A transcription factor map as revealed by a genome-wide gene expression analysis of whole-blood mRNA transcriptome in multiple sclerosis

Background Several lines of evidence suggests that transcription factors are involved in the pathogenesis of Multiple Sclerosis (MS) but a complete mapping the whole network has been elusive. One of the reasons is that there are several clinical subtypes of MS and transcription factors which may be involved in one subtype may not be in others. We investigated the possibility that this network could be mapped using microarray technologies and modern bioinformatics methods on a dataset from whole blood in 99 untreated MS patients (36 Relapse Remitting MS, 43 Primary Progressive MS, and 20 Secondary Progressive MS) and 45 age-matched healthy controls, Methodology/Principal Findings We have used two different analytical methodologies: a differential expression analysis and a differential co-expression analysis, which have converged on a significant number of regulatory motifs that seem to be statistically overrepresented in genes which are either differentially expressed (or differentially co-expressed) in cases and controls (e.g. V$KROX_Q6, p-value < 3.31E-6; V$CREBP1_Q2, p-value < 9.93E-6, V$YY1_02, p-value < 1.65E-5). Conclusions/significance: Our analysis uncovered a network of transcription factors that potentially dysregulate several genes in MS or one or more of its disease subtypes. Analysing the published literature we have found that these transcription factors are involved in the early T-lymphocyte specification and commitment as well as in oligodendrocytes dedifferentiation and development. The most significant transcription factors motifs were for the Early Growth response EGR/KROX family, ATF2, YY1 (Yin and Yang 1), E2F-1/DP-1 and E2F-4/DP-2 heterodimers, SOX5, and CREB and ATF families.

Real - time prediction of rainfall induced instability of residual soil slopes associated with deep cracks

The early warning based on real-time prediction of rain-induced instability of natural residual slopes helps to minimise human casualties due to such slope failures. Slope instability prediction is complicated, as it is influenced by many factors, including soil properties, soil behaviour, slope geometry, and the location and size of deep cracks in the slope. These deep cracks can facilitate rainwater infiltration into the deep soil layers and reduce the unsaturated shear strength of residual soil. Subsequently, it can form a slip surface, triggering a landslide even in partially saturated soil slopes. Although past research has shown the effects of surface-cracks on soil stability, research examining the influence of deep-cracks on soil stability is very limited. This study aimed to develop methodologies for predicting the real-time rain-induced instability of natural residual soil slopes with deep cracks. The results can be used to warn against potential rain-induced slope failures. The literature review conducted on rain induced slope instability of unsaturated residual soil associated with soil crack, reveals that only limited studies have been done in the following areas related to this topic: - Methods for detecting deep cracks in residual soil slopes. - Practical application of unsaturated soil theory in slope stability analysis. - Mechanistic methods for real-time prediction of rain induced residual soil slope instability in critical slopes with deep cracks. Two natural residual soil slopes at Jombok Village, Ngantang City, Indonesia, which are located near a residential area, were investigated to obtain the parameters required for the stability analysis of the slope. A survey first identified all related field geometrical information including slope, roads, rivers, buildings, and boundaries of the slope. Second, the electrical resistivity tomography (ERT) method was used on the slope to identify the location and geometrical characteristics of deep cracks. The two ERT array models employed in this research are: Dipole-dipole and Azimuthal. Next, bore-hole tests were conducted at different locations in the slope to identify soil layers and to collect undisturbed soil samples for laboratory measurement of the soil parameters required for the stability analysis. At the same bore hole locations, Standard Penetration Test (SPT) was undertaken. Undisturbed soil samples taken from the bore-holes were tested in a laboratory to determine the variation of the following soil properties with the depth: - Classification and physical properties such as grain size distribution, atterberg limits, water content, dry density and specific gravity. - Saturated and unsaturated shear strength properties using direct shear apparatus. - Soil water characteristic curves (SWCC) using filter paper method. - Saturated hydraulic conductivity. The following three methods were used to detect and simulate the location and orientation of cracks in the investigated slope: (1) The electrical resistivity distribution of sub-soil obtained from ERT. (2) The profile of classification and physical properties of the soil, based on laboratory testing of soil samples collected from bore-holes and visual observations of the cracks on the slope surface. (3) The results of stress distribution obtained from 2D dynamic analysis of the slope using QUAKE/W software, together with the laboratory measured soil parameters and earthquake records of the area. It was assumed that the deep crack in the slope under investigation was generated by earthquakes. A good agreement was obtained when comparing the location and the orientation of the cracks detected by Method-1 and Method-2. However, the simulated cracks in Method-3 were not in good agreement with the output of Method-1 and Method-2. This may have been due to the material properties used and the assumptions made, for the analysis. From Method-1 and Method-2, it can be concluded that the ERT method can be used to detect the location and orientation of a crack in a soil slope, when the ERT is conducted in very dry or very wet soil conditions. In this study, the cracks detected by the ERT were used for stability analysis of the slope. The stability of the slope was determined using the factor of safety (FOS) of a critical slip surface obtained by SLOPE/W using the limit equilibrium method. Pore-water pressure values for the stability analysis were obtained by coupling the transient seepage analysis of the slope using finite element based software, called SEEP/W. A parametric study conducted on the stability of an investigated slope revealed that the existence of deep cracks and their location in the soil slope are critical for its stability. The following two steps are proposed to predict the rain-induced instability of a residual soil slope with cracks. (a) Step-1: The transient stability analysis of the slope is conducted from the date of the investigation (initial conditions are based on the investigation) to the preferred date (current date), using measured rainfall data. Then, the stability analyses are continued for the next 12 months using the predicted annual rainfall that will be based on the previous five years rainfall data for the area. (b) Step-2: The stability of the slope is calculated in real-time using real-time measured rainfall. In this calculation, rainfall is predicted for the next hour or 24 hours and the stability of the slope is calculated one hour or 24 hours in advance using real time rainfall data. If Step-1 analysis shows critical stability for the forthcoming year, it is recommended that Step-2 be used for more accurate warning against the future failure of the slope. In this research, the results of the application of the Step-1 on an investigated slope (Slope-1) showed that its stability was not approaching a critical value for year 2012 (until 31st December 2012) and therefore, the application of Step-2 was not necessary for the year 2012. A case study (Slope-2) was used to verify the applicability of the complete proposed predictive method. A landslide event at Slope-2 occurred on 31st October 2010. The transient seepage and stability analyses of the slope using data obtained from field tests such as Bore-hole, SPT, ERT and Laboratory tests, were conducted on 12th June 2010 following the Step-1 and found that the slope in critical condition on that current date. It was then showing that the application of the Step-2 could have predicted this failure by giving sufficient warning time.

The molecular bases of training adaptation

Skeletal muscle is a malleable tissue capable of altering the type and amount of protein in response to disruptions to cellular homeostasis. The process of exercise-induced adaptation in skeletal muscle involves a multitude of signalling mechanisms initiating replication of specific DNA genetic sequences, enabling subsequent translation of the genetic message and ultimately generating a series of amino acids that form new proteins. The functional consequences of these adaptations are determined by training volume, intensity and frequency, and the half-life of the protein. Moreover, many features of the training adaptation are specific to the type of stimulus, such as the mode of exercise. Prolonged endurance training elicits a variety of metabolic and morphological changes, including mitochondrial biogenesis, fast-to-slow fibre-type transformation and substrate metabolism. In contrast, heavy resistance exercise stimulates synthesis of contractile proteins responsible for muscle hypertrophy and increases in maximal contractile force output. Concomitant with the vastly different functional outcomes induced by these diverse exercise modes, the genetic and molecular mechanisms of adaptation are distinct. With recent advances in technology, it is now possible to study the effects of various training interventions on a variety of signalling proteins and early-response genes in skeletal muscle. Although it cannot presently be claimed that such scientific endeavours have influenced the training practices of elite athletes, these new and exciting technologies have provided insight into how current training techniques result in specific muscular adaptations, and may ultimately provide clues for future and novel training methodologies. Greater knowledge of the mechanisms and interaction of exercise-induced adaptive pathways in skeletal muscle is important for our understanding of the aetiology of disease, maintenance of metabolic and functional capacity with aging, and training for athletic performance. This article highlights the effects of exercise on molecular and genetic mechanisms of training adaptation in skeletal muscle.

The role of the cultural intermediary within professional participatory communication : lessons from ABC Pool

As media institutions are encouraged to explore new production methodologies in the current economic crisis, they align with Schumpeter’s creative destruction provocation by exhibiting user-led political, organisation and socio-technical innovations. This paper highlights the significance of the cultural intermediary within the innovative, co-creative production arrangements for cultural artefacts by media professionals in institutional online communities. An institutional online community is defined as one that is housed, resourced and governed by commercial or non- commercial institutions and is not independently facilitated. Web 2.0 technologies have mobilised collaborative peer production activities for online content creation and professional media institutions face challenges in engaging participatory audiences in practices that are beneficial for all concerned stakeholders. The interests of those stakeholders often do not align, highlighting the need for an intermediary role that understands and translates the norms, rhetoric tropes and day-to-day activities between the individuals engaging in participatory communication activities for successful negotiation within the production process. This paper specifically explores the participatory relationship between the public service broadcaster (PSB), the Australian Broadcasting Corporation (ABC) and one of its online communities, ABC Pool (www.abc.net.au/pool). ABC Pool is an online platform developed and resourced by the ABC to encourage co-creation between audience members engaging in the production of user-generated content (UGC) and the professional producers housed within the ABC Radio Division. This empirical research emerges from a three-year research project where I employed an ethnographic action research methodology and was embedded at the ABC as the community manager of ABC Pool. In participatory communication environments, users favour meritocratic heterarchical governance over traditional institutional hierarchical systems (Malaby 2009). A reputation environment based on meritocracy requires an intermediary to identify the stakeholders, understand their interests and communicate effectively between them to negotiate successful production outcomes (Bruns 2008; Banks 2009). The community manager generally occupies this role, however it has emerged that other institutional production environments also employ an intermediary role under alternative monikers(Hutchinson 2012). A useful umbrella term to encompass the myriad of roles within this space is the cultural intermediary. The ABC has experimented with three institutional online community governance models that engage in cultural intermediation in differing decentralised capacities. The first and most closed is a single point of contact model where one cultural intermediary controls all of the communication of the participatory project. The second is a model of multiple cultural intermediaries engaging in communication between the institutional online community stakeholders simultaneously. The third is most open yet problematic as it promotes and empowers community participants to the level of cultural intermediaries. This paper uses the ABC Pool case study to highlight the differing levels of openness within cultural intermediation during the co-creative production process of a cultural artifact.

Exosomes in prostate cancer: Putting together the pieces of a puzzle

Exosomes have been shown to act as mediators for cell to cell communication and as a potential source of biomarkers for many diseases, including prostate cancer. Exosomes are nanosized vesicles secreted by cells and consist of proteins normally found in multivesicular bodies, RNA, DNA and lipids. As a potential source of biomarkers, exosomes have attracted considerable attention, as their protein content resembles that of their cells of origin, even though it is noted that the proteins, miRNAs and lipids found in the exosomes are not a reflective stoichiometric sampling of the contents from the parent cells. While the biogenesis of exosomes in dendritic cells and platelets has been extensively characterized, much less is known about the biogenesis of exosomes in cancer cells. An understanding of the processes involved in prostate cancer will help to further elucidate the role of exosomes and other extracellular vesicles in prostate cancer progression and metastasis. There are few methodologies available for general isolation of exosomes, however validation of those methodologies is necessary to study the role of exosomal-derived biomarkers in various diseases. In this review, we discuss “exosomes” as a member of the family of extracellular vesicles and their potential to provide candidate biomarkers for prostate cancer.

Artscience in practice : exploring the critical and creative potentials of transdisciplinary art and science practice using a methodological and conceptual framework of creative becoming

In response to a growing interest in art and science interactions and transdisciplinary research strategies, this research project examines the critical and conceptual affordances of ArtScience practice and outlines a new experiential methodology for practice-lead research using a framework of creative becoming. In doing so, the study contributes to the field of ArtScience and transdisciplinary practice, by providing new strategies for creative development and critical enquiry across art and science.

Risky business : mapping ethical landscapes and negotiating governance tensions when researching female offending

Whilst there is an excellent and growing body of literature around female criminality underpinned by feminist methodologies, the nitty gritty of the methodological journey is nowhere as well detailed as it is in the context of the Higher Degree Research (HDR) thesis. Thus the purpose of this paper is threefold: i) to explore a range of feminist methodologies underpinning 20 Australian HDR theses focussing on female criminality; ii) to identify and map the governance/ethics tensions experienced by these researchers whilst undertaking high risk research in the area of female offending; and iii) to document strategies drawn from negotiations, resolutions and outcomes to a range of gate-keeping issues. By exploring the strategies used by these researchers, this paper aims to: promote discussion on feminist methodologies; highlight pathways that may be created when negotiating the challenging process of accessing data pertinent to this relatively understudied area; contribute to a community of practice; and provide useful insights into what Mason & Stubbs (2010:16) refer to as “the open and honest reflexivity through the research process by describing the assumptions, and hiccups” for future researchers navigating governance landscapes.

Recent developments and research needs in modeling lane changing

This paper comprehensively reviews recent developments in modeling lane-changing behavior. The major lane changing models in the literature are categorized into two groups: models that aim to capture the lane changing decision-making process, and models that aim to quantify the impact of lane changing behavior on surrounding vehicles. The methodologies and important features (including their limitations) of representative models in each category are outlined and discussed. Future research needs are determined.

The multi-platform user engagement and data visualisation tool

The ability to identify and assess user engagement with transmedia productions is vital to the success of individual projects and the sustainability of this mode of media production as a whole. It is essential that industry players have access to tools and methodologies that offer the most complete and accurate picture of how audiences/users engage with their productions and which assets generate the most valuable returns of investment. Drawing upon research conducted with Hoodlum Entertainment, a Brisbane-based transmedia producer, this project involved an initial assessment of the way engagement tends to be understood, why standard web analytics tools are ill-suited to measuring it, how a customised tool could offer solutions, and why this question of measuring engagement is so vital to the future of transmedia as a sustainable industry. Working with data provided by Hoodlum Entertainment and Foxtel Marketing, the outcome of the study was a prototype for a custom data visualisation tool that allowed access, manipulation and presentation of user engagement data, both historic and predictive. The prototyped interfaces demonstrate how the visualization tool would collect and organise data specific to multiplatform projects by aggregating data across a number of platform reporting tools. Such a tool is designed to encompass not only platforms developed by the transmedia producer but also sites developed by fans. This visualisation tool accounted for multiplatform experience projects whose top level is comprised of people, platforms and content. People include characters, actors, audience, distributors and creators. Platforms include television, Facebook and other relevant social networks, literature, cinema and other media that might be included in the multiplatform experience. Content refers to discreet media texts employed within the platform, such as tweet, a You Tube video, a Facebook post, an email, a television episode, etc. Core content is produced by the creators’ multiplatform experiences to advance the narrative, while complimentary content generated by audience members offers further contributions to the experience. Equally important is the timing with which the components of the experience are introduced and how they interact with and impact upon each other. Being able to combine, filter and sort these elements in multiple ways we can better understand the value of certain components of a project. It also offers insights into the relationship between the timing of the release of components and user activity associated with them, which further highlights the efficacy (or, indeed, failure) of assets as catalysts for engagement. In collaboration with Hoodlum we have developed a number of design scenarios experimenting with the ways in which data can be visualised and manipulated to tell a more refined story about the value of user engagement with certain project components and activities. This experimentation will serve as the basis for future research.

The role of the molecular footprint of EGFR in tailoring treatment decisions in NSCLC

The majority of patients with non-small-cell lung cancer (NSCLC) present with advanced disease, with targeted therapies providing some improvement in clinical outcomes. The epidermal growth factor receptor (EGFR) tyrosine kinase (TK) plays an important role in the pathogenesis of NSCLC. Tyrosine kinase inhibitors (TKIs), which target the EGFR TK domain, have proven to be an effective treatment strategy; however, patient responses to treatment vary considerably. Therefore, the identification of patients most likely to respond to treatment is essential to optimise the benefit of TKIs. Tumour-associated activating mutations in EGFR can identify patients with NSCLC who are likely to have a good response to TKIs. Nonetheless, the majority of patients relapse within a year of starting treatment. Studies of tumours at relapse have demonstrated expression of a T790M mutation in exon 20 of the EGFR TK domain in approximately 50% of cases. Although conferring resistance to reversible TKIs, these patients may remain sensitive to new-generation irreversible/panerb inhibitors. A number of techniques have been employed for genotypic assessment of tumourassociated DNA to identify EGFR mutations, each of which has advantages and disadvantages. This review presents an overview of the current methodologies used to identify such molecular markers. Recent developments in technology may make the monitoring of changes in patients' tumour genotypes easier in clinical practice, which may enable patients' treatment regimens to be tailored during the course of their disease, potentially leading to improved patient outcomes.

Learner-focused evaluation cycles : facilitating learning using feedforward, concurrent and feedback evaluation

There is a growing trend to offer students learning opportunities that are flexible, innovative and engaging. As educators embrace student-centred agile teaching and learning methodologies, which require continuous reflection and adaptation, the need to evaluate students’ learning in a timely manner has become more pressing. Conventional evaluation surveys currently dominate the evaluation landscape internationally, despite recognition that they are insufficient to effectively evaluate curriculum and teaching quality. Surveys often: (1) fail to address the issues for which educators need feedback, (2) constrain student voice, (3) have low response rates and (4) occur too late to benefit current students. Consequently, this paper explores principles of effective feedback to propose a framework for learner-focused evaluation. We apply a three-stage control model, involving feedforward, concurrent and feedback evaluation, to investigate the intersection of assessment and evaluation in agile learning environments. We conclude that learner-focused evaluation cycles can be used to guide action so that evaluation is not undertaken simply for the benefit of future offerings, but rather to benefit current students by allowing ‘real-time’ learning activities to be adapted in the moment. As a result, students become co-producers of learning and evaluation becomes a meaningful, responsive dialogue between students and their instructors.

Sub-cellular localization of membrane proteins

In eukaryotes, numerous complex sub-cellular structures exist. The majority of these are delineated by membranes. Many proteins are trafficked to these in order to be able to carry out their correct physiological function. Assigning the sub-cellular location of a protein is of paramount importance to biologists in the elucidation of its role and in the refinement of knowledge of cellular processes by tracing certain activities to specific organelles. Membrane proteins are a key set of proteins as these form part of the boundary of the organelles and represent many important functions such as transporters, receptors, and trafficking. They are, however, some of the most challenging proteins to work with due to poor solubility, a wide concentration range within the cell and inaccessibility to many of the tools employed in proteomics studies. This review focuses on membrane proteins with particular emphasis on sub-cellular localization in terms of methodologies that can be used to determine the accurate location of membrane proteins to organelles. We also discuss what is known about the membrane protein cohorts of major organelles.

Stereotypes of age differences in personality traits : universal and accurate?

Age trajectories for personality traits are known to be similar across cultures. To address whether stereotypes of age groups reflect these age-related changes in personality, we asked participants in 26 countries (N = 3,323) to rate typical adolescents, adults, and old persons in their own country. Raters across nations tended to share similar beliefs about different age groups; adolescents were seen as impulsive, rebellious, undisciplined, preferring excitement and novelty, whereas old people were consistently considered lower on impulsivity, activity, antagonism, and Openness. These consensual age group stereotypes correlated strongly with published age differences on the five major dimensions of personality and most of 30 specific traits, using as criteria of accuracy both self-reports and observer ratings, different survey methodologies, and data from up to 50 nations. However, personal stereotypes were considerably less accurate, and consensual stereotypes tended to exaggerate differences across age groups.

Found in translation : debating the abstract elements of cultures through actor training styles

While the synthesis of acting methodologies in intercultural acting has been discussed at length, little discussion has focussed on the potential of diverse actor training styles to affect performance making and audience reception. This article explores a project where the abstract elements of the British and American cultures were translated in rehearsal and in production through the purposeful juxtaposition of two differing actor training styles: the British ‘traditional’ approach and the American Method. William Nicholson’s Shadowlands was produced by Crossbow Productions at the Brisbane Powerhouse in 2010. Nicholson’s play contains a discourse on the cultural cringe of British – American relations. As a research project, the production aimed to extend and augment audience experience of the socio-cultural tensions inherent in the play by juxtaposing two seemingly culturally inscribed approaches to acting. Actors were chosen who had been trained under a traditional conservatoire approach and the American Method. A brief overview of these acting approaches is followed by a discussion centred on the project. This article analyses how from the casting room to the rehearsal room to the mise en scene and into the audience discussions, cultural issues were articulated, translated and debated through the language of acting.

Empirical facts : a rationale for expanding lawyers' methodological expertise

This article examines the importance of the social evidence base in relation to the development of the law. It argues that there is a need for those lawyers who play a part in law reform (legislators and those involved in the law reform process) and for those who play a part in formulating policy-based common law rules (judges and practitioners) to know more about how facts are established in the social sciences. It argues that lawyers need sufficient knowledge and skills in order to be able to critically assess the facts and evidence base when examining new legislation and also when preparing, arguing and determining the outcomes of legal disputes. For this reason the article argues that lawyers need enhanced training in empirical methodologies in order to function effectively in modern legal contexts.