Mastering the canonical loop of serine protease inhibitors : enhancing potency by optimising the internal hydrogen bond network

Background Canonical serine protease inhibitors commonly bind to their targets through a rigid loop stabilised by an internal hydrogen bond network and disulfide bond(s). The smallest of these is sunflower trypsin inhibitor (SFTI-1), a potent and broad-range protease inhibitor. Recently, we re-engineered the contact β-sheet of SFTI-1 to produce a selective inhibitor of kallikrein-related peptidase 4 (KLK4), a protease associated with prostate cancer progression. However, modifications in the binding loop to achieve specificity may compromise structural rigidity and prevent re-engineered inhibitors from reaching optimal binding affinity. Methodology/Principal Findings In this study, the effect of amino acid substitutions on the internal hydrogen bonding network of SFTI were investigated using an in silico screen of inhibitor variants in complex with KLK4 or trypsin. Substitutions favouring internal hydrogen bond formation directly correlated with increased potency of inhibition in vitro. This produced a second generation inhibitor (SFTI-FCQR Asn14) which displayed both a 125-fold increased capacity to inhibit KLK4 (Ki = 0.0386±0.0060 nM) and enhanced selectivity over off-target serine proteases. Further, SFTI-FCQR Asn14 was stable in cell culture and bioavailable in mice when administered by intraperitoneal perfusion. Conclusion/Significance These findings highlight the importance of conserving structural rigidity of the binding loop in addition to optimising protease/inhibitor contacts when re-engineering canonical serine protease inhibitors.

Enabling innovation and facilitating learning in kifs: the role of HRM practices

The aim of this paper is to contribute to our understanding of the link between HR practices, learning orientation and types of innovation in knowledge-intensive firms (KIFs). To this end, we first compiled a comprehensive overview of the existing literature on HR practices aimed at supporting innovation. On the basis of this literature, we then collected and analyzed data from a qualitative study of 19 Danish KIFs recognized for their innovation performance, focusing on links between the HR practices they use to support exploratory and exploitive learning behaviors to enhance incremental and/or radical innovation. The findings from this study demonstrate that KIFs utilize a range of HR practices that enable different learning orientations, based on the type of innovation compatible with their organizational goals.

3D mesenchymal stem/stromal cell osteogenesis and autocrine signalling

Mesenchymal stem/stromal cells (MSC) are rapidly becoming a leading candidate for use in tissue regeneration, with first generation of therapies being approved for use in orthopaedic repair applications. Capturing the full potential of MSC will likely require the development of novel in vitro culture techniques and devices. Herein we describe the development of a straightforward surface modification of an existing commercial product to enable the efficient study of three dimensional (3D) human bone marrow-derived MSC osteogenic differentiation. Hundreds of 3D microaggregates, of either 42 or 168 cells each, were cultured in osteogenic induction medium and their differentiation was compared with that occurring in traditional two dimensional (2D) monolayer cultures. Osteogenic gene expression and matrix composition was significantly enhanced in the 3D microaggregate cultures. Additionally, BMP-2 gene expression was significantly up-regulated in 3D cultures at day 3 and 7 by approximately 25- and 30-fold, respectively. The difference in BMP-2 gene expression between 2D and 3D cultures was negligible in the more mature day 14 osteogenic cultures. These data support the notion that BMP-2 autocrine signalling is up-regulated in 3D MSC cultures, enhancing osteogenic differentiation. This study provides both mechanistic insight into MSC differentiation, as well as a platform for the efficient generation of microtissue units for further investigation or use in tissue engineering applications.

The culture of the journey as structure of the landscape: an inquiry on mobility facilities and identity of place

The structure of the travel, meant as cultural activity, is proposed as a key to read and design the urban or rural landscape.

Creative industries and innovation in a knowledge economy

The cultural and creative industries contribute to the knowledge economy by their role in reproducing cultural knowledge and through provision of entertainment, experience and leisure goods with cultural content, for which they are widely acknowledged as suffering serious market failure problems (Baumol and Bowen, 1966; Throsby and Withers, 1979). But they also contribute to the innovation process, an aspect that has only recently been appreciated. Specifically, the creative industries are a driver of the knowledge economy by their contribution to the innovation process on the demand side of consumer uptake of new ideas and by their facilitation of consumer-producer interaction. The creative industries are, in this respect, a legitimate part of the innovation system of a knowledge economy.

Integrity, attribution, and exploitation : contractual and normative moral rights protection in open licensing

Over the last twenty years, the use of open content licenses has become increasingly and surprisingly popular. The use of such licences challenges the traditional incentive-based model of exclusive rights under copyright. Instead of providing a means to charge for the use of particular works, what seems important is mitigating against potential personal harm to the author and, in some cases, preventing non-consensual commercial exploitation. It is interesting in this context to observe the primacy of what are essentially moral rights over the exclusionary economic rights. The core elements of common open content licences map somewhat closely to continental conceptions of the moral rights of authorship. Most obviously, almost all free software and free culture licences require attribution of authorship. More interestingly, there is a tension between social norms developed in free software communities and those that have emerged in the creative arts over integrity and commercial exploitation. For programmers interested in free software, licence terms that prohibit commercial use or modification are almost completely inconsistent with the ideological and utilitarian values that underpin the movement. For those in the creative industries, on the other hand, non-commercial terms and, to a lesser extent, terms that prohibit all but verbatim distribution continue to play an extremely important role in the sharing of copyright material. While prohibitions on commercial use often serve an economic imperative, there is also a certain personal interest for many creators in avoiding harmful exploitation of their expression – an interest that has sometimes been recognised as forming a component of the moral right of integrity. One particular continental moral right – the right of withdrawal – is present neither in Australian law or in any of the common open content licences. Despite some marked differences, both free software and free culture participants are using contractual methods to articulate the norms of permissible sharing. Legal enforcement is rare and often prohibitively expensive, and the various communities accordingly rely upon shared understandings of acceptable behaviour. The licences that are commonly used represent a formalised expression of these community norms and provide the theoretically enforceable legal baseline that lends them legitimacy. The core terms of these licences are designed primarily to alleviate risk in sharing and minimise transaction costs in sharing and using copyright expression. Importantly, however, the range of available licences reflect different optional balances in the norms of creating and sharing material. Generally, it is possible to see that, stemming particularly from the US, open content licences are fundamentally important in providing a set of normatively accepted copyright balances that reflect the interests sought to be protected through moral rights regimes. As the cost of creation, distribution, storage, and processing of expression continues to fall towards zero, there are increasing incentives to adopt open content licences to facilitate wide distribution and reuse of creative expression. Thinking of these protocols not only as reducing transaction costs but of setting normative principles of participation assists in conceptualising the role of open content licences and the continuing tensions that permeate modern copyright law.

Queer, student, activism

Queer student activists are a visible aspect of Australian tertiary communities. I explore the findings of interviews with eight queer student activists, whom were active between 2003 and 2006, in which they discuss their understandings of queer student activism and the way they see the university setting shaping their activism. These findings illustrate how the intersections of queer, student, activism, and their associated contexts, create a particular type of activism. This article thus contributes to queer history by demonstrating how one specific cultural subset does queer activism.

Domestic energy monitoring in Victorian households with PV solar installations : feasibility report for GV Community Energy

Australia requires decisive action on climate change and issues of sustainability. The Urban Informatics Research Lab has been funded by the Queensland State Government to conduct a three year study (2009 – 2011) exploring ways to support Queensland residents in making more sustainable consumer and lifestyle choices. We conduct user-centred design research that inform the development of real-time, mobile, locational, networked information interfaces, feedback mechanisms and persuasive and motivational approaches that in turn assist in-situ decision making and environmental awareness in everyday settings. The study aims to deliver usable and useful prototypes offering individual and collective visualisations of ecological impact and opportunities for engagement and collaboration in order to foster a participatory and sustainable culture of life in Australia. Raising people’s awareness with environmental data and educational information does not necessarily trigger sufficient motivation to change their habits towards a more environmentally friendly and sustainable lifestyle. Our research seeks to develop a better understanding how to go beyond just informing and into motivating and encouraging action and change. Drawing on participatory culture, ubiquitous computing, and real-time information, the study delivers research that leads to viable new design approaches and information interfaces which will strengthen Australia’s position to meet the targets of the Clean Energy Future strategy, and contribute to the sustainability of a low-carbon future in Australia. As part of this program of research, the Urban Informatics Research Lab has been invited to partner with GV Community Energy Pty Ltd on a project funded by the Victorian Government Sustainability Fund. This feasibility report specifically looks at the challenges and opportunities of energy monitoring in households in Victoria that include a PV solar installation. The report is structured into two parts: In Part 1, we first review a range of energy monitoring solutions, both stand-alone and internet-enabled. This section primarily focusses on the technical capacilities. However, in order to understand this information and make an informed decision, it is crucial to understand the basic principles and limitations of energy monitoring as well as the opportunities and challenges of a networked approach towards energy monitoring which are discussed in Section 2.

Waterfall : Nature and Culture

Many people take pleasure in visiting waterfalls and much has been written on the subject. Numerous accounts of Niagara Falls were published after Hennepin's late seventeenth-centure descriptions, particularly from the early nineteenth century, but is was only later that other waterfalls became the subject of books. George Holley's Niagara and Other Famous Cataracts of the World, published in 1883, and John Gibson's Great Waterfalls, Cataracts and Geysers, published in 1887, are early examples of global accounts of major falls. Most books about waterfalls are guides to the falls of a particular country, state or region. Apart from a few slim illustrated volumes, few books have been puslished on the world's waterfalls since Edward Rashleigh's Among the Waterfalls (1935). Most of these are slim pictorial volumes, some aimed at the children's market. Geologist Richard Maxwell Pearl published a series of waterfall articles in his journal Earth Science between 1973 and 1975, apparently with the intention of turning them into a book, but this never materialized. My book, the culmination of more than a decade of waterfalls research, is comprehensive in its approach, but is not intended to describe as many of the world's waterfalls as possible. This is far from my aim, and readers may be disappointed at my omission of falls they feel deserved mention. What I have attempted to do is celebrate the delights of these beautiful wonders of nature by considering them from many points of view, emphasizing the roles that they play in the human experience. To be as representative as possible, I draw on examples of waterfalls from all over the world, some famous, many not. North and South America, Europe, Africa, Asia and Oceania and, with recent global warming, the Earth's polar regions, all feature in the discussion. Even though there are already enough books and articles about Niagara Falls to fill a large library, it has been impossible to avoid making frequent reference to this great cataract, which has been so important in the history of travel and tourism, power generation, urban development and art. Amoung the issues that I consider is the human impact on waterfalls, particularly the effects of hydropower schemes and tourism development. Also considered are artificial waterfalls, which have long been features of the designed landscape. Their contemporay role is poignantly exemplified in the design of the National September 11 Memorial, in which the footprints of the Twin Towers are traced by walls of waterfalls. A geographer and urban and regional planner by training, I have ventured into many other fields of knowledge that are outside my areas of expertise. I apologize for any errors that I may have made in my book and invite correction.

Creative industries in China : art, design and media

Creative industries in China provides a fresh account of China’s emerging commercial cultural sector. The author shows how developments in Chinese art, design and media industries are reflected in policy, in market activity, and grassroots participation. Never has the attraction of being a media producer, an artist, or a designer in China been so enticing. National and regional governments offer financial incentives; consumption of cultural goods and services have increased; creative workers from Europe, North America and Asia are moving to Chinese cities; culture is increasingly positioned as a pillar industry. But what does this mean for our understanding of Chinese society? Can culture be industrialised following the low-cost model of China’s manufacturing economy. Is the national government really committed to social liberalisation? This engaging book is a valuable resource for students and scholars interested in social change in China. It draws on leading Chinese scholarship together with insights from global media studies, economic geography and cultural studies.

Creative industries after the first decade of debate

It has now been over a decade since the concept of creative industries was first put into the public domain by the Blair Labour government’s Creative Industries Mapping Documents in Britain. The concept has gained traction globally, but it has also been understood and developed in different ways in Europe, Asia, Australia, New Zealand, and North America, as well as through international bodies such as UNCTAD and UNESCO. A review of the policy literature reveals that although questions and issues remain around definitional coherence, there is some degree of consensus emerging about the size, scope, and significance of the sectors in question in both advanced and developing economies. At the same time, debate about the concept remains highly animated in media, communication, and cultural studies, with its critics dismissing the concept outright as a harbinger of neoliberal ideology in the cultural sphere. This article couches such critiques in light of recent debates surrounding the intellectual coherence of the concept of neoliberalism, arguing that this term itself possesses problems when taken outside of the Anglo-American context in which it originated. It is argued that issues surrounding the nature of participatory media culture, the relationship between cultural production and economic innovation, and the future role of public cultural institutions can be developed from within a creative industries framework and that writing off such arguments as a priori ideological and flawed does little to advance debates about twentieth-century information and media culture.

Mutans Streptococci and Lactobacilli Colonization in Predentate Children from the Neonatal Period to Seven Months of Age

Background/Aims: The aim of this study was to investigate the colonization of mutans streptococci (MS) and lactobacilli (LB) in predentate children from the neonatal period to 7 months. Methods: A total of 957 mother-and-child pairs were recruited from birth and followed up at 7 months. The 283 children who did not have erupted teeth at the second visit were included in the study. Oral mucosal swabs were taken, and the presence of MS and LB was determined using a commercial microbiological culture kit. Results: At mean ages of 34 days and 7 months, 9 and 11% of the infants, respectively, showed the presence of MS. In contrast, LB presence increased from 24 to 47% (p < 0.0001). MS presence in the neonatal period was associated with maternal MS counts of >105 CFU/ml (p = 0.05), while LB presence was associated with natural birth (p = 0.03) and maternal LB presence (p = 0.02). At 7 months, MS presence was associated with maternal MS counts (p = 0.02) and LB counts of >105 CFU/ml (p = 0.007). Additional predictors of MS presence at 7 months were a child’s MS counts of >105 CFU/ml at the neonatal visit (p = 0.019) and nighttime bottle feeding (p = 0.024). LB presence at 7 months was associated with maternal LB (p < 0.001) and MS presence (p = 0.02). Conclusions: MS and LB can be detected by culture in the oral cavity as early as 34 days after birth. Their infection rates increase to 11 and 47%, respectively, by the time the children reach the end of the predentate stage of oral development.

Branding "Created in China" : the rise of Chinese fashion designers

This article discusses the importance of aesthetic recognition and branding for Chinese fashion designers as prerequisites for their successful positioning in a globalized marketplace. Fundamental to this process is the communication of their aesthetic in their branding process. In addition, the emergence of fashion designers of Asian-American descent who align their creative vision with a globally mainstream audience has created momentum for the new generation of mainland Chinese designers. Chinese creativity is moving to center stage as the country’s role as a leading consumer market with brands of domestic origin strengthens. Thus the aim of this article is to uncover the tension between what is, on the one hand, the need to embrace a global market, and, on the other, the desire to create the elements of a distinctly Chinese brand through aesthetic references to Chinese culture and iconography. We argue that one core element of branding is reference to heritage and tradition. Therefore to satisfy an increasingly sophisticated Chinese consumer, Chinese designers need to be able to incorporate these elements into a characteristic and well-promoted personal vision.