PEGylation of lysine residues reduces the pro-migratory activity of IGF-I

Background: The insulin-like growth factor (IGF) system is composed of ligands and receptors which regulate cell proliferation, survival, differentiation and migration. Some functions are regulated via intracellular signaling cascades, others by involvement of the extracellular milieu, including binding proteins and other extracellular matrix proteins. However, understanding of their functions and the exact nature of these interactions remains incomplete. Methods: IGF-I was PEGylated at its lysine sites - K27, K65 and K68. Binding of PEG-IGF-I to the IGFBPs was analyzed using BIAcore and its ability to activate the IGF-IR was assessed using IGF-IR phosphorylation assay. Furthermore, functional consequences of PEGylating the lysine residues of IGF-I was investigated using cell viability and cell migration assays. In addition, particular downstream signaling pathways regularly implicated in these mechanisms were also dissected using phospho-AKT and phospho-ERK1/2 assays. Results: In this study, IGF-I specifically PEGylated at lysine 27 (PEG-K27), 65 (PEG-K65) or 68 (PEG-K68) were employed. Receptor phosphorylation was only reduced by 2-fold with PEG-K65 and PEG-K68 over all the time points tested, and as observed in two cell types, 3T3 fibroblasts and MCF-7 breast cancer cells. PEGylation at K27 resulted in a much larger effect, with more than 10-fold lower activation for 3T3 fibroblasts and a ~3 fold reduced IGF-IR activation for MCF-7 breast cancer cells over 15 minutes. In addition, all PEG-IGF-I variants demonstrated a ten-fold reduction in the association rate to IGF binding proteins (IGFBPs). Functionally, all PEG variants completely lost their ability to induce cell migration in the presence of IGFBP-3/vitronectin (VN) complexes as compared to IGF-I; in contrast, cell viability was fully preserved. Further investigations into the downstream signaling pathways revealed that the PI3-K/AKT pathway was preferentially affected upon treatment with the PEG-IGF-I variants compared to the MAPK/ERK pathway. Conclusion: PEGylation of IGF-I has an impact on cell migration but not cell viability. General significance: PEG-IGF-I may differentially modulate IGF-I mediated functions that are dependent on its interaction with its receptor as well as key extracellular proteins such as VN and IGFBPs.

A new life of Hans Christian Andersen : a study of the ‘peculiar nature’ of an author’s life

A review of "Hans Christian Andersen : European Witness" by Paul Binding (Yale UP, 2014). How a writer bears witness to his age is necessarily the expression of many things, not least the possibly quite peculiar nature of an author’s life. Literary works often emerge from complex upbringings, from periods of youthful isolation spent reading and writing. More still seem to have been written as a result of the fraught relationships that befall authors, perhaps because authors so often view their relationships with a degree of creative and critical distance. And yet, if a writer’s output evidences an unusual life, it also witnesses broader questions being asked by a community as a whole. At some level, even the most remarkable figures are typical of their age, and reflections of it. By the close of Paul Binding’s study of the life and works of Hans Christian Andersen (1805–75), we are reminded that extraordinary feats of originality and imagination are often the result of how unique minds enter wider discourses...

A communication model and partitioning algorithm for streaming applications for an embedded MPSoC

Energy efficient embedded computing enables new application scenarios in mobile devices like software-defined radio and video processing. The hierarchical multiprocessor considered in this work may contain dozens or hundreds of resource efficient VLIW CPUs. Programming this number of CPU cores is a complex task requiring compiler support. The stream programming paradigm provides beneficial properties that help to support automatic partitioning. This work describes a compiler for streaming applications targeting the self-build hierarchical CoreVA-MPSoC multiprocessor platform. The compiler is supported by a programming model that is tailored to fit the streaming programming paradigm. We present a novel simulated-annealing (SA) based partitioning algorithm, called Smart SA. The overall speedup of Smart SA is 12.84 for an MPSoC with 16 CPU cores compared to a single CPU implementation. Comparison with a state of the art partitioning algorithm shows an average performance improvement of 34.07%.

Masculinity, sexuality, theology and child sexual abuse by personnel in Christian institutions

There growing recognition that a contributor to the repeat crises of child sexual abuse (CSA) by personnel in Christian institutions (PICIs), is the often gendered culture of Christian institutions themselves. This work explores theological discursive constructions of masculinity and sexuality and their implications for addressing CSA by PICIs. The perspectives discussed here are of PICIs who participated in a research project conducted in Australia. From these perspectives male gendered and sexual performance is constructed through discourse as both an explanation and solution to offending behaviour. Similarly, sexuality is viewed as God-given, heteronormative and legitimately expressed only within the bounds of marriage. This work draws on Foucault and feminist discourses as they relate to CSA by PICIs and institutional discourses. This work offers a perspective of PICIs that may not otherwise be heard in the common discourses of CSA in Christian Institutions.

On the symbiosis of law and truth in Christian theology: Reconciling universal and particular through the Pauline law of love

This article argues that the secular liberal and positivist foundations of the modern Western legal system render it violent. In particular, the liberal exclusion of faith and subjectivity in favour of abstract and universal reason in conjunction with its privileging of individual autonomy at the expense of the community leads to alienation of the individual from the community. Similarly, the positivist exclusion of faith and theology from law, with its enforced conformity to the posited law, also results in this violence of alienation. In response, this article proposes a new foundation for law, a natural law based in the truth of Trinitarian theology articulated by John Milbank. In the Trinity, the members exist as a perfect unity in diversity, providing a model for the reconciliation of the legal individual and community: the law of love. Through the law of love as the basic norm, individuals love their neighbours as themselves, reconciling the particular and the universal, and providing a community of peace rather than violence.

Gaming well: Links between videogames and flourishing mental health

This paper is a review of the state of play of research linking videogaming and flourishing, and explores the role of videogames and technology to improve mental health and well-being. Its purpose is to develop understandings about the positive intersection of gaming and well-being, to document evidence regarding links between videogames and positive mental health, and to provide guidelines for use by other researchers as they design and use tools and games to improve mental health and well-being. Using Huppert's (Huppert and So, 2013) proposition that to flourish is more than the absence of mental disorder but rather a combination of feeling good and functioning effectively, resulting in high levels of mental well-being, and Seligman's (Seligman, 2011) PERMA theory of well-being, the paper identifies strengths in existing games that generate positive affect, positive functioning, and positive social functioning, contributing to, and supporting mental health and well-being.

Videogames: Dispelling myths and tabloid headlines that videogames are bad

Videogamers are often portrayed as adolescent overweight males eating fast food in their bedroom, and videogames often blamed in the media for violent crime, obesity, social isolation and depression. However videogaming is a mainstream activity. In Australia 65% of the population play videogames (Digital Australia 2014), and humanity as a species play about 3 billion hours of videogames a week. This paper dispels the myths and sensationalised negative tabloid headlines that videogames are bad by presenting the latest research showing that videogames can help fight depression, improve brain function and stimulate creativity; that gamers have higher levels of family closeness and better attachment to school; and that videogames help boys and young men to relax, cope and socialise. Children and adolescents deliberately choose to play videogames in the knowledge that they will feel better as a result, and videogame play allow players to express themselves in ways they may not feel comfortable doing in real life because of their appearance, gender, sexuality, and/or age. The potential benefits of videogames to the individual and to society are yet to be fully realised. However already videogames are helping many gamers to flourish in life.

The right fit: Christian Street House

Embracing the pleasures of constraint, this new house by James Russell Architect was designed to contextually inspired principles, creating a social and relaxed environment that suits the location’s subtropical way of life.

Genetic studies of body mass index yield new insights for obesity biology

Obesity is heritable and predisposes to many diseases. To understand the genetic basis of obesity better, here we conduct a genome-wide association study and Metabochip meta-analysis of body mass index (BMI), a measure commonly used to define obesity and assess adiposity, in up to 339,224 individuals. This analysis identifies 97 BMI-associated loci (P < 5 × 10−8), 56 of which are novel. Five loci demonstrate clear evidence of several independent association signals, and many loci have significant effects on other metabolic phenotypes. The 97 loci account for ~2.7% of BMI variation, and genome-wide estimates suggest that common variation accounts for >20% of BMI variation. Pathway analyses provide strong support for a role of the central nervous system in obesity susceptibility and implicate new genes and pathways, including those related to synaptic function, glutamate signalling, insulin secretion/action, energy metabolism, lipid biology and adipogenesis.

FTO genotype is associated with phenotypic variability of body mass index

There is evidence across several species for genetic control of phenotypic variation of complex traits1, 2, 3, 4, such that the variance among phenotypes is genotype dependent. Understanding genetic control of variability is important in evolutionary biology, agricultural selection programmes and human medicine, yet for complex traits, no individual genetic variants associated with variance, as opposed to the mean, have been identified. Here we perform a meta-analysis of genome-wide association studies of phenotypic variation using ~170,000 samples on height and body mass index (BMI) in human populations. We report evidence that the single nucleotide polymorphism (SNP) rs7202116 at the FTO gene locus, which is known to be associated with obesity (as measured by mean BMI for each rs7202116 genotype)5, 6, 7, is also associated with phenotypic variability. We show that the results are not due to scale effects or other artefacts, and find no other experiment-wise significant evidence for effects on variability, either at loci other than FTO for BMI or at any locus for height. The difference in variance for BMI among individuals with opposite homozygous genotypes at the FTO locus is approximately 7%, corresponding to a difference of ~0.5 kilograms in the standard deviation of weight. Our results indicate that genetic variants can be discovered that are associated with variability, and that between-person variability in obesity can partly be explained by the genotype at the FTO locus. The results are consistent with reported FTO by environment interactions for BMI8, possibly mediated by DNA methylation9, 10. Our BMI results for other SNPs and our height results for all SNPs suggest that most genetic variants, including those that influence mean height or mean BMI, are not associated with phenotypic variance, or that their effects on variability are too small to detect even with samples sizes greater than 100,000.

Meta-analysis identifies 13 new loci associated with waist-hip ratio and reveals sexual dimorphism in the genetic basis of fat distribution

Waist-hip ratio (WHR) is a measure of body fat distribution and a predictor of metabolic consequences independent of overall adiposity. WHR is heritable, but few genetic variants influencing this trait have been identified. We conducted a meta-analysis of 32 genome-wide association studies for WHR adjusted for body mass index (comprising up to 77,167 participants), following up 16 loci in an additional 29 studies (comprising up to 113,636 subjects). We identified 13 new loci in or near RSPO3, VEGFA, TBX15-WARS2, NFE2L3, GRB14, DNM3-PIGC, ITPR2-SSPN, LY86, HOXC13, ADAMTS9, ZNRF3-KREMEN1, NISCH-STAB1 and CPEB4 (P = 1.9 × 10−9 to P = 1.8 × 10−40) and the known signal at LYPLAL1. Seven of these loci exhibited marked sexual dimorphism, all with a stronger effect on WHR in women than men (P for sex difference = 1.9 × 10−3 to P = 1.2 × 10−13). These findings provide evidence for multiple loci that modulate body fat distribution independent of overall adiposity and reveal strong gene-by-sex interactions.

What is a “Christian” jurisprudence?

The term ‘jurisprudence’ is derived etymologically from the Latin juris, meaning law, and prudentia, meaning wisdom. So jurisprudence simply means the wisdom of the law, or, as it has come to mean in scholarly legal circles these days, the theory of law. It asks fundamental questions regarding the nature and definition of law. And so, the question I wish to pose to us today is what does a truly “Christian” theory of law look like? One that is faithful to, as taken from the conference brochure, the “historic Christian faith” in its “principles and practice”. To contextualise this question, I must give you a deceptively brief and superficial overview of prevailing theories of law – and for those of you who know more about the topic, I apologise for the crass nature of my summary – time prevents me from doing any more...