein-truncating variant of CHEK2, 1100delC, is associated with a moderate increase in breast cancer risk. We have determined the prevalence of this allele in index cases from 300 Australian multiple-case breast cancer families, 95% of which had been found to be negative for mutations in BRCA1 and BRCA2. Only two (0.6%) index cases heterozygous for the CHEK2 mutation were identified. All available relatives in these two families were genotyped, but there was no evidence of co-segregation between the CHEK2 variant and breast cancer. Lymphoblastoid cell lines established from a heterozygous carrier contained approximately 20% of the CHEK2 1100delC mRNA relative to wild-type CHEK2 transcript. However, no truncated CHK2 protein was detectable. Analyses of expression and phosphorylation of wild-type CHK2 suggest that the variant is likely to act by haploinsufficiency. Analysis of CDC25A degradation, a downstream target of CHK2, suggests that some compensation occurs to allow normal degradation of CDC25A. Such compensation of the 1100delC defect in CHEK2 might explain the rather low breast cancer risk associated with the CHEK2 variant, compared to that associated with truncating mutations in BRCA1 or BRCA2.

Multiple human single-stranded DNA binding proteins function in genome maintenance : structural, biochemical and functional analysis

DNA exists predominantly in a duplex form that is preserved via specific base pairing. This base pairing affords a considerable degree of protection against chemical or physical damage and preserves coding potential. However, there are many situations, e.g. during DNA damage and programmed cellular processes such as DNA replication and transcription, in which the DNA duplex is separated into two singlestranded DNA (ssDNA) strands. This ssDNA is vulnerable to attack by nucleases, binding by inappropriate proteins and chemical attack. It is very important to control the generation of ssDNA and protect it when it forms, and for this reason all cellular organisms and many viruses encode a ssDNA binding protein (SSB). All known SSBs use an oligosaccharide/oligonucleotide binding (OB)-fold domain for DNA binding. SSBs have multiple roles in binding and sequestering ssDNA, detecting DNA damage, stimulating strand-exchange proteins and helicases, and mediation of protein–protein interactions. Recently two additional human SSBs have been identified that are more closely related to bacterial and archaeal SSBs. Prior to this it was believed that replication protein A, RPA, was the only human equivalent of bacterial SSB. RPA is thought to be required for most aspects of DNA metabolism including DNA replication, recombination and repair. This review will discuss in further detail the biological pathways in which human SSBs function.

Model and prototype for querying multiple linked scientific datasets

Scientists need to transfer semantically similar queries across multiple heterogeneous linked datasets. These queries may require data from different locations and the results are not simple to combine due to differences between datasets. A query model was developed to make it simple to distribute queries across different datasets using RDF as the result format. The query model, based on the concept of publicly recognised namespaces for parts of each scientific dataset, was implemented with a configuration that includes a large number of current biological and chemical datasets. The configuration is flexible, providing the ability to transparently use both private and public datasets in any query. A prototype implementation of the model was used to resolve queries for the Bio2RDF website, including both Bio2RDF datasets and other datasets that do not follow the Bio2RDF URI conventions.

A polymorphism in the dysbindin gene (DTNBP1) associated with multiple psychiatric disorders including schizophrenia

Background A number of studies have found associations between dysbindin (DTNBP1) polymorphisms and schizophrenia. Recently we identified a DTNBP1 SNP (rs9370822) that is strongly associated with schizophrenia. Individuals diagnosed with schizophrenia were nearly three times as likely to carry the CC genotype compared to the AA genotype. Methods To investigate the importance of this SNP in the function of DTNBP1, a number of psychiatric conditions including addictive behaviours and anxiety disorders were analysed for association with rs9370822. Results The DTNBP1 polymorphism was significantly associated with post-traumatic stress disorder (PTSD) as well as nicotine and opiate dependence but not alcohol dependence. Individuals suffering PTSD were more than three times as likely to carry the CC genotype compared to the AA genotype. Individuals with nicotine or opiate dependence were more than twice as likely to carry the CC genotype compared to the AA genotype. Conclusions This study provides further support for the importance of DTNBP1 in psychiatric conditions and suggests that there is a common underlying molecular defect involving DTNBP1 that contributes to the development of several anxiety and addictive disorders that are generally recognised as separate clinical conditions. These disorders may actually be different expressions of a single metabolic pathway perturbation. As our participant numbers are limited our observations should be viewed with caution until they are independently replicated.

Primary students’ interpretation of maps : gesture use and mapping knowledge

Maps are used to represent three-dimensional space and are integral to a range of everyday experiences. They are increasingly used in mathematics, being prominent both in school curricula and as a form of assessing students understanding of mathematics ideas. In order to successfully interpret maps, students need to be able to understand that maps: represent space, have their own perspective and scale, and their own set of symbols and texts. Despite the fact that maps have an increased prevalence in society and school, there is evidence to suggest that students have difficulty interpreting maps. This study investigated 43 primary-aged students’ (aged 9-12 years) verbal and gestural behaviours as they engaged with and solved map tasks. Within a multiliteracies framework that focuses on spatial, visual, linguistic, and gestural elements, the study investigated how students interpret map tasks. Specifically, the study sought to understand students’ skills and approaches used to solving map tasks and the gestural behaviours they utilised as they engaged with map tasks. The investigation was undertaken using the Knowledge Discovery in Data (KDD) design. The design of this study capitalised on existing research data to carry out a more detailed analysis of students’ interpretation of map tasks. Video data from an existing data set was reorganised according to two distinct episodes—Task Solution and Task Explanation—and analysed within the multiliteracies framework. Content Analysis was used with these data and through anticipatory data reduction techniques, patterns of behaviour were identified in relation to each specific map task by looking at task solution, task correctness and gesture use. The findings of this study revealed that students had a relatively sound understanding of general mapping knowledge such as identifying landmarks, using keys, compass points and coordinates. However, their understanding of mathematical concepts pertinent to map tasks including location, direction, and movement were less developed. Successful students were able to interpret the map tasks and apply relevant mathematical understanding to navigate the spatial demands of the map tasks while the unsuccessful students were only able to interpret and understand basic map conventions. In terms of their gesture use, the more difficult the task, the more likely students were to exhibit gestural behaviours to solve the task. The most common form of gestural behaviour was deictic, that is a pointing gesture. Deictic gestures not only aided the students capacity to explain how they solved the map tasks but they were also a tool which assisted them to navigate and monitor their spatial movements when solving the tasks. There were a number of implications for theory, learning and teaching, and test and curriculum design arising from the study. From a theoretical perspective, the findings of the study suggest that gesturing is an important element of multimodal engagement in mapping tasks. In terms of teaching and learning, implications include the need for students to utilise gesturing techniques when first faced with new or novel map tasks. As students become more proficient in solving such tasks, they should be encouraged to move beyond a reliance on such gesture use in order to progress to more sophisticated understandings of map tasks. Additionally, teachers need to provide students with opportunities to interpret and attend to multiple modes of information when interpreting map tasks.

Expression and connection : the integration of the reflective learning process and the writing process into social network sites

A number of instructors have recently adopted social network sites (SNSs) for learning. However, the learning design of SNSs often remains at a preliminary level similar to a personal log book because it does not properly include reflective learning elements such as individual reflection and collaboration. This article looks at the reflective learning process and the public writing process as a way of improving the quality of reflective learning on SNSs. It proposes a reflective learning model on SNSs based on two key pedagogical concepts for social networking: individual expression and collaborative connection. It is expected that the model would be helpful for instructors in designing a reflective learning process on SNSs in an effective and flexible way.