A variant of the breast cancer type 2 susceptibility protein (BRC) repeat is essential for the RECQL5 Helicase to interact with RAD51 Recombinase for genome stabilization

The BRC repeat is a structural motif in the tumor suppressor BRCA2 (breast cancer type 2 susceptibility protein), which promotes homologous recombination (HR) by regulating RAD51 recombinase activity. To date, the BRC repeat has not been observed in other proteins, so that its role in HR is inferred only in the context of BRCA2. Here, we identified a BRC repeat variant, named BRCv, in the RECQL5 helicase, which possesses anti-recombinase activity in vitro and suppresses HR and promotes cellular resistance to camptothecin-induced replication stress in vivo. RECQL5-BRCv interacted with RAD51 through two conserved motifs similar to those in the BRCA2-BRC repeat. Mutations of either motif compromised functions of RECQL5, including association with RAD51, inhibition of RAD51-mediated D-loop formation, suppression of sister chromatid exchange, and resistance to camptothecin-induced replication stress. Potential BRCvs were also found in other HR regulatory proteins, including Srs2 and Sgs1, which possess anti-recombinase activities similar to that of RECQL5. A point mutation in the predicted Srs2-BRCv disrupted the ability of the protein to bind RAD51 and to inhibit D-loop formation. Thus, BRC is a common RAD51 interaction module that can be utilized by different proteins to either promote HR, as in the case of BRCA2, or to suppress HR, as in RECQL5.

Treatment with the vascular disruptive agent OXi4503 induces an immediate and widespread epithelial to mesenchymal transition in the surviving tumor

Epithelial to mesenchymal transition (EMT) is considered an important mechanism in tumor resistance to drug treatments; however, in vivo observation of this process has been limited. In this study we demonstrated an immediate and widespread EMT involving all surviving tumor cells following treatment of a mouse model of colorectal liver metastases with the vascular disruptive agent OXi4503. EMT was characterized by significant downregulation of E-cadherin, relocation and nuclear accumulation of b-catenin as well as significant upregulation of ZEB1 and vimentin. Concomitantly, significant temporal upregulation in hypoxia and the pro-angiogenic growth factors hypoxia-inducible factor 1-alpha, hepatocyte growth factor, vascular endothelial growth factor and transforming growth factor-beta were seen within the surviving tumor. The process of EMT was transient and by 5 days after treatment tumor cell reversion to epithelial morphology was evident. This reversal, termed mesenchymal to epithelial transition (MET) is a process implicated in the development of new metastases but has not been observed in vivo histologically. Similar EMT changes were observed in response to other antitumor treatments including chemotherapy, thermal ablation, and antiangiogenic treatments in our mouse colorectal metastasis model and in a murine orthotopic breast cancer model after OXi4503 treatment. These results suggest that EMT may be an early mechanism adopted by tumors in response to injury and hypoxic stress, such that inhibition of EMT in combination with other therapies could play a significant role in future cancer therapy.

BRAF inhibitor therapy for melanoma, thyroid and colorectal cancers : development of resistance and future prospects

BRAF is a major oncoprotein and oncogenic mutations in BRAF are found in a significant number of cancers, including melanoma, thyroid cancer, colorectal cancer and others. Consequently, BRAF inhibitors have been developed as treatment options for cancers with BRAF mutations which have shown some success in improving patient outcomes in clinical trials. Development of resistance to BRAF kinase inhibitors is common, however, and overcoming this resistance is an area of significant concern for clinicians, patients and researchers alike. In this review, we identify the mechanisms of BRAF kinase inhibitor resistance and discuss the implications for strategies to overcome this resistance in the context of new approaches such as multi-kinase targeted therapies and emerging RNA interference based technologies.

E-government policies for broadband adoption : the case of the UK Government

Broadband technology has been introduced to the business community and the public as a fast and easy way of exploiting the Internet. The benefits of its use (fast reliable connections, always on) have been widely realised and broadband diffusion is one of the items at the top of the agenda for technology related polices of governments worldwide. Broadband diffusion and capacity development are central to debates in many countries concerning the role of the government in developing efficient broadband policies particularly in terms of the usage of public money. In this paper we examine the impact of government polices to broadband adoption in the case of the UK government, a country that is striving to have the most extensive and competitive broadband market in the G7 by 2005. We analyse specific institutional actions related to IT diffusion as pursued by the government with the view to identify best practices in government intervention. We believe that are our analysis is useful for broadband strategies in particular and technology in general when applied elsewhere.

Resistance or covert infection : baculovirus studies re-examined

Recently, Boots & Begon (1993) described the development of resistance to granulosis virus (GV) (Baculoviridae) infection in the moth Plodia interpunctella, following prolonged exposure to virus in laboratory cultures. Resistant insects exhibited reduced fitness in other respects, namely slower development and reduced egg viability, compared to control insects. These results were interpreted as pleiotropic effects of selection at the loci controlling resistance. Similar results have been described in a previous study: Fuxa & Richter (1989) used artificial selection to increase resistance to nuclear polyhedrasis virus (NPV) (Baculoviridae) infection in the moth Spodoptera frugiperda. The resulting gain in resistance they interpreted as the result of an increase in the frequency of alleles conferring resistance. Again, resistant insects exhibited maladaptive traits compared to controls, including a shorter adult life span, reduced number of eggs and reduced egg viability. In both studies the suggestion is made that selection against maladaptive traits will result in a decline in resistance, once selection for resistance is removed. Boots & Begon (1993) described a decrease in development time (towards that of control insects) within two generations of removing selection for resistance. Fuxa & Richter (1989) describe a decrease in resistance, so that within two generations of relaxing selection, previously resistant lines were not significantly more resistant than control insects. . .

Unswitch-ABL drugs overcome resistance in chronic myeloid leukemia

ABL inhibitors have revolutionized the clinical management of chronic myeloid leukemia, but the BCR-ABLT315I mutation confers resistance to currently approved drugs. Chan et al. show, in this issue of Cancer Cell, that " switch-control" inhibitors block BCR-ABLT315I activity by preventing ABL from switching from the inactive to active conformation.

Submission to the Australian Government’s Online Copyright Infringement Discussion Paper

Now is not the time to increase the strength of copyright law. Copyright law is facing a crisis of legitimacy: consumers increasingly appear to doubt its moral weight. To a large extent, this can be traced to the fact that Australian consumers do not believe they are being treated fairly by (predominantly US-based) copyright producers and distributors. Compared to their overseas peers, Australian consumers pay much more for access to books, films, television, and computer games, and are often subjected to long delays before material is available in Australia. Our research shows that this perceived unfairness increases the willingness of Australian consumers to seek out alternative distribution channels. Put simply, the failure of content distributors to meet consumer demand in Australia is a leading factor in copyright infringement. This submission argues that the best strategy to reduce copyright infringement in Australia, at the present time, is for distributors to focus on providing timely, affordable, convenient and fair access to copyright goods. Until this is done, the prevalence of copyright infringement in Australia should be seen as essentially a market problem, rather than a legal one. The Australian Government, meanwhile, should address the recommendations of the IT Pricing Report as a matter a priority. As a first step, the Government should urgently consider repealing the IP exception to competition law in s 51(3), as recommended by the Ergas committee, the IT Pricing report, and the ALRC. This change alone may go a long way to enhancing the efficiency of the copyright market in Australia.

Southern New England Social and Community Plan 2009 - Covering Local Government Authorities: Armidale Dumaresq, Guyra, Uralla and Walcha

The Southern New England (SNE) Social and Community Plan is a guide to collaborative, integrated planning involving the three spheres of government, the community and commercial sectors. The Plan is based on social justice principles such as: • Equity - fairness in resource distribution, particularly for those most in need • Access - fairer access for everyone to the economic resources and services essential to meeting their basic needs and improving their quality of life • Rights - recognition and promotion of civil rights • Participation - better opportunities for genuine participation and consultation about decisions affecting people's lives. The Plan is also aimed at improving the accountability of decision-makers, and should help the councils, in conjunction with their communities meet the state government's social justice commitments. Preparation of a social and community plan is required at least every five years, and as with most councils, Armidale Dumaresq Council (ADC) has produced two already, one in 1999 and one in 2004, following the amalgamation of the former Armidale City and Dumaresq Shire Councils in 2000. Those Councils formerly prepared their own Plans in 1999, based on shared consultancy work on a community profile. This is the first joint Southern New England Plan, featuring Armidale Dumaresq, Walcha, Uralla and Guyra Councils. This Social Plan has aimed to identify and address the needs of the local community by: • describing who makes up the community • summarising key priority issues • assessing the effectiveness of any previous plans • recommending strategic ways for council and other government and non-government agencies to met community needs.

A model to estimate the durability performance of both normal and light-weight concrete

There has been an increasing focus on the development of test methods to evaluate the durability performance of concrete. This paper contributes to this focus by presenting a study that evaluates the effect of water accessible porosity and oven-dry unit weight on the resistance of both normal and light-weight concrete to chloride-ion penetration. Based on the experimental results and regression analyses, empirical models are established to correlate the total charge passed and the chloride migration coefficient with the basic properties of concrete such as water accessible porosity, oven dry unit weight, and compressive strength. These equations can be broadly applied to both normal and lightweight aggregate concretes. The model was also validated by an independent set of experimental results from two different concrete mixtures. The model provides a very good estimate on the concrete’s durability performance in respect to the resistance to chloride ion penetration.

Subtropical values and principles of subtropical design for the South East Queensland region : a report for the Office of Urban Management Queensland Government

The Office of Urban Management recognises that the values which characterise the SEQ region as 'subtropical' are important determinants of form in urban and regional planning. Subtropical values are those qualities on which our regional identity depends. A built environment which responds positively to these values is a critical ingredient for achieving a desirable future for the region. The Centre for Subtropical Design has undertaken this study to identify the particular set of values which characterises SEQ, and to translate theses values into design principals that will maintain and reinforce the value set. The principles not only apply to the overall balance between the natural environment and the built environment, but can be applied by local government authorities to guide local planning schemes and help shape specific built for outcomes.

A conjugative plasmid carrying the carbapenem resistance gene blaOXA-23 in AbaR4 in an extensively resistant GC1 Acinetobacter baumannii isolate

OBJECTIVES: To locate the acquired bla(OXA-23) carbapenem resistance gene in an Australian A. baumannii global clone 1 (GC1) isolate. METHODS: The genome of the extensively antibiotic-resistant GC1 isolate A85 harbouring bla(OXA-23) in Tn2006 was sequenced using Illumina HiSeq, and the reads were used to generate a de novo assembly. PCR was used to assemble relevant contigs. Sequences were compared with ones in GenBank. Conjugation experiments were conducted. RESULTS: The sporadic GC1 isolate A85, recovered in 2003, was extensively resistant, exhibiting resistance to imipenem, meropenem and ticarcillin/clavulanate, to cephalosporins and fluoroquinolones and to the older antibiotics gentamicin, kanamycin and neomycin, sulfamethoxazole, trimethoprim and tetracycline. Genes for resistance to older antibiotics are in the chromosome, in an AbaR3 resistance island. A second copy of the ampC gene in Tn6168 confers cephalosporin resistance and the gyrA and parC genes have mutations leading to fluoroquinolone resistance. An 86 335 bp repAci6 plasmid, pA85-3, carrying bla(OXA-23) in Tn2006 in AbaR4, was shown to transfer imipenem, meropenem and ticarcillin/clavulanate resistance into a susceptible recipient. A85 also contains two small cryptic plasmids of 2.7 and 8.7 kb. A85 is sequence type ST126 (Oxford scheme) and carries a novel KL15 capsule locus and the OCL3 outer core locus. CONCLUSIONS: A85 represents a new GC1 lineage identified by the novel capsule locus but retains AbaR3 carrying genes for resistance to older antibiotics. Resistance to imipenem, meropenem and ticarcillin/clavulanate has been introduced into A85 by pA85-3, a repAci6 conjugative plasmid carrying Tn2006 in AbaR4.

The provision of visitable housing in Australia: Down to the detail

In response to the ratification of the United Nations Convention of the Rights of People with Disabilities (CRPD), Australian housing industry leaders, supported by the Australian Government, committed to transform their practices voluntarily through the adoption of a national guideline, called Livable Housing Design. They set a target in 2010 that all new housing would be visitable by 2020. Research in this area suggests that the anticipated voluntary transformation is unrealistic and that mandatory regulation will be necessary for any lasting transformation to occur. It also suggests that the assumptions underpinning the Livable Housing Design agreement are unfounded. This paper reports on a study that problematised these assumptions. The study used eleven newly-constructed dwellings in three housing contexts in Brisbane, Australia. It sought to understand the logics-of-practice in providing, and not providing, visitable housing. By examining the specific details that make a dwelling visitable, and interpreting the accounts of builders, designers and developers, the study identified three logics-of-practice which challenged the assumptions underpinning the Livable Housing Design agreement: focus on the point of sale; an aversion to change and deference to external regulators on matters of social inclusion. These were evident in all housing contexts indicating a dominant industry culture regardless of housing context or policy intention. The paper suggests that financial incentives for both the builder and the buyer, demonstration by industry leaders and, ultimately, national regulation is a possible pathway for the Livable Housing Design agreement to reach the 2020 goal. The paper concludes that the Australian Government has three options: to ignore its obligations under the CRPD; to revisit the Livable Housing Design agreement in the hope that it works; or to regulate the housing industry through the National Construction Code to ensure the 2020 target is reached.

A values analysis of attitudes towards the use of law to prevent obesity: How might these values inform public health law theory and practice?

This thesis asks whether values, like government duty, individual responsibility, community and social justice, influence the way that scholars and research participants think about the use of law to prevent obesity. It explores the way participants speak about values when expressing their support for or against a variety of government regulatory interventions, including taxation, food labelling reforms and advertising restrictions. This research contributes to our understanding of theories of public health law and public health ethics. The qualitative findings also have implications for policy development, in advocating for a variety of government interventions to prevent obesity.

Proteogenomics of selective susceptibility to endotoxin using circulating acute phase biomarkers and bioassay development in sheep: a review

Scientists have injected endotoxin into animals to investigate and understand various pathologies and novel therapies for several decades. Recent observations have shown that there is selective susceptibility to Escherichia coli lipopolysaccharide (LPS) endotoxin in sheep, despite having similar breed characteristics. The reason behind this difference is unknown, and has prompted studies aiming to explain the variation by proteogenomic characterisation of circulating acute phase biomarkers. It is hypothesised that genetic trait, biochemical, immunological and inflammation marker patterns contribute in defining and predicting mammalian response to LPS. This review discusses the effects of endotoxin and host responses, genetic basis of innate defences, activation of the acute phase response (APR) following experimental LPS challenge, and the current approaches employed in detecting novel biomarkers including acute phase proteins (APP) and micro-ribonucleic acids (miRNAs) in serum or plasma. miRNAs are novel targets for elucidating molecular mechanisms of disease because of their differential expression during pathological, and in healthy states. Changes in miRNA profiles during a disease challenge may be reflected in plasma. Studies show that gel-based two-dimensional electrophoresis (2-DE) coupled with either matrix-assisted laser desorption/ionisation time-of-flight mass spectrometry (MALDI-TOF MS) or liquid chromatography-mass spectrometry (LC-MS/MS) are currently the most used methods for proteome characterisation. Further evidence suggests that proteomic investigations are preferentially shifting from 2-DE to non-gel based LC-MS/MS coupled with data extraction by sequential window acquisition of all theoretical fragment-ion spectra (SWATH) approaches that are able to identify a wider range of proteins. Enzyme-linked immunosorbent assay (ELISA), quantitative real-time polymerase chain reaction (qRT-PCR), and most recently proteomic methods have been used to quantify low abundance proteins such as cytokines. qRT-PCR and next generation sequencing (NGS) are used for the characterisation of miRNA. Proteogenomic approaches for detecting APP and novel miRNA profiling are essential in understanding the selective resistance to endotoxin in sheep. The results of these methods could help in understanding similar pathology in humans. It might also be helpful in the development of physiological and diagnostic screening assays for determining experimental inclusion and endpoints, and in clinical trials in future

Speaking of supervision: A dialogic approach to building higher degree research supervision capacity in the creative arts

In the emergent field of creative practice higher degrees by research, first generation supervisors have developed new models of supervision for an unprecedented form of research that combines creative practice and written thesis. In a national research project, entitled 'Effective supervision of creative practice higher research degrees', we set out to capture and share early supervisors' insights, strategies and approaches to supporting their creative practice PhD students. From the insights we gained during the early interview process, we expanded our research methods in line with a distributed leadership model and developed a dialogic framework. This led us to unanticipated conclusions and unexpected recommendations. In this study, we primarily draw on philosopher and literary theorist Mikhail Bakhtin's dialogics to explain how giving precedence to the voices of supervisors not only facilitated the articulation of dispersed tacit knowledge, but also led to other 20 discoveries. These include the nature of supervisors' resistance to prescribed models, policies and central academic development programmes; the importance of polyvocality and responsive dialogue in enabling continued innovation in the field; the benefits to supervisors of reflecting, discussing and sharing practices with colleagues; and the value of distributed leadership and dialogue to academic development and supervision capacity building in research education.