PARP inhibition induces BAX/BAK-independent synthetic lethality of BRCA1-deficient non-small cell lung cancer

Evasion of apoptosis contributes to both tumourigenesis and drug resistance in non-small cell lung carcinoma (NSCLC). The pro-apoptotic BCL-2 family proteins BAX and BAK are critical regulators of mitochondrial apoptosis. New strategies for targeting NSCLC in a mitochondria-independent manner should bypass this common mechanism of apoptosis block. BRCA1 mutation frequency in lung cancer is low; however, decreased BRCA1 mRNA and protein expression levels have been reported in a significant proportion of lung adenocarcinomas. BRCA1 mutation/deficiency confers a defect in homologous recombination DNA repair that has been exploited by synthetic lethality through inhibition of PARP (PARPi) in breast and ovarian cells; however, it is not known whether this same synthetic lethal mechanism exists in NSCLC cells. Additionally, it is unknown whether the mitochondrial apoptotic pathway is required for BRCA1/PARPi-mediated synthetic lethality. Here we demonstrate that silencing of BRCA1 expression by RNA interference sensitizes NSCLC cells to PARP inhibition. Importantly, this sensitivity was not attenuated in cells harbouring mitochondrial apoptosis block induced by co-depletion of BAX and BAK. Furthermore, we demonstrate that BRCA1 inhibition cannot override platinum resistance, which is often mediated by loss of mitochondrial apoptosis signalling, but can still sensitize to PARP inhibition. Finally we demonstrate the existence of a BRCA1-deficient subgroup (11–19%) of NSCLC patients by analysing BRCA1 protein levels using immunohistochemistry in two independent primary NSCLC cohorts. Taken together, the existence of BRCA1-immunodeficient NSCLC suggests that this molecular subgroup could be effectively targeted by PARP inhibitors in the clinic and that PARP inhibitors could be used for the treatment of BRCA1-immunodeficient, platinum-resistant tumours.

Meaningful musical engagement : the potential impact of generative music systems on learning experiences

In order to create music, the student must establish a relationship with the musical materials. In this thesis, I examine the capacity of a generative music system called jam2jam to offer individuals a virtual musical play-space to explore. I outline the development of an iteration of software development named jam2jam blue and the evolution of a games-like user interface in the research design that jointly revealed the nature of this musical exploration. The findings suggest that the jam2jam blue interface provided an expressive gestural instrument to jam and experience musicmaking. By using the computer as an instrument, participants in this study were given access to meaningful musical experiences in both solo and ensemble situations and the researcher is allowed a view of their development of a relationship with the musical materials from the perspective of the individual participants. Through an iterative software development methodology, pedagogy and experience design were created simultaneously. The research reveals the potential for the jam2jam software to be used as a reflective tool for feedback and assessment purposes. The power of access to ensemble music making is realised though the participants’ virtual experiences which are brought into their physical space by sharing their experience with others. It is suggested that this interaction creates an environment conducive to self-initiated learning in which music is the language of interaction. The research concludes that the development of a relationship between the explorer and the musical materials is subject to the collaborative nature of the interaction through which the music is experienced.

The music of the spheres

This article describes a method for making a spectroscope from scrap materials, i.e. a fragment of compact disc, a cardboard box, a tube and a digital camera to record the spectrum. An image processing program such as ImageJ can be used to calculate the wavelength of emission and absorption lines from the digital photograph. Multiple images of a spectrum can be stacked to reduce random noise, enabling spectra of faint objects to be obtained. Some basic experiments are described, such as viewing the spectrum produced by various types of lamp and the Sun. © 2012 IOP Publishing Ltd.

Is the unigram relevance model term independent? Classifying term dependencies in query expansion

This paper develops a framework for classifying term dependencies in query expansion with respect to the role terms play in structural linguistic associations. The framework is used to classify and compare the query expansion terms produced by the unigram and positional relevance models. As the unigram relevance model does not explicitly model term dependencies in its estimation process it is often thought to ignore dependencies that exist between words in natural language. The framework presented in this paper is underpinned by two types of linguistic association, namely syntagmatic and paradigmatic associations. It was found that syntagmatic associations were a more prevalent form of linguistic association used in query expansion. Paradoxically, it was the unigram model that exhibited this association more than the positional relevance model. This surprising finding has two potential implications for information retrieval models: (1) if linguistic associations underpin query expansion, then a probabilistic term dependence assumption based on position is inadequate for capturing them; (2) the unigram relevance model captures more term dependency information than its underlying theoretical model suggests, so its normative position as a baseline that ignores term dependencies should perhaps be reviewed.

Clines in cuticular hydrocarbons in two Drosophila species with independent population histories

We took a comparative approach utilizing clines to investigate the extent to which natural selection may have shaped population divergence in cuticular hydrocarbons (CHCs) that are also under sexual selection in Drosophila. We detected the presence of CHC clines along a latitudinal gradient on the east coast of Australia in two fly species with independent phylogenetic and population histories, suggesting adaptation to shared abiotic factors. For both species, significant associations were detected between clinal variation in CHCs and temperature variation along the gradient, suggesting temperature maxima as a candidate abiotic factor shaping CHC variation among populations. However, rainfall and humidity correlated with CHC variation to differing extents in the two species, suggesting that response to these abiotic factors may vary in a species-specific manner. Our results suggest that natural selection, in addition to sexual selection, plays a significant role in structuring among-population variation in sexually selected traits in Drosophila.

The sound of music : sharing song selections between collocated strangers in public urban places

This paper presents Capital Music, a mobile application enabling real-time sharing of song choices with collocated urban dwellers. Due to the real-time, location-based peer-to-peer approach of the application, a user experience study was performed utilising the Wizard of Oz method. The study provides insight into how sharing non-privacy sensitive but personal data in an anonymous way can influence the user experience of people in public urban places. We discuss the findings in relation to how Capital Music influences the process of “cocooning” in public urban places, the practice of designing anonymous interactions between collocated strangers, and how the sharing of song choices can create a sense of commonality between anonymous users in the urban space. The outcomes of this study are relevant for future location-based social networking applications that aim to create interactions between collocated strangers.

Preparing for portfolio careers in Australian music : setting a research agenda

In the twenty-first century, Australian musicians increasingly maintain ‘portfolio’ careers, in which they combine diverse employment arrangements and activities. Often, these incorporate industry sectors outside of music. This career pattern is widespread but not well understood, largely because of the limitations of existing research. The lack of knowledge about musicians’ work and careers means that Australia currently may not provide appropriate and effective policy, funding, initial training and continuing career support across the diverse music sector. This article discusses existing research relating to the careers and skilling needs of musicians in Australia, and outlines a targeted agenda for further research that has the potential to inform stronger alignment between the requirements of building sustainable music careers and musicians’ education and training.

An open-source approach to music education through jam2jam XO

This article examines the philosophy and practice of open-source technology in the development of the jam2jam XO software for the One Laptop Per Child (OLPC) computer. It explores how open-source software principles, pragmatist philosophy, improvisation and constructionist epistemologies are operationalized in the design and development of music software, and how such reflection reveals both the strengths and weaknesses of the open-source software development paradigm. An overview of the jam2jam XO platform, its development processes and music educational uses is provided and resulting reflections on the strengths and weaknesses of open-source development for music education are discussed. From an educational and software development perspective, the act of creating open-source software is shown to be a valuable enterprise, however, just because the source code, creative content and experience design are accessible and 'open' to be changed, does not guarantee that educational practices in the use of that software will change. Research around the development and use of jam2jam XO suggests that open-source software development principles can have an impact beyond software development and on to aspects of experience design and learning relationships.

A survey of tagging techniques for music, speech and environmental sound

Sound tagging has been studied for years. Among all sound types, music, speech, and environmental sound are three hottest research areas. This survey aims to provide an overview about the state-of-the-art development in these areas.We discuss about the meaning of tagging in different sound areas at the beginning of the journey. Some examples of sound tagging applications are introduced in order to illustrate the significance of this research. Typical tagging techniques include manual, automatic, and semi-automatic approaches.After reviewing work in music, speech and environmental sound tagging, we compare them and state the research progress to date. Research gaps are identified for each research area and the common features and discriminations between three areas are discovered as well. Published datasets, tools used by researchers, and evaluation measures frequently applied in the analysis are listed. In the end, we summarise the worldwide distribution of countries dedicated to sound tagging research for years.

Independent people

A 3,000-word essay about Iceland