Discovery and characterization of IGFBP-mediated endocytosis in the human retinal pigment epithelial cell line ARPE-19

Insulin-like growth factor binding proteins (IGFBPs) are prime regulators of IGF-action in numerous cell types including the retinal pigment epithelium (RPE). The RPE performs several functions essential for vision, including growth factor secretion and waste removal via a phagocytic process mediated in part by vitronectin (Vn). In the course of studying the effects of IGFBPs on IGF-mediated VEGF secretion and Vn-mediated phagocytosis in the RPE cell line ARPE-19, we have discovered that these cells avidly ingest synthetic microspheres (2.0 μm diameter) coated with IGFBPs. Given the novelty of this finding and the established role for endocytosis in mediating IGFBP actions in other cell types, we have explored the potential role of candidate cell surface receptors. Moreover, we have examined the role of key IGFBP structural motifs, by comparing responses to three members of the IGFBP family (IGFBP-3, IGFBP-4 and IGFBP-5) which display overlapping variations in primary structure and glycosylation status. Coating of microspheres (FluoSpheres®, sulfate modified polystyrene filled with a fluorophore) was conducted at 37 °C for 1 h using 20 μg/mL of test protein, followed by extensive washing. Binding of proteins was confirmed using a microBCA assay. The negative control consisted of microspheres treated with 0.1% bovine serum albumin (BSA), and all test samples were post-treated with BSA in an effort to coat any remaining free protein binding sites, which might otherwise encourage non-specific interactions with the cell surface. Serum-starved cultures of ARPE-19 cells were incubated with microspheres for 24 h, using a ratio of approximately 100 microspheres per cell. Uptake of microspheres was quantified using a fluorometer and was confirmed visually by confocal fluorescence microscopy. The ARPE-19 cells displayed little affinity for BSA-treated microspheres, but avidly ingested large quantities of those pre-treated with Vn (ANOVA; p < 0.001). Strong responses were also observed towards recombinant formulations of non-glycosylated IGFBP-3, glycosylated IGFBP-3 and glycosylated IGFBP-5 (all p < 0.001), while glycosylated IGFBP-4 induced a relatively minor response (p < 0.05). The response to IGFBP-3 was unaffected in the presence of excess soluble IGFBP-3, IGF-I or Vn. Likewise, soluble IGFBP-3 did not induce uptake of BSA-treated microspheres. Antibodies to either the transferrin receptor or type 1 IGF-receptor displayed slight inhibitory effects on responses to IGFBPs and Vn. Heparin abolished responses to Vn, IGFBP-5 and non-glycosylated IGFBP-3, but only partially inhibited the response to glycosylated IGFBP-3. Our results demonstrate for the first time IGFBP-mediated endocytosis in ARPE-19 cells and suggest roles for the IGFBP-heparin-binding domain and glycosylation status. These findings have important implications for understanding the mechanisms of IGFBP actions on the RPE, and in particular suggest a role for IGFBP-endocytosis.

Choosing to become a 'lost cause': the perverse effects of benefit preconditions

This paper argues that preconditions for welfare benefit entitlements based on labour market prospects can be counterproductive when they create an incentive for individuals to abstain from any investment earlier in life that could improve future prospects. Benefit entitlements based partly on investments made prior to labour market entry are then Pareto-improving.

Creative Industries

We are experiencing a period of profound social and economic transformation. This is a shift from an industrial economy to a knowledge economy (or a “creative economy”; or an “economy of the imagination”.) This new, emerging economic system is fundamentally organised around people (not machines or buildings); and around place. We heard Richard Florida argue that creative, talented people won’t go to where the job is, but vice versa, the job will come to them. So according to Florida, where we live is becoming the primary factor in global economic development. (Incidentally, it is worth contrasting this idea with the alternative proposition - put by speakers at this Forum - of “new nomadism”, that is, that creativity is nomadic and not bound by place.)

An analysis of the determinants of job satisfaction when individuals' baseline satisfaction levels may differ.

A growing literature seeks to explain differences in individuals' self-reported satisfaction with their jobs. The evidence so far has mainly been based on cross-sectional data and when panel data have been used, individual unobserved heterogeneity has been modelled as an ordered probit model with random effects. This article makes use of longitudinal data for Denmark, taken from the waves 1995-1999 of the European Community Household Panel, and estimates fixed effects ordered logit models using the estimation methods proposed by Ferrer-i-Carbonel and Frijters (2004) and Das and van Soest (1999). For comparison and testing purposes a random effects ordered probit is also estimated. Estimations are carried out separately on the samples of men and women for individuals' overall satisfaction with the jobs they hold. We find that using the fixed effects approach (that clearly rejects the random effects specification), considerably reduces the number of key explanatory variables. The impact of central economic factors is the same as in previous studies, though. Moreover, the determinants of job satisfaction differ considerably between the genders, in particular once individual fixed effects are allowed for.

A primeira universidade de economia criativa do mundo: Entrevista com Paul Makeham

This interview (translated and published in Portuguese) was commissioned and conducted by the editors of the Brazilian Guide to Cultural Production 2010-2011 (Edicoes SESC SP, 2010). It covers a range of topics including definitions of the Creative Industries; the value of innovation and creativity in business and education; QUT's Creative Industries Faculty; and the relationship between creative industries and the arts.

"Re-imagining animation : the changing face of the moving image by Paul Wells and Johnny Hardstaff" (Book Review)

Advances in digital technology have caused a radical shift in moving image culture. This has occurred in both modes of production and sites of exhibition, resulting in a blurring of boundaries that previously defined a range of creative disciplines. Re-Imagining Animation: The Changing Face of the Moving Image, by Paul Wells and Johnny Hardstaff, argues that as a result of these blurred disciplinary boundaries, the term “animation” has become a “catch all” for describing any form of manipulated moving image practice. Understanding animation predicates the need to (re)define the medium within contemporary moving image culture. Via a series of case studies, the book engages with a range of moving image works, interrogating “how the many and varied approaches to making film, graphics, visual artefacts, multimedia and other intimations of motion pictures can now be delineated and understood” (p. 7). The structure and clarity of content make this book ideally suited to any serious study of contemporary animation which accepts animation as a truly interdisciplinary medium.

Prospective, non-randomized phase 2 clinical trial of carboplatin plus paclitaxel with sequential radical pelvic radiotherapy for uterine papillary serous carcinoma

Objective Uterine Papillary Serous Carcinoma (UPSC) is uncommon and accounts for less than 5% of all uterine cancers. Therefore the majority of evidence about the benefits of adjuvant treatment comes from retrospective case series. We conducted a prospective multi-centre non-randomized phase 2 clinical trial using four cycles of adjuvant paclitaxel plus carboplatin chemotherapy followed by pelvic radiotherapy, in order to evaluate the tolerability and safety of this approach. Methods This trial enrolled patients with newly diagnosed, previously untreated patients with stage 1b-4 (FIGO-1988) UPSC with a papillary serous component of at least 30%. Paclitaxel (175 mg/m2) and carboplatin (AUC 6) were administered on day 1 of each 3-week cycle for 4 cycles. Chemotherapy was followed by external beam radiotherapy to the whole pelvis (50.4 Gy over 5.5 weeks). Completion and toxicity of treatment (Common Toxicity Criteria, CTC) and quality of life measures were the primary outcome indicators. Results Twenty-nine of 31 patients completed treatment as planned. Dose reduction was needed in 9 patients (29%), treatment delay in 7 (23%), and treatment cessation in 2 patients (6.5%). Hematologic toxicity, grade 3 or 4 occurred in 19% (6/31) of patients. Patients' self-reported quality of life remained stable throughout treatment. Thirteen of the 29 patients with stages 1–3 disease (44.8%) recurred (average follow up 28.1 months, range 8–60 months). Conclusion This multimodal treatment is feasible, safe and tolerated reasonably well and would be suitable for use in multi-institutional prospective randomized clinical trials incorporating novel therapies in patients with UPSC.

Multi-objective four-dimensional vehicle motion planning in large dynamic environments

This paper presents Multi-Step A* (MSA*), a search algorithm based on A* for multi-objective 4D vehicle motion planning (three spatial and one time dimension). The research is principally motivated by the need for offline and online motion planning for autonomous Unmanned Aerial Vehicles (UAVs). For UAVs operating in large, dynamic and uncertain 4D environments, the motion plan consists of a sequence of connected linear tracks (or trajectory segments). The track angle and velocity are important parameters that are often restricted by assumptions and grid geometry in conventional motion planners. Many existing planners also fail to incorporate multiple decision criteria and constraints such as wind, fuel, dynamic obstacles and the rules of the air. It is shown that MSA* finds a cost optimal solution using variable length, angle and velocity trajectory segments. These segments are approximated with a grid based cell sequence that provides an inherent tolerance to uncertainty. Computational efficiency is achieved by using variable successor operators to create a multi-resolution, memory efficient lattice sampling structure. Simulation studies on the UAV flight planning problem show that MSA* meets the time constraints of online replanning and finds paths of equivalent cost but in a quarter of the time (on average) of vector neighbourhood based A*.

An interview with Dr. Benjamin Isakhan : on the alternative histories of democracy

Dr. Isakahn is currently a research associate with the Centre for Dialogue at La Trobe University in Australia. His latest works include several forthcoming books: Democracy in Iraq is a monograph soon to be released; whilst The Edinburgh Companion to the History of Democracy and The Secret History of Democracy, both done in concert with Stephen Stockwell, are edited collections. His most recent articles include “Targeting the Symbolic Dimension of Baathist Iraq,” “Measuring Islam in Australia” and “Manufacturing Consent in Iraq.” For further information regarding Dr. Isakhan and his works, please visit his website, www.benjaminisakhan.com.

"As ideias são mais importantes que os produtos", diz Paul Makeham" [Ideas are more important than products, says Paul Makeham]

This interview with Paul Makeham was conducted in 2010 by Felipe Carneiro from Brazilian business magazine Exame. Structured around Exame's "seven questions" format ("Sete Perguntas"), the interview ranges across topics relating to the creative economy, including the increasingly important role of creativity in business, and the role of education in promoting creativity.

Deceit and Bruno Taut's Glashaus

The historical context surrounding Bruno Taut's Glashaus has been established through work of authors like Reyner Banham, Dennis Sharp and Ian Boyd-Whyte. However, these English language translations, are mostly derived from secondary sources such as Adolf Behne and Paul Scheerbart. Surprisingly, Taut's own writings largely do not feature in this prevailing account of his work. Since 1990, strong doubts have arisen about this conventional picture of Taut's Glashaus. Manfred spiedel, for instance, minimizes Paul Scheerbart's contribution to the design by arguing that Scheerbart met Taut only a few months before the construction of the Glashaus, that is, after Taut had finished his preliminary sketches. Kurt Junghanns goes further and asserts that the Glashaus design was complete beefore Taut and Scheerbart ever met. In 2005, Kai Gutschow published The Culture of Criticism: Adolf Behne and the Development of Modern Architecture in Germany, 1910 - 1914. Most startling, Gutschow asserts that Behne acts as the propagandist for the Glashaus by fabricating its link with Expressionism. This is particularly troubling because nobody contributed more to establishing the link between the Glashaus, Bruno Taut and Expressionism than Behne. As a result of this new evidence, this paper concurs that the established historical understanding of the Glashaus is flawed. By returning to Taut's own writings, a reinterpretation can be offered that strongly links the Glashaus to the Victoria regia lily and Strasbourg Cathedral. The significance of this approach is that it re-establishes Taut's own rational behind the design of the Glashaus, and thus contributes to the re-evaluation of the generally accepted histories of the Modern movement.