Synthesis of novel inhibitors blocking Wnt signaling downstream of β-Catenin

Large scale screening of libraries consisting of natural and small molecules led to the identification of many small molecule inhibitors repressing Wnt/β-Catenin signaling. However, targeted synthesis of novel Wnt pathway inhibitors has been rarely described. We developed a modular and expedient way to create the aromatic ring system with an aliphatic ring in between. Our synthesis opens up the possibility, in principle, to substitute all positions at the ring system with any desired substituent. Here, we tested five different haloquinone analogs carrying methoxy- and hydroxy-groups at different positions. Bona fide Wnt activity assays in cell culture and in Xenopus embryos revealed that two of these compounds act as potent inhibitors of aberrant activated Wnt/β-Catenin signaling.

Reversible addition fragmentation chain transfer (RAFT) polymerization : mechanism, process and applications

The present article gives an overview of the reversible addition fragmentation chain transfer (RAFT) process. RAFT is one of the most versatile living radical polymerization systems and yields polymers of predictable chain length and narrow molecular weight distribution. RAFT relies on the rapid exchange of thiocarbonyl thio groups between growing polymeric chains. The key strengths of the RAFT process for polymer design are its high tolerance of monomer functionality and reaction conditions, the wide range of well-controlled polymeric architectures achievable, and its (in-principle) non-rate-retarding nature. This article introduces the mechanism of polymerization, the range of polymer molecular weights achievable, the range of monomers in which polymerization is controlled by RAFT, the various polymeric architectures that can be obtained, the type of end-group functionalities available to RAFT-made polymers, and the process of RAFT polymerization.

Biophilic urbanism : harnessing natural elements to enhance the performance of constructed assets

Creating climate resilient, low-carbon urban environments and assets is a policy goal of many governments and city planners today, and an important issue for constructed asset owners. Stakeholders and decision makers in urban environments are also responding to growing evidence that cities need to increase their densities to reduce their footprint in the face of growing urban populations. Meanwhile, research is highlighting the importance of balancing such density with urban nature, to provide a range of health and wellbeing benefits to residents as well as to mitigate the environmental and economic impacts of heavily built up, impervious urban areas. Concurrently achieving this suite of objectives requires the coordination and cooperation of multiple stakeholder groups, with urban development and investment increasingly involving many private and public actors. Strategies are needed that can provide ‘win-win’ outcomes to benefit these multiple stakeholders, and provide immediate benefits while also addressing the emerging challenges of climate change, resource shortages and urban population growth. Within this context, ‘biophilic urbanism’ is emerging as an important design principle for buildings and urban areas. Through the use of a suite of natural design elements, biophilic urbanism has the potential to address multiple pressures related to climate change, increasing urban populations, finite resources and human’s inherent need for contact with nature. The principle directs the creation of urban environments that are conducive to life, delivering a range of benefits to stakeholders including building owners, occupiers and the surrounding community. This paper introduces the principle of biophilic urbanism and discusses opportunities for improved building occupant experience and performance of constructed assets, as well as addressing other sustainability objectives including climate change mitigation and adaptation. The paper presents an emerging process for considering biophilic design opportunities at different scales and highlights implications for the built environment industry. This process draws on findings of a study of leading cities internationally and learnings related to economic and policy considerations. This included literature review, two stakeholder workshops, and extensive industry consultation, funded by the Sustainable Built Environment National Research Centre through core project partners Western Australian Department of Finance, Parsons Brinckerhoff, Townsville City Council CitySolar Program, Green Roofs Australasia, and PlantUp.

Considering a whole-of-community approach to integrating nature in cities, an international case study of Vauban, Germany

Globally, cities face a convergence of complex and rapidly evolving challenges, including climate change, resource shortages, population growth and urbanization, and financial pressures. Biophilic urbanism is an emerging design principle capable of considering the multidimensional and interdependent complexities of urban systems and infrastructure, which through the use of natural design features, can meet society’s inherent need for contact with nature, and assist efforts to respond to these growing challenges. Considering the imperative for addressing these challenges, this paper proposes that significant lessons can be learned from existing examples of biophilic urbanism, avoiding ‘re-invention of the wheel’ and facilitating accelerated innovation in other areas. Vauban is a 38-hectare brownfield development located 3 kilometers from the centre of Germany’s ‘ecological capital’ of Freiburg city. It was developed using an innovative process with strong community participation and reinterpreted developer roles to produce an example of integrated sustainability. Innovation in transport, energy, housing, development and water treatment has enabled a relatively high-density, mixed-use development that integrates a considerable amount of nature. This paper discusses Vauban in light of research undertaken over the last two years through the Sustainable Built Environment National Research Centre in Australia, to investigate emerging elements of ‘biophilic urbanism’ (nature-loving cities), and their potential to be mainstreamed within urban environments. The paper considers the interplay between the policies, community dynamics and innovations in Vauban, within the context of the culture, history and practice of sustainability in Germany, and how these have enabled nature to be integrated into the urban environment of Vauban while achieving other desirable goals for urban areas. It highlights potential applications from Vauban for Australian cities.

Output feedback optimal control with contraints

In Chapters 1 through 9 of the book (with the exception of a brief discussion on observers and integral action in Section 5.5 of Chapter 5) we considered constrained optimal control problems for systems without uncertainty, that is, with no unmodelled dynamics or disturbances, and where the full state was available for measurement. More realistically, however, it is necessary to consider control problems for systems with uncertainty. This chapter addresses some of the issues that arise in this situation. As in Chapter 9, we adopt a stochastic description of uncertainty, which associates probability distributions to the uncertain elements, that is, disturbances and initial conditions. (See Section 12.6 for references to alternative approaches to model uncertainty.) When incomplete state information exists, a popular observer-based control strategy in the presence of stochastic disturbances is to use the certainty equivalence [CE] principle, introduced in Section 5.5 of Chapter 5 for deterministic systems. In the stochastic framework, CE consists of estimating the state and then using these estimates as if they were the true state in the control law that results if the problem were formulated as a deterministic problem (that is, without uncertainty). This strategy is motivated by the unconstrained problem with a quadratic objective function, for which CE is indeed the optimal solution (˚Astr¨om 1970, Bertsekas 1976). One of the aims of this chapter is to explore the issues that arise from the use of CE in RHC in the presence of constraints. We then turn to the obvious question about the optimality of the CE principle. We show that CE is, indeed, not optimal in general. We also analyse the possibility of obtaining truly optimal solutions for single input linear systems with input constraints and uncertainty related to output feedback and stochastic disturbances.We first find the optimal solution for the case of horizon N = 1, and then we indicate the complications that arise in the case of horizon N = 2. Our conclusion is that, for the case of linear constrained systems, the extra effort involved in the optimal feedback policy is probably not justified in practice. Indeed, we show by example that CE can give near optimal performance. We thus advocate this approach in real applications.

Validation tool for traction force microscopy

Traction force microscopy (TFM) is commonly used to estimate cells’ traction forces from the deformation that they cause on their substrate. The accuracy of TFM highly depends on the computational methods used to measure the deformation of the substrate and estimate the forces, and also on the specifics of the experimental set-up. Computer simulations can be used to evaluate the effect of both the computational methods and the experimental set-up without the need to perform numerous experiments. Here, we present one such TFM simulator that addresses several limitations of the existing ones. As a proof of principle, we recreate a TFM experimental set-up, and apply a classic 2D TFM algorithm to recover the forces. In summary, our simulator provides a valuable tool to study the performance, refine experimentally, and guide the extraction of biological conclusions from TFM experiments.

Pandemic planning as risk management : how fared the Australian Federation?

The role of law in managing public health challenges such as influenza pandemics poses special challenges. This article reviews Australian plans in the context of the H1N1 09 experience to assess whether risk management was facilitated or inhibited by the "number" of levels or phases of management, the degree of prescriptive detail for particular phases, the number of plans, the clarity of the relationship between them, and the role of the media. Despite differences in the content and form of the plans at the time of the H1N1 09 emerging pandemic, the article argues that in practice, the plans proved to be responsive and robust bases for managing pandemic risks. It is suggested that this was because the plans proved to be frameworks for coordination rather than prescriptive straitjackets, to be only one component of the regulatory response, and to offer the varied tool box of possible responses, as called for by the theory of responsive regulation. Consistent with the principle of subsidiarity, it is argued that the plans did not inhibit localised responses such as selective school closures or rapid responses to selected populations such as cruise ship passengers.

Non-linear refined finite element elastic analysis of steel frames with generalized transverse member loads

In the finite element modelling of steel frames, external loads usually act along the members rather than at the nodes only. Conventionally, when a member is subjected to these transverse loads, they are converted to nodal forces which act at the ends of the elements into which the member is discretised by either lumping or consistent nodal load approaches. For a contemporary geometrically non-linear analysis in which the axial force in the member is large, accurate solutions are achieved by discretising the member into many elements, which can produce unfavourable consequences on the efficacy of the method for analysing large steel frames. Herein, a numerical technique to include the transverse loading in the non-linear stiffness formulation for a single element is proposed, and which is able to predict the structural responses of steel frames involving the effects of first-order member loads as well as the second-order coupling effect between the transverse load and the axial force in the member. This allows for a minimal discretisation of a frame for second-order analysis. For those conventional analyses which do include transverse member loading, prescribed stiffness matrices must be used for the plethora of specific loading patterns encountered. This paper shows, however, that the principle of superposition can be applied to the equilibrium condition, so that the form of the stiffness matrix remains unchanged with only the magnitude of the loading being needed to be changed in the stiffness formulation. This novelty allows for a very useful generalised stiffness formulation for a single higher-order element with arbitrary transverse loading patterns to be formulated. The results are verified using analytical stability function studies, as well as with numerical results reported by independent researchers on several simple structural frames.

Neutral and charged boron-doped fullerenes for CO2 adsorption

Recently, the capture and storage of CO2 have attracted research interest as a strategy to reduce the global emissions of greenhouse gases. It is crucial to find suitable materials to achieve an efficient CO2 capture. Here we report our study of CO2 adsorption on boron-doped C60 fullerene in the neutral state and in the 1e−-charged state. We use first principle density functional calculations to simulate the CO2 adsorption. The results show that CO2 can form weak interactions with the BC59 cage in its neutral state and the interactions can be enhanced significantly by introducing an extra electron to the system.

Community media production : access, institutions, and ethics

In policy terms, community media are known as the “third sector” of the media. The description reflects the historical expectation that community media can fulfill a need not met by the commercial and public service broadcasters. A defining element of this “need” has been the means to production for nonprofessionals, particularly groups not represented in the mainstream media. The historical construction of community media reveals production to be a guiding principle; both a means and an end in itself. This chapter examines the various rationales underpinning community media production, including empowerment, media diversity, and the independent producer movement. Using case studies from youth media, the chapter critiques producer-centric models of community media. In the contemporary media environment, production alone cannot meet the social needs that community media were established to address. Instead, I propose a rationale that combines both production and consumption ethics.

An analysis of ranking principles and retrieval strategies

The assumptions underlying the Probability Ranking Principle (PRP) have led to a number of alternative approaches that cater or compensate for the PRP’s limitations. All alternatives deviate from the PRP by incorporating dependencies. This results in a re-ranking that promotes or demotes documents depending upon their relationship with the documents that have been already ranked. In this paper, we compare and contrast the behaviour of state-of-the-art ranking strategies and principles. To do so, we tease out analytical relationships between the ranking approaches and we investigate the document kinematics to visualise the effects of the different approaches on document ranking.

University of Glasgow at ImageCLEFPhoto 2009 : optimising similarity and diversity in image retrieval

In this paper we describe the approaches adopted to generate the runs submitted to ImageCLEFPhoto 2009 with an aim to promote document diversity in the rankings. Four of our runs are text based approaches that employ textual statistics extracted from the captions of images, i.e. MMR [1] as a state of the art method for result diversification, two approaches that combine relevance information and clustering techniques, and an instantiation of Quantum Probability Ranking Principle. The fifth run exploits visual features of the provided images to re-rank the initial results by means of Factor Analysis. The results reveal that our methods based on only text captions consistently improve the performance of the respective baselines, while the approach that combines visual features with textual statistics shows lower levels of improvements.

Label-free SERS for natural product provenance

Introduction Natural product provenance is important in the food, beverage and pharmaceutical industries, for consumer confidence and with health implications. Raman spectroscopy has powerful molecular fingerprint abilities. Surface Enhanced Raman Spectroscopy’s (SERS) sharp peaks allow distinction between minimally different molecules, so it should be suitable for this purpose. Methods Naturally caffeinated beverages with Guarana extract, coffee and Red Bull energy drink as a synthetic caffeinated beverage for comparison (20 µL ea.) were reacted 1:1 with Gold nanoparticles functionalised with anti-caffeine antibody (ab15221) (10 minutes), air dried and analysed in a micro-Raman instrument. The spectral data was processed using Principle Component Analysis (PCA). Results The PCA showed Guarana sourced caffeine varied significantly from synthetic caffeine (Red Bull) on component 1 (containing 76.4% of the variance in the data). See figure 1. The coffee containing beverages, and in particular Robert Timms (instant coffee) were very similar on component 1, but the barista espresso showed minor variance on component 1. Both coffee sourced caffeine samples varied with red Bull on component 2, (20% of variance). ************************************************************ Figure 1 PCA comparing a naturally caffeinated beverage containing Guarana with coffee. ************************************************************ Discussion PCA is an unsupervised multivariate statistical method that determines patterns within data. Figure 1 shows Caffeine in Guarana is notably different to synthetic caffeine. Other researchers have revealed that caffeine in Guarana plants is complexed with tannins. Naturally sourced/ lightly processed caffeine (Monster Energy, Espresso) are more inherently different than synthetic (Red Bull) /highly processed (Robert Timms) caffeine, in figure 1, which is consistent with this finding and demonstrates this technique’s applicability. Guarana provenance is important because it is still largely hand produced and its demand is escalating with recognition of its benefits. This could be a powerful technique for Guarana provenance, and may extend to other industries where provenance / authentication are required, e.g. the wine or natural pharmaceuticals industries.

Endothelial precursor cells home to a vascularized tissue engineering chamber by application of the angiogenic chemokine CXCl12

Tissue engineering of vascularized constructs has great utility in reconstructive surgery. While we have been successful in generating vascularized granulation-like tissue and adipose tissue in an in vivo tissue engineering chamber, production of other differentiated tissues in a stable construct remains a challenge. One approach is to utilize potent differentiation factors, which can influence the base tissue. Endothelial precursor cells (EPCs) have the ability to both carry differentiation factors and home to developing vasculature. In this study, proof-of-principle experiments demonstrate that such cells can be recruited from the circulation into an in vivo tissue engineering chamber. CXC chemokine ligand 12 (CXCL12)/stromal cell-derived factor 1 was infused into the chamber through Alzet osmotic pumps and chamber cannulation between days 0 and 7, and facilitated recruitment of systemically inoculated exogenous human EPCs injected on day 6. CXCL12 infusion resulted in an eightfold increase in EPC recruitment, 2 (p = 0.03) and 7 days postinfusion (p = 0.008). Delivery of chemotactic/proliferation and/or differentiation factors and appropriately timed introduction of effective cells may allow us to better exploit the regenerative potential of the established chamber construct. © Copyright 2009, Mary Ann Liebert, Inc. 2009.

The responsibility to protect in the Asia-Pacific region

In 2005, governments around the world unanimously agreed to the principle of the responsibility to protect (R2P), which holds that all states have a responsibility to protect their populations from genocide and mass atrocities, that the international community should assist them to fulfil this duty, and that the international community should take timely and decisive measures to protect populations from such crimes when their host state fails to do so. Progressing R2P from words to deeds requires international consensus about the principle’s meaning and scope. To achieve a global consensus on this, we need to better understand the position of governments around the world, including in the Asia-Pacific region, which has long been associated with an enduring commitment to a traditional concept of sovereignty. The present article contributes to such an endeavour through its three sections. The first part charts the nature of the international consensus on R2P and examines the UN secretary-general’s approach. The second looks in detail at the positions of the Asia-Pacific region’s governments on the R2P principle. The final part explores the way forward for progressing the R2P principle in the Asia-Pacific region.