Targeting mutant fibroblast growth factor receptors in cancer

Fibroblast growth factor receptors (FGFRs) play diverse roles in the control of cell proliferation, cell differentiation, angiogenesis and development. Activating the mutations of FGFRs in the germline has long been known to cause a variety of skeletal developmental disorders, but it is only recently that a similar spectrum of somatic FGFR mutations has been associated with human cancers. Many of these somatic mutations are gain-of-function and oncogenic and create dependencies in tumor cell lines harboring such mutations. A combination of knockdown studies and pharmaceutical inhibition in preclinical models has further substantiated genomically altered FGFR as a therapeutic target in cancer, and the oncology community is responding with clinical trials evaluating multikinase inhibitors with anti-FGFR activity and a new generation of specific pan-FGFR inhibitors.

A sequential Monte Carlo approach to design for population pharmacokinetics studies

Here we present a sequential Monte Carlo approach that can be used to find optimal designs. Our focus is on the design of phase III clinical trials where the derivation of sampling windows is required, along with the optimal sampling schedule. The search is conducted via a particle filter which traverses a sequence of target distributions artificially constructed via an annealed utility. The algorithm derives a catalogue of highly efficient designs which, not only contain the optimal, but can also be used to derive sampling windows. We demonstrate our approach by designing a hypothetical phase III clinical trial.

Methods used in cross-cultural comparisons of somatic symptoms and their determinants

This paper is the third in a series of reviews of cross-cultural studies of symptoms at midlife. The goal of this review is to examine methods used previously in cross-cultural studies of menopause and women's health at midlife to (1) identify challenges in the measurement of somatic symptoms across cultures and (2) recommend questions and tools that can be used in future research. This review also aims to examine the determinants of somatic symptoms. The review concludes that methods used for assessing somatic symptoms differ across studies. Somatic symptoms, particularly, aches, pain, and fatigue have a high prevalence. Statistically significant differences were seen in the prevalence of somatic symptoms across cultures. Based on the number of studies that demonstrated cross-cultural differences in symptom prevalence, we recommend that the following symptoms be included in future studies of symptoms at midlife: headaches, aches/pain, palpitations, dizziness, fatigue, breathing difficulties, numbness or tingling, and gastrointestinal difficulties. We also recommend that objective measures of physical function be administered when possible to supplement subjective self-evaluation.

Facilitating growth in prospective teachers’ knowledge : teaching geometry in primary schools

This paper reports on a study that focused on growth of understanding about teaching geometry by a group of prospective teachers engaged in lesson plan study within a computer-supported collaborative learning (CSCL) environment. Participation in the activity was found to facilitate considerable growth in the participants’ pedagogical-content knowledge (PCK). Factors that influenced growth in PCK included the nature of the lesson planning task, the cognitive scaffolds inserted into the CSCL virtual space, the meta-language scaffolds provided to the participants, and the provision of both private and public discourse spaces. The paper concludes with recommendations for enhancing effective knowledge-building discourse about mathematics PCK within prospective teacher education CSCL environments.

Topological map induction using neighbourhood information of places

In topological mapping, perceptual aliasing can cause different places to appear indistinguishable to the robot. In case of severely corrupted or non-available odometry information, topological mapping is difficult as the robot is challenged with the loop-closing problem; that is to determine whether it has visited a particular place before. In this article we propose to use neighbourhood information to disambiguate otherwise indistinguishable places. Using neighbourhood information for place disambiguation is an approach that neither depends on a specific choice of sensors nor requires geometric information such as odometry. Local neighbourhood information is extracted from a sequence of observations of visited places. In experiments using either sonar or visual observations from an indoor environment the benefits of using neighbourhood clues for the disambiguation of otherwise identical vertices are demonstrated. Over 90% of the maps we obtain are isomorphic with the ground truth. The choice of the robot’s sensors does not impact the results of the experiments much.

Teachers’ and children’s personal epistemologies for moral education : Case studies in early years elementary education

While there is strong interest in teaching values in Australia and internationally there is little focus on young children’s moral values learning in the classroom. Research shows that personal epistemology influences teaching and learning in a range of education contexts, including moral education. This study examines relationships between personal epistemologies (children’s and teachers’), pedagogies, and school contexts for moral learning in two early years classrooms. Interviews with teachers and children and analysis of school policy revealed clear patterns of personal epistemologies and pedagogies within each school. A whole school approach to understanding personal epistemologies and practice for moral values learning is suggested.

Imagination for re-engagement from the margins of education

For marginalised secondary school students, mainstream education may no longer appear to be an inviting place. While proposed solutions to problems of disengagement and marginalisation appear to concentrate on finding ways to coerce students back to mainstream education through, for example, ‘learning or earning’ legislation, this article suggests that more effective solutions may be found by engaging with the students in the margins that they occupy. Following discussion of key influences on student disengagement and a theory of imaginations, a ‘students-as-researchers’ (SaR) model of working with young people is discussed to demonstrate that, through the scaffolded application of active imagination, it is possible for such students to identify and create their own connections to the mainstream. The SaR model is illustrated through reference to groups of disaffected high school students who participated in an action research project to investigate apparent low aspiration for tertiary education among their peers at schools serving low-income communities in Queensland, Australia.

Combined time- and space-resolved Raman spectrometer for the non-invasive depth profiling of chemical hazards

A time-resolved inverse spatially offset Raman spectrometer was constructed for depth profiling of Raman-active substances under both the lab and the field environments. The system operating principles and performance are discussed along with its advantages relative to traditional continuous wave spatially offset Raman spectrometer. The developed spectrometer uses a combination of space- and time-resolved detection in order to obtain high-quality Raman spectra from substances hidden behind coloured opaque surface layers, such as plastic and garments, with a single measurement. The time-gated spatially offset Raman spectrometer was successfully used to detect concealed explosives and drug precursors under incandescent and fluorescent background light as well as under daylight. The average screening time was 50 s per measurement. The excitation energy requirements were relatively low (20 mW) which makes the probe safe for screening hazardous substances. The unit has been designed with nanosecond laser excitation and gated detection, making it of lower cost and complexity than previous picosecond-based systems, to provide a functional platform for in-line or in-field sensing of chemical substances.

Renal bioenergetics during early gram-negative mammalian sepsis and angiotensin II infusion

Purpose: To measure renal adenosine triphosphate (ATP) (bioenergetics) during hypotensive sepsis with or without angiotensin II (Ang II) infusion. Methods: In anaesthetised sheep implanted with a renal artery flow probe and a magnetic resonance coil around one kidney, we induced hypotensive sepsis with intravenous Escherichia coli injection. We measured mean arterial pressure (MAP), heart rate, renal blood flow RBF and renal ATP levels using magnetic resonance spectroscopy. After 2 h of sepsis, we randomly assigned sheep to receive an infusion of Ang II or vehicle intravenously and studied the effect of treatment on the same variables. Results: After E. coli administration, the experimental animals developed hypotensive sepsis (MAP from 92 ± 9 at baseline to 58 ± 4 mmHg at 4 h). Initially, RBF increased, then, after 4 h, it decreased below control levels (from 175 ± 28 at baseline to 138 ± 27 mL/min). Despite decreased RBF and hypotension, renal ATP was unchanged (total ATP to inorganic phosphate ratio from 0.69 ± 0.02 to 0.70 ± 0.02). Ang II infusion restored MAP but caused significant renal vasoconstriction. However, it induced no changes in renal ATP (total ATP to inorganic phosphate ratio from 0.79 ± 0.03 to 0.80 ± 0.02). Conclusions:During early hypotensive experimental Gram-negative sepsis, there was no evidence of renal bioenergetic failure despite decreased RBF. In this setting, the addition of a powerful renal vasoconstrictor does not lead to deterioration in renal bioenergetics.

'In the hands of the Receivers': The Politics of Literacy in The Savage by David Almond and Dave McKean

David Almond and Dave McKean's The Savage is a hybrid prose and graphic novel which tells the story of one young man’s maturation through literacy. The protagonist learns to deal with the death of his father and his own 'savage' self by writing a graphic novel. This article reads The Savage in the context of earlier, 'Northern' literacy narrative - particularly Tony Harrison's poem "Them & [uz]" and Barry Hines' Kes — through the discourse of neoliberalism and the notion of the reluctant boy reader. It is suggested that Almond and McKean are influenced by currently dominant ideologies of gender and literacy.

Source characterisation of road dust based on chemical and mineralogical composition

Road dust contain potentially toxic pollutants originating from a range of anthropogenic sources common to urban land uses and soil inputs from surrounding areas. The research study analysed the mineralogy and morphology of dust samples from road surfaces from different land uses and background soil samples to characterise the relative source contributions to road dust. The road dust consist primarily of soil derived minerals (60%) with quartz averaging 40-50% and remainder being clay forming minerals of albite, microcline, chlorite and muscovite originating from surrounding soils. About 2% was organic matter primarily originating from plant matter. Potentially toxic pollutants represented about 30% of the build-up. These pollutants consist of brake and tire wear, combustion emissions and fly ash from asphalt. Heavy metals such as Zn, Cu, Pb, Ni, Cr and Cd primarily originate from vehicular traffic while Fe, Al and Mn primarily originate from surrounding soils. The research study confirmed the significant contribution of vehicular traffic to dust deposited on urban road surfaces.

Balanced skills among nascent entrepreneurs

This paper examines the effects and origins of balanced skills among nascent entrepreneurs. In a first step we apply Lazear’s jack-of-all-trades theory to investigate performance effects of a balanced skill set. Second, we investigate potential sources of balanced skills, thereby testing the investment hypothesis against the endowment hypothesis. Analyzing data on high-potential nascent projects, we find support for the notion that balanced skills are important for making progress in the venture creation process. Regarding the origins of balanced skills, the data support both hypotheses. In line with the investment hypothesis an early interest in an entrepreneurial career, prior managerial and entrepreneurial experience are significantly related with a more balanced skill set. Supporting the endowment hypothesis, an entrepreneurial personality profile indicating entrepreneurial talent is correlated with a balanced skill set. Our results thus hint at the need for theories on the origins of a balanced skill set that integrate both views.

Behaviour and design of cold-formed steel beams subject to lateral-torsional buckling

Cold-formed steel beams are increasingly used as floor joists and bearers in buildings. Their behaviour and moment capacities are influenced by lateral-torsional buckling when they are not laterally restrained adequately. Past research on lateral-torsional buckling has concentrated on hot-rolled steel beams. Hence a numerical study was undertaken to investigate the lateral-torsional buckling behaviour of simply supported cold-formed steel lipped channel beams subjected to uniform bending. For this purpose a finite element model was developed using ABAQUS and its accuracy was verified using available numerical and experimental results. It was then used in a detailed parametric study to simulate the lateral-torsional buckling behaviour and capacity of cold-formed steel beams under varying conditions. The moment capacity results were compared with the predictions from the current design rules in many cold-formed steel codes and suitable recommendations were made. European design rules were found to be conservative while Australian/New Zealand and North American design rules were unconservative. Hence the moment capacity design equations in these codes were modified in this paper based on the available finite element analysis results. This paper presents the details of the parametric study, recommendations to current design rules and the new design rules proposed in this research for lateral-torsional buckling of cold-formed steel lipped channel beams.