Homodimerization controls the fibroblast growth factor 9 subfamily's receptor binding and heparan sulfate-dependent diffusion in the extracellular matrix

Uncontrolled fibroblast growth factor (FGF) signaling can lead to human diseases, necessitating multiple layers of self-regulatory control mechanisms to keep its activity in check. Herein, we demonstrate that FGF9 and FGF20 ligands undergo a reversible homodimerization, occluding their key receptor binding sites. To test the role of dimerization in ligand autoinhibition, we introduced structure-based mutations into the dimer interfaces of FGF9 and FGF20. The mutations weakened the ability of the ligands to dimerize, effectively increasing the concentrations of monomeric ligands capable of binding and activating their cognate FGF receptor in vitro and in living cells. Interestingly, the monomeric ligands exhibit reduced heparin binding, resulting in their increased radii of heparan sulfate-dependent diffusion and biologic action, as evidenced by the wider dilation area of ex vivo lung cultures in response to implanted mutant FGF9-loaded beads. Hence, our data demonstrate that homodimerization autoregulates FGF9 and FGF20's receptor binding and concentration gradients in the extracellular matrix. Our study is the first to implicate ligand dimerization as an autoregulatory mechanism for growth factor bioactivity and sets the stage for engineering modified FGF9 subfamily ligands, with desired activity for use in both basic and translational research.

Dynamic axial ligand-site exchange in facially discriminated ruthenium(II) carbonyl and rhodium(III) halide metalloporphyrins

For a series of six-coordinate Ru(II)(CO)L or Rh(III)(X–)L porphyrins which are facially differentiated by having a naphthoquinol- or hydroquinol-containing strap across one face, we show that ligand migration from one face to the other can occur under mild conditions, and that ligand site preference is dependent on the nature of L and X–. For bulky nitrogen-based ligands, the strap can be displaced sideways to accommodate the ligand on the same side as the strap. For the ligand pyrazine, we show 1 H NMR evidence for monodentate and bidentate binding modes on both faces, dependent on ligand concentration and metalloporphyrin structure, and that inter-facial migration is rapid under normal conditions. For monodentate substituted pyridine ligands there is a site dependence on structure, and we show clear evidence of dynamic ligand migration through a series of ligand exchange reactions.

The impact of nonlinear exposure risk relationships on seasonal time series data: modelling danish neonatal birth anthropometric data

Background Birth weight and length have seasonal fluctuations. Previous analyses of birth weight by latitude effects identified seemingly contradictory results, showing both 6 and 12 monthly periodicities in weight. The aims of this paper are twofold: (a) to explore seasonal patterns in a large, Danish Medical Birth Register, and (b) to explore models based on seasonal exposures and a non-linear exposure-risk relationship. Methods Birth weight and birth lengths on over 1.5 million Danish singleton, live births were examined for seasonality. We modelled seasonal patterns based on linear, U- and J-shaped exposure-risk relationships. We then added an extra layer of complexity by modelling weighted population-based exposure patterns. Results The Danish data showed clear seasonal fluctuations for both birth weight and birth length. A bimodal model best fits the data, however the amplitude of the 6 and 12 month peaks changed over time. In the modelling exercises, U- and J-shaped exposure-risk relationships generate time series with both 6 and 12 month periodicities. Changing the weightings of the population exposure risks result in unexpected properties. A J-shaped exposure-risk relationship with a diminishing population exposure over time fitted the observed seasonal pattern in the Danish birth weight data. Conclusion In keeping with many other studies, Danish birth anthropometric data show complex and shifting seasonal patterns. We speculate that annual periodicities with non-linear exposure-risk models may underlie these findings. Understanding the nature of seasonal fluctuations can help generate candidate exposures.

FGFR2 mutations are rare across histologic subtypes of ovarian cancer

OBJECTIVE: Ovarian cancer is the leading cause of death from gynecologic malignancies in the Western world. Fibroblast growth factor receptor (FGFR) signaling has been implicated to play a role in ovarian tumorigenesis. Mutational activation of one member of this receptor family, FGFR2, is a frequent event in endometrioid endometrial cancer. Given the similarities in the histologic and molecular genetics of ovarian and endometrial cancers, we hypothesized that activating FGFR2 mutations may occur in a subset of endometrioid ovarian tumors, and possibly other histotypes. METHODS: Six FGFR2 exons were sequenced in 120 primary ovarian tumors representing the major histologic subtypes. RESULTS: FGFR2 mutation was detected at low frequency in endometrioid (1/46, 2.2%) and serous (1/41, 2.4%) ovarian cancer. No mutations were detected in clear cell, mucinous, or mixed histology tumors or in the ovarian cancer cell lines tested. Functional characterization of the FGFR2 mutations confirmed that the mutations detected in ovarian cancer result in receptor activation. CONCLUSIONS: Despite the low incidence of FGFR2 mutations in ovarian cancer, the two FGFR2 mutations identified in ovarian tumors (S252W, Y376C) overlap with the oncogenic mutations previously identified in endometrial tumors, suggesting activated FGFR2 may contribute to ovarian cancer pathogenesis in a small subset of ovarian tumors.

ICU nurses' experiences and perspectives of caring for obstetric patients in intensive care: A qualitative study

Aims and objectives.  The aim of this study was to gain an understanding of the experiences and perspectives of intensive care nurses caring for critically ill obstetric patients. Background.  Current literature suggests critically ill obstetric patients need specialised, technically appropriate care to meet their specific needs with which many intensive care nurses are unfamiliar. Furthermore, there is little research and evidence to guide the care of this distinct patient group. Design.  This study used a descriptive qualitative design. Methods.  Two focus groups were used to collect data from 10 Australian intensive care units nurses in May 2007. Open-ended questions were used to guide the discussion. Latent content analysis was used to analyse the data set. Each interview lasted no longer than 60 minutes and was recorded using audio tape. The full interviews were transcribed prior to in-depth analysis to identify major themes. Results.  The themes identified from the focus group interviews were competence with knowledge and skills for managing obstetric patients in the intensive care unit, confidence in caring for obstetric patients admitted to the intensive care unit and acceptance of an expanded scope of practice perceived to include fundamental midwifery knowledge and skills. Conclusion.  The expressed lack of confidence and competence in meeting the obstetric and support needs of critically ill obstetric women indicates a clear need for greater assistance and education of intensive care nurses. This in turn may encourage critical care nurses to accept an expanded role of clinical practice in caring for critically ill obstetric patients. Relevance to clinical practice.  Recognition of the issues for nurses in successfully caring for obstetric patients admitted to an adult intensive care setting provides direction for designing education packages, ensuring specific carepaths and guidelines are in place and that support from a multidisciplinary team is available including midwifery staff.

Theorising a model for teaching and assessing reflective learning in higher education

The importance of reflection in higher education, and across disciplinary fields is widely recognised; it is generally included in university graduate attributes, professional standards and program objectives. Furthermore, reflection is commonly embedded into assessment requirements in higher education subjects, often without necessary scaffolding or clear expectations for students. Despite the rhetoric around the importance of reflection for ongoing learning, there is scant literature on any systematic, developmental approach to teaching reflective learning across higher education programs/courses. Given that professional or academic reflection is not intuitive, and requires specific pedagogic intervention to do well, a program/course-wide approach is essential. This paper draws on current literature to theorise a new, transferable and customisable model for teaching and assessing reflective learning across higher education, which foregrounds and explains the pedagogic field of higher education as a multi-dimensional space. We argue that explicit and strategic pedagogic intervention, supported by dynamic resources, is necessary for successful, broad-scale approaches to reflection in higher education.

Conceptualising and teaching discursive and performative reflection in higher education

The importance of reflection in higher education, and across disciplinary fields is widely recognised. It is generally embedded in university graduate attributes, professional standards and course objectives. Furthermore, reflection is commonly included in assessment requirements in higher education subjects, often without necessary scaffolding or clear expectations for students. It is essential that academic staff have substantive knowledge and clear expectations about the aims of reflective activities, the most effective mode of representation, and appropriate teaching strategies to support students in deep, critical reflection. The paper argues the case for reflection to be represented in different modes, using discursive (language) or performative (symbolic practice) forms of expression according to disciplinary context and individual communicative strengths. It introduces key discursive and expressive elements that constitute different modes of representation in reflective tasks. This functional analysis of textual elements provides explicit knowledge for teaching and assessing multiple modes of reflection in higher education.

An experimental research investigation into disused flat rail wagons as bridges with applications for low volume rural roads in Australia

An experimental laboratory investigation was carried out to assess the structural adequacy of a disused PHO Class Flat Bottom Rail Wagon (FRW) for a single lane low volume road bridge application as per the design provisions of the Australian Bridge Design Standard AS 5100(2004). The investigation also encompassed a review into the risk associated with the pre-existing damage in wagons incurred during their service life on rail. The main objective of the laboratory testing of the FRW was to physically measure its performance under the same applied traffic loading it would be required to resist as a road bridge deck. In order to achieve this a full width (5.2m) single lane, single span (approximately 10m), simply supported bridge would be required to be constructed and tested in a structural laboratory. However, the available clear spacing between the columns of the loading portal frame encountered within the laboratory was insufficient to accommodate the 5.2m wide bridge deck excluding clearance normally considered necessary in structural testing. Therefore, only half of the full scale bridge deck (single FRW of width 2.6m) was able to be accommodated and tested; with the continuity of the bridge deck in the lateral direction applied as boundary constraints along the full length of the FRW at six selected locations. This represents a novel approach not yet reported in the literature for bridge deck testing to the best of the knowledge of the author. The test was carried out under two loadings provided in AS 5100 (2004) – one stationary W80 wheel load and the second a moving axle load M1600. As the bridge investigated in the study is a single lane single span low volume road bridge, the risk of pre-existing damage and the expected high cycle fatigue failure potential was assessed as being minimal and hence the bridge deck was not tested structurally for fatigue/ fracture. The high axle load requirements have instead been focussed upon the investigation into the serviceability and ultimate limit state requirements. The testing regime adopted however involved extensive recording of strains and deflections at several critical locations of the FRW. Three locations of W80 point load and two locations of the M1600 Axle load were considered for the serviceability testing; the FRW was also tested under the ultimate load dictated by the M1600. The outcomes of the experimental investigation have demonstrated that the FRW is structurally adequate to resist the prescribed traffic loadings outlaid in AS 5100 (2004). As the loading was directly applied on to the FRW, the laboratory testing is assessed as being significantly conservative. The FRW bridge deck in the field would only resist the load transferred by the running platform, where, depending on the design, composite action might exist – thereby the share of the loading which needs to be resisted by the FRW would be smaller than the system tested in the lab. On this basis, a demonstration bridge is under construction at the time of writing this thesis and future research will involve field testing in order to assess its performance.

Microarray expression profiling in melanoma reveals a BRAF mutation signature

We have used microarray gene expression profiling and machine learning to predict the presence of BRAF mutations in a panel of 61 melanoma cell lines. The BRAF gene was found to be mutated in 42 samples (69%) and intragenic mutations of the NRAS gene were detected in seven samples (11%). No cell line carried mutations of both genes. Using support vector machines, we have built a classifier that differentiates between melanoma cell lines based on BRAF mutation status. As few as 83 genes are able to discriminate between BRAF mutant and BRAF wild-type samples with clear separation observed using hierarchical clustering. Multidimensional scaling was used to visualize the relationship between a BRAF mutation signature and that of a generalized mitogen-activated protein kinase (MAPK) activation (either BRAF or NRAS mutation) in the context of the discriminating gene list. We observed that samples carrying NRAS mutations lie somewhere between those with or without BRAF mutations. These observations suggest that there are gene-specific mutation signals in addition to a common MAPK activation that result from the pleiotropic effects of either BRAF or NRAS on other signaling pathways, leading to measurably different transcriptional changes.

Moral and social development : teachers’ knowledge of learning and teaching strategies in the early years

The intention of the analysis in this paper was to determine, from interviews with eleven early years’ teachers, what knowledge guided their teaching of moral behaviour. Six of the teachers defined moral behaviour in terms of social conventions only. Children’s learning was attributed by five of the teachers to incidental/contextual issues. Nine of the teachers used discussion of issues, in various contexts, as a way of teaching about social and moral issues. The majority of the teachers (n=7) gave the source of their knowledge of pedagogy as practical as opposed to theoretically informed. There was no clear relationship between their definitions, understanding of children’s learning, pedagogy or source of knowledge. Most of the teachers were using discussion, negotiation and reflection to develop the children’s moral and social behaviour. This is probably effective; however, it suggests a strong need for teaching of moral development to be given more prominence and addressed directly in in-service courses so that teachers are clear about their intentions and the most effective ways of achieving them.

Contesting lost ground for the middle years in Australia : using the case study of Queensland

Over the past twenty years Australia has witnessed an extraordinary rise of the middle year’s movement. In more recent years, however, there is concern that middle years has fallen from the mainstream education agenda (Australian Research Alliance for Children and Youth, 2011). At a national level, evidence of this fall can be seen in the new national curriculum frameworks where reference to middle years is significantly absent, such as The Shape of the Australian Curriculum Version 2.0, (Australian Curriculum, Assessment and Reporting Authority, 2010). Evidence of the fall at a state level can be seen in Queensland Government’s 2015 commencement of junior secondary, rather than middle years, as outlined in A Flying Start for Queensland children: Why year 7 will be part of high school from 2015 (Queensland Government, 2011a). This announcement came after the Queensland government had undertaken an extensive consultation period exploring the possible uptake of middle years at a systemic level. While some may argue that middle years practices can be seen to be embedded in both the national curriculum and the junior secondary reform – it is the fact that middle years practices and philosophies are implicitly embedded (hidden) rather than being made explicitly and systematically mainstreamed (broadly accepted), that causes us grave concern. As such, we argue that this is clear indication that the middle years are being marginalized from the overarching educational agendas in Australia.

Prevalence of malnutrition in Parkinson's disease : a systematic review

Parkinson's disease (PD) patients may be at higher risk of malnutrition because of the symptoms associated with the disease and the side effects of the medication used to manage it. A decline in nutritional status is associated with many adverse outcomes related to health and quality of life. It is not clear, however, to what extent this population is currently affected by malnutrition. The objective of this review was to systematically assess the methodology and outcomes of studies reporting the prevalence of malnutrition in PD patients. Studies that attempted to classify participants with PD into nutritional risk and/or malnutrition categories using body mass index, weight change, anthropometric measures, and nutritional screening and assessment scores were included. The prevalence of malnutrition ranged from 0% to 24% in PD patients, while 3–60% of PD patients were reported to be at risk of malnutrition. There was a large degree of variation among studies in the methods chosen, the definition of malnutrition using those methods, and the detail in which the methodological protocols were reported. The true extent of malnutrition in the PD population has yet to be accurately quantified. It is important, however, to screen for malnutrition at the time of PD diagnosis.

The risks and returns of new public management : political business

Purpose – This article aims to consider success in terms of the financial returns and risks of new public management (NPM) in state-owned enterprises (SOEs). Design/methodology/approach – Financial returns of New Zealand SOEs were examined through a review of their annual reports over a five-year period. Dimensions of risk were examined through interviews conducted in two phases over a two-year period with senior executives from 12 of the (then) 17 SOEs operating in New Zealand. Findings – Findings indicate the potential for SOEs to operate as profitable government investments, with clear support for positive financial returns under NPM. However, variations noted within individual SOEs also indicate that profitable and commercial operations may not be possible in all cases. An examination of the risks associated with SOEs’ operations reveals a number of dimensions of risk, encompassing financial, political (including regulatory), reputational, and public accountability aspects. Practical implications – There is a need for an enhanced awareness on the part of internal and external stakeholders (such as the government and general public) of the risks SOEs face in pursuing higher levels of profitability. Also required, is a more acute understanding on the part of internal and external stakeholders (e.g. government and the public) of the need for SOEs to manage the range of risks identified, given the potentially delicate balance between risk and return. Originality/value – While previous studies have considered the financial returns of SOEs, or the risks faced by the public sector in terms of accountability, few have addressed the two issues collectively in a single context.

Surrogacy and IVF

While in the past surrogacy was illegal in Queensland, since June 2010 the Surrogacy Act 2010 (Qld) (“the Act”) has made altruistic surrogacy arrangements lawful in Queensland. In addition, it provides a mechanism for transfer of legal parentage from the surrogate to the person(s) wishing to have a child (the intended parent(s)). Commercial surrogacy – where a payment, reward or other material benefit of advantage (other than the reimbursement of the “birth mother’s surrogacy costs” (s11 of the Act) is made for entering into a surrogacy arrangement – remains unlawful. The paramount guiding principle underpinning the Act is that of the wellbeing and best interests of a child born as a result of surrogacy. The Surrogacy Act 2010 (Qld) allows a single person or a couple (heterosexual or same sex couples) to enter into an agreement with a woman, and her partner (if she has one), to become pregnant with the intention that the child will be relinquished to the intended parent(s). The Act also provides a mechanism for the intended parent(s) to be legally recognised as the parent(s) of the child. In order for the intended parent(s) to be legally recognised (via a parentage order, discussed below) it must be shown that the surrogacy arrangement was entered into when all the parties were over 25 years of age and the intended parent(s) are male or, in a heterosexual or lesbian couple the female(s) are not likely to conceive or give birth to a healthy child due to medical reasons. The arrangement must be entered into before the surrogate becomes pregnant and all parties must have obtained independent legal advice and counselling about the proposed arrangement, and evidence of this is required at the time a parentage order is applied for. For the purposes of the Act it does not matter how the surrogate conceives the child or if the child is genetically related to the parties. During the period of the pregnancy, the surrogate has the right to manage her pregnancy in the way she wishes. Although she cannot profit from acting as a surrogate, section 11 states that she is entitled to surrogacy costs. These include, for example, reasonable medical costs related to pregnancy and the birth of the child; counselling and legal costs associated with the surrogacy arrangement; actual lost earnings because of leave taken during pregnancy or following birth and any reasonable travel expenses incurred. The surrogacy arrangement itself is not legally enforceable; however, obligations to pay a surrogate’s surrogacy costs are enforceable unless she chooses not to relinquish the child to the intending parents. While the Act does not specifically deal with the situation where the surrogate decides she is unprepared to relinquish the child to the intended parents, there have been examples where parties have entered into these kinds of arrangements, and the arrangements have become difficult. For example, the Family Court case of Re Evelyn (1998) FLC 92–807 involved a child born to a surrogate mother who decided not to surrender her. The child was the genetic child of the surrogate mother and the husband of the couple who had contracted with the surrogate mother. Both sets of parents brought proceedings in the court, seeking that the child live with them. In hearing the application, the court applied the paramount principle of the ‘best interests of the child’. The court made clear that there is no presumption in favour of the birth mother, although in this case the court found that the child may be better placed with the surrogate mother’s family.

TAFE-horticulture teachers’ conceptions of curriculum changes in Queensland, 1990-2003

The period from 1990-2003 was one of unprecedented curriculum change in the Queensland TAFE sector in general and Horticulture in particular. While curriculum theory had been clear for many years that teachers should be involved deeply in the curriculum process, data collected at the end of that period reveals that TAFE Horticulture teachers felt excluded and manipulated by the curriculum developers. With the benefit of distance, this thesis examines TAFE teachers’ conceptions of curriculum change in Horticulture and considers whether events since then have justified their reservations. The research paradigm of this study was informed by the qualitative research orientation of phenomenography based on extended interviews. The study revealed that teachers held eight qualitatively different conceptions of curriculum development. Some viewed the changes as representing a reduction in the quality of education, some as a retreat from education and training while others saw it as a reduction in the quality of teaching delivery. There were teachers who saw it as a way of saving money and others as causing instability and uncertainty, as exploitation of staff and a cause of extra (often unnecessary) work. Most saw the changes as imposed from above with the changes experienced as destructive to staff morale. Despite the generally negative conceptions of curriculum change, the study confirms the importance of teachers being regarded as central in the curriculum change process.