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.

Spatially stratified sampling using auxiliary information for geostatistical mapping

This paper presents a method of spatial sampling based on stratification by Local Moran’s I i calculated using auxiliary information. The sampling technique is compared to other design-based approaches including simple random sampling, systematic sampling on a regular grid, conditional Latin Hypercube sampling and stratified sampling based on auxiliary information, and is illustrated using two different spatial data sets. Each of the samples for the two data sets is interpolated using regression kriging to form a geostatistical map for their respective areas. The proposed technique is shown to be competitive in reproducing specific areas of interest with high accuracy.

Validating a model of cooperative procurement in the construction industry

Project management in the construction industry involves coordination of many tasks and individuals, affected by complexity and uncertainty, which increases the need for efficient cooperation. Procurement is crucial since it sets the basis for cooperation between clients and contractors. This is true whether the project is local, regional or global in scope. Traditionally, procurement procedures are competitive, resulting in conflicts, adversarial relationships and less desirable project results. The purpose of this paper is to propose and empirically test an alternative procurement model based on cooperative procurement procedures that facilitates cooperation between clients and contractors in construction projects. The model is based on four multi-item constructs – incentive-based compensation, limited bidding options, partner selection and cooperation. Based on a sample of 87 client organisations, the model was empirically tested and exhibited strong support, including content, nomological, convergent and discriminant validity, as well as reliability. Our findings indicate that partner selection based on task related attributes mediates the relationship between two important pre-selection processes (incentive-based compensation and limited bid invitation) and preferred outcome of cooperation. The contribution of the paper is identifying valid and reliable measurement constructs and confirming a unique sequential order for achieving cooperation. Moreover, the findings are applicable for many types of construction projects because of the similarities in the construction industry worldwide.

Early signaling responses to divergent exercise stimuli in skeletal muscle from well-trained humans

Skeletal muscle from strength- and endurance-trained individuals represents diverse adaptive states. In this regard, AMPK-PGC-1α signaling mediates several adaptations to endurance training, while up-regulation of the Akt-TSC2-mTOR pathway may underlie increased protein synthesis after resistance exercise. We determined the effect of prior training history on signaling responses in seven strength-trained and six endurance-trained males who undertook 1 h cycling at 70% VO2peak or eight sets of five maximal repetitions of isokinetic leg extensions. Muscle biopsies were taken at rest, immediately and 3 h postexercise. AMPK phosphorylation increased after cycling in strength-trained (54%; P<0.05) but not endurance-trained subjects. Conversely, AMPK was elevated after resistance exercise in endurance- (114%; P<0.05), but not strengthtrained subjects. Akt phosphorylation increased in endurance- (50%; P<0.05), but not strengthtrained subjects after cycling but was unchanged in either group after resistance exercise. TSC2 phosphorylation was decreased (47%; P<0.05) in endurance-trained subjects following resistance exercise, but cycling had little effect on the phosphorylation state of this protein in either group. p70S6K phosphorylation increased in endurance- (118%; P<0.05), but not strength-trained subjects after resistance exercise, but was similar to rest in both groups after cycling. Similarly, phosphorylation of S6 protein, a substrate for p70 S6K, was increased immediately following resistance exercise in endurance- (129%; P<0.05), but not strength-trained subjects. In conclusion, a degree of “response plasticity” is conserved at opposite ends of the endurancehypertrophic adaptation continuum. Moreover, prior training attenuates the exercise specific signaling responses involved in single mode adaptations to training.

Numerical exploration of plastic deformation mechanisms of copper nanowires with surface defects

Based on the molecular dynamics simulation, plastic deformation mechanisms associated with the zigzag stress curves in perfect and surface defected copper nanowires under uniaxial tension are studied. In our previous study, it has found that the surface defect exerts larger influence than the centro-plane defect, and the 45o surface defect appears as the most influential surface defect. Hence, in this paper, the nanowire with a 45o surface defect is chosen to investigate the defect’s effect to the plastic deformation mechanism of nanowires. We find that during the plastic deformation of both perfect and defected nanowires, decrease regions of the stress curve are accompanied with stacking faults generation and migration activities, but during stress increase, the structure of the nanowire appears almost unchanged. We also observe that surface defects have obvious influence on the nanowire’s plastic deformation mechanisms. In particular, only two sets of slip planes are found to be active and twins are also observed in the defected nanowire.

Approximate Membership Localization within a Web-Based Join Framework

In this paper, we propose a search-based approach to join two tables in the absence of clean join attributes. Non-structured documents from the web are used to express the correlations between a given query and a reference list. To implement this approach, a major challenge we meet is how to efficiently determine the number of times and the locations of each clean reference from the reference list that is approximately mentioned in the retrieved documents. We formalize the Approximate Membership Localization (AML) problem and propose an efficient partial pruning algorithm to solve it. A study using real-word data sets demonstrates the effectiveness of our search-based approach, and the efficiency of our AML algorithm.

Destination positioning opportunities using personal values : elicited through the Repertory Test with Laddering Analysis

While in many travel situations there is an almost limitless range of available destinations, travellers will usually only actively consider two to six in their decision set. One of the greatest challenges facing destination marketers is positioning their destination, against the myriad of competing places that offer similar features, into consumer decision sets. Since positioning requires a narrow focus, marketing communications must present a succinct and meaningful proposition, the selection of which is often problematic for destination marketing organisations (DMO), which deal with a diverse and often eclectic range of attributes in addition to self-interested and demanding stakeholders who have interests in different market segments. This paper reports the application of two qualitative techniques used to explore the range of cognitive attributes, consequences and personal values that represent potential positioning opportunities in the context of short break holidays. The Repertory Test is an effective technique for understanding the salient attributes used by a traveller to differentiate destinations, and Laddering Analysis enables the researcher to explore the smaller set of consequences and personal values guiding such decision making. A key finding of the research was that while individuals might vary in their repertoire of salient attributes, there was a commonality of shared consequences and values. This has important implications for DMOs, since a brand positioning theme that is based on a value will subsume multiple and diverse attributes. It is posited that such a theme will appeal to a broader range of travellers, as well as appease a greater number of destination stakeholders, than would an attribute based theme.

The promise of computational journalism

Computational journalism involves the application of software and technologies to the activities of journalism, and it draws from the fields of computer science, the social sciences, and media and communications. New technologies may enhance the traditional aims of journalism, or may initiate greater interaction between journalists and information and communication technology (ICT) specialists. The enhanced use of computing in news production is related in particular to three factors: larger government data sets becoming more widely available; the increasingly sophisticated and ubiquitous nature of software; and the developing digital economy. Drawing upon international examples, this paper argues that computational journalism techniques may provide new foundations for original investigative journalism and increase the scope for new forms of interaction with readers. Computer journalism provides a major opportunity to enhance the delivery of original investigative journalism, and to attract and retain readers online.

Systemic inflammatory responses to maximal versus submaximal lengthening contractions of the elbow flexors

We compared changes in markers of muscle damage and systemic inflammation after submaximal and maximal lengthening muscle contractions of the elbow flexors. Using a cross-over design, 10 healthy young men not involved in resistance training completed a submaximal trial (10 sets of 60 lengthening contractions at 10% maximum isometric strength, 1 min rest between sets), followed by a maximal trial (10 sets of three lengthening contractions at 100% maximum isometric strength, 3 min rest between sets). Lengthening contractions were performed on an isokinetic dynamometer. Opposite arms were used for the submaximal and maximal trials, and the trials were separated by a minimum of two weeks. Blood was sampled before, immediately after, 1 h, 3 h, and 1-4 d after each trial. Total leukocyte and neutrophil numbers, and the serum concentration of soluble tumor necrosis factor-alpha receptor 1 were elevated after both trials (P < 0.01), but there were no differences between the trials. Serum IL-6 concentration was elevated 3 h after the submaximal contractions (P < 0.01). The concentrations of serum tumor necrosis factor-alpha, IL-1 receptor antagonist, IL-10, granulocyte-colony stimulating factor and plasma C-reactive protein remained unchanged following both trials. Maximum isometric strength and range of motion decreased significantly (P < 0.001) after both trials, and were lower from 1-4 days after the maximal contractions compared to the submaximal contractions. Plasma myoglobin concentration and creatine kinase activity, muscle soreness and upper arm circumference all increased after both trials (P < 0.01), but were not significantly different between the trials. Therefore, there were no differences in markers of systemic inflammation, despite evidence of greater muscle damage following maximal versus submaximal lengthening contractions of the elbow flexors.

Exploring the parameter space of a rabbit ventricular action potential model to investigate the effect of variation on action potential and calcium transients

Computational models for cardiomyocyte action potentials (AP) often make use of a large parameter set. This parameter set can contain some elements that are fitted to experimental data independently of any other element, some elements that are derived concurrently with other elements to match experimental data, and some elements that are derived purely from phenomenological fitting to produce the desired AP output. Furthermore, models can make use of several different data sets, not always derived for the same conditions or even the same species. It is consequently uncertain whether the parameter set for a given model is physiologically accurate. Furthermore, it is only recently that the possibility of degeneracy in parameter values in producing a given simulation output has started to be addressed. In this study, we examine the effects of varying two parameters (the L-type calcium current (I(CaL)) and the delayed rectifier potassium current (I(Ks))) in a computational model of a rabbit ventricular cardiomyocyte AP on both the membrane potential (V(m)) and calcium (Ca(2+)) transient. It will subsequently be determined if there is degeneracy in this model to these parameter values, which will have important implications on the stability of these models to cell-to-cell parameter variation, and also whether the current methodology for generating parameter values is flawed. The accuracy of AP duration (APD) as an indicator of AP shape will also be assessed.

Stability and change

This special feature section of Journal of Management & Organization (Volume 17/1 - March 2011) sets out to widen understanding of the processes of stability and change in today's organizations, with a particular emphasis on the contribution of institutional approaches to organizational studies. Institutional perspectives on organization theory assume that rational, economic calculations, such as the maximization of profits or the optimization of resource allocation, are not sufficient to understand the behavior of organizations and their strategic choices. Institutionalists acknowledge the great uncertainty associated with the conduct of organizations and suggest that taken-for-granted values, beliefs and meanings within and outside organizations also play an important role in the determination of legitimate action.

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.

Quality of life and genetics in men with prostate cancer

As family history has been established as a risk factor for prostate cancer, attempts have been made to isolate predisposing genetic variants that are related to hereditary prostate cancer. With many genetic variants still to be identified and investigated, it is not yet possible to fully understand the impact of genetic variants on prostate cancer development. The high survival rates among men with prostate cancer have meant that other issues, such as quality of life (QoL), have also become important. Through their effect on a person’s health, a range of inherited genetic variants may potentially influence QoL in men with prostate cancer, even prior to treatment. Until now, limited research has been conducted on the relationship between genetics and QoL. Thus, this study contributes to an emerging field by aiming to identify certain genetic variants related to the QoL found in men with prostate cancer. It is hoped that this study may lead to future research that will identify men who have an increased risk of a poor QoL following prostate cancer treatment, which will aid in developing treatments that are individually tailored to support them. Previous studies have established that genetic variants of Vascular Endothelial Growth Factor (VEGF) and Insulin-like Growth Factor 1 (IGF-1) may play a role in prostate cancer development. VEGF and IGF-1 have also been reported to be associated with QoL in people with ovarian cancer and colorectal cancer, respectively. This study completed a series of secondary analyses using two major data-sets (from 850 men newly diagnosed with prostate cancer, and approximately 550 men from the general Queensland population), in which genetic variants of VEGF and IGF-1 were investigated for associations with prostate cancer susceptibility and QoL. The first aim of this research was to investigate genetic variants in the VEGF and IGF-I gene for an association with the risk of prostate cancer. It was found that one IGF-1 genetic variant (rs35765) had a statistically significant association with prostate cancer (p = 0.04), and one VEGF genetic variant (rs2146323) had a statistically significant association with advanced prostate cancer (p = 0.02). The estimates suggest that carriers of the CA and AA genotype for rs35765 may have a reduced risk of developing prostate cancer (Odds Ratio (OR) = 0.72, 95% Confidence Interval (CI) = 0.55, 0.95, OR = 0.60, 95% CI = 0.26, 1.39, respectively). Meanwhile, carriers of the CA and AA genotype for rs2146323 may be at increased risk of advanced prostate cancer, which was determined by a Gleason score of above 7 (OR = 1.72, 95% CI = 1.12, 2.63, OR = 1.90, 95% CI = 1.08, 3.34, respectively). Utilising the widely used short-form health survey, the SF-36v2, the second aim of this study was to investigate the relationship between prostate cancer and QoL prior to treatment. Assessing QoL at this time-point was important as little research has been conducted to evaluate if prostate cancer affects QoL regardless of treatment. The analyses found that mean SF-36v2 scale scores related to physical health were higher by at least 0.3 Standard Deviations (SD) among men with prostate cancer than the general population comparison group. This difference was considered clinically significant (defined by group differences in mean SF-36v2 scores by at least 0.3 SD). These differences were also statistically significant (p<0.05). Mean QoL scale scores related to mental health were similar between men with prostate cancer and those from the general population comparison group. The third aim of this study was to investigate genetic variants in the VEGF and IGF-1 gene for an association with QoL in prostate cancer patients prior to their treatment. It was essential to evaluate these relationships prior to treatment, before the involvement of these genes was potentially interrupted by treatment. The analyses found that some genetic variants had a small clinically significant association (0.3 SD) to some QoL domains experienced by these men. However, most relationships were not statistically significant (p>0.05). Most of the associations found identified that a small sub-group of men with prostate cancer (approximately 2%) reported, on average, a slightly better QoL than the majority of the prostate cancer patients. The fourth aim of this research was to investigate whether associations between genetic variants in VEGF and IGF-1 and QoL were specific to men with prostate cancer, or were also applicable to the general male population. It was found that twenty out of one-hundred relationships between the genetic variants of VEGF and IGF-1 and QoL health-measures and scales examined differed between these groups. In the majority of the relationships involving VEGF SNPs that differed, a clinically significant difference (0.3 or more SD) between mean scores among the genotype groups in prostate cancer patients was found, while mean scores among men from the general-population comparison group were similar. For example, prostate cancer participants who carried at least one T allele (CT or TT genotype) for rs3024994 had a clinically significant higher (0.3 SD) mean QoL score in terms of the role-physical scale, than participants who carried the CC genotype. This was not seen among men from the general population sample, as the mean score was similar between genotype groups. The opposite was seen in regards to the IGF-1 SNPs examined. Overall, these relationships were not considered to directly impact on the clinical options for men with prostate cancer. As this study utilised secondary data from two separate studies, there are a number of important limitations that should be acknowledged including issues of multiple comparisons, power, and missing or unavailable data. It is recommended that this study be replicated as a better-designed study that takes greater consideration of the many factors involved in prostate cancer and QoL. Investigation into other genetic variants of VEGF or IGF-1 is also warranted, as is consideration of other genes and their relationship with QoL. Through identifying certain genetic variants that have a modest association to prostate cancer, this project adds to the knowledge surrounding VEGF and IGF-1 and their role in prostate cancer susceptibility. Importantly, this project has also introduced the potential role genetics plays in QoL, through investigating the relationships between genetic variants of VEGF and IGF-1 and QoL.

Regeneration

This presentation relates to a paper presenting an explanation of why the reuse of building components after demolition or deconstruction is critical to the future of the construction industry. An examination of the historical cause and response to climate change sets the scene as to why governance is becoming increasingly focused on the built environment as a mechanism to controlling waste generation associated with the process of demolition, construction and operation. Through an annotated description to the evolving design and construction methodology of a range of timber dwellings (typically 'Queenslanders' during the eras of 1880-1900, 1900-1920 & 1920-1940) the paper offers an evaluation to the variety of materials, which can be used advantageously by those wishing to 'regenerate' a Queenslander. This analysis of 'regeneration' details the constraints when considering relocation and/ or reuse by adaption including deconstruction of building components against the legislative framework requirements of the Queensland Building Act 1975 and the Queensland Sustainable Planning Act 2009, with a specific examination to those of the Building Codes of Australia. The paper concludes with a discussion of these constraints, their impacts on 'regeneration' and the need for further research to seek greater understanding of the practicalities and drivers of relocation, adaptive and building components suitability for reuse after deconstruction.