Catching Reality or Bowing Disciplines: How to Move the Study of Citizenship

In his contribution, Joppke justifies his selection of foundational scholars by linking each to what he sees as the three key facets of citizenship: status, rights and identity. Maarten Vink explicitly links his research agenda to the first, status, and outlines why it is so important. In identifying three facets of citizenship, Joppke acknowledges that some academics would include political participation, but he ultimately decides against it. But here we can, and should, broaden citizenship studies by bringing in insights from the behavioral politics tradition in domestic politics - when and why people engage in political acts - and from the social movements literature in sociology. I believe that the American debate on immigration reform, admittedly stalled, would not have advanced as far as it has without the social movement activism of DREAMers - unauthorized young people pushing for a path to citizenship - and the belief that Barack Obama won re-election in part because of the Latino vote. Importantly, one type of political activism demands formal citizenship, the other does not. As many contributors note, the “national models” approach has had a significant impact on citizenship studies. Whether one views such models through a cultural, institutional or historical lens, this tends to be a top-down, macro-level framework. What about immigrants’ agency? In Canada, although the ruling Conservative government is shifting citizenship discourse to a more traditional language - as Winter points out - it has not reduced immigration, ended dual citizenship, or eliminated multiculturalism, all goals of the Reform Party that the current prime minister once helped build. “Lock-in” effects (or policy feedback loops) based on high immigrant naturalization and the coming of age of a second-generation with citizenship also d emands study, in North America and elsewhere. Much of the research thus far suggests that political decisions over citizenship status and rights do not seem linked to immigrants’ political activism. State-centered decision-making may have characterized policy in the early post-World War II period in Europe (and East Asia?), but does it continue to hold today? Majority publics and immigrant-origin residents are increasingly politicized around citizenship and immigration. Does immigrant agency extend citizenship status, rights and identity to those born outside the polity? Is electoral power key, or is protest necessary? How is citizenship practiced, and contested, irrespective of formal status? These are important and understudied empirical questions, ones that demand theoretical creativity - across sub-fields and disciplines - in conceptualizing and understanding citizenship in contemporary times.

Iniciativas institucionales y asociativas destinadas a la integración sociocultural a través del deporte en París y Madrid

El deporte como fenómeno social y cultural ha sido ampliamente reivindicado por sus virtudes integradoras. A la actividad físico-deportiva, ya sea de competición o recreativa, se le han atribuido unos valores integradores que permitirían un ascenso de estatus social, argumento justificado en parte por los éxitos de jugadores de origen inmigrante en el deporte profesional. Por otro lado, el tejido asociativo, y especialmente el generado por la comunidad migrante, también utiliza la organización deportiva como forma de solidaridad y reivindicación identitaria. El objetivo de la tesis es analizar la formulación de los programas deportivos formulados a nivel político y asociativo en los barrios con mayor presencia de jóvenes inmigrantes y/o de segunda generación de París y Madrid destinadas a su integración sociocultural y analizar la implementación de dichas iniciativas. El método de recogida de datos consistió en la realización de 72 entrevistas en profundidad a varios niveles de responsabilidad política y de tipología de entidades sociales, así como el análisis documental de fuentes institucionales y asociativas. Los resultados muestran diferencias entre el planteamiento y la ejecución de las iniciativas condicionadas por el modelo de integración de cada contexto –oposición del modelo republicano en París al deporte comunitarista– y por la situación de crisis económica –fragilidad de los programas por el recorte presupuestario y subvenciones en el contexto madrileño–. Las conclusiones de esta tesis buscan profundizar en la verdadera contribución del deporte a la integración social y cultural de los jóvenes de origen inmigrante, y por extensión, a las sociedades culturalmente plurales. RÉSUMÉ Le sport en tant que phénomène social et culturel a été largement revendiqué pour ses vertus intégratrices. À l'activité physique et sportive, en forme de compétition où de loisirs, ont a attribué certaines valeurs intégratrices qui permettent une ascension de statut social, argument justifié en partie par le succès des joueurs d'origine immigrée dans le sport professionnel. Par ailleurs, le tissu associatif, et surtout celui engendré par la communauté migrante, a également utilisé l'organisation sportive comme une forme de solidarité et de revendication identitaire. L'objectif de la thèse est d'analyser la formulation des programmes sportifs à niveau politique et associatif dans les quartiers ayant une plus grande présence de jeunes immigrants et / ou deuxième génération de Paris et de Madrid, destinés à leur intégration socioculturelle et d'analyser la mise en oeuvre de ces initiatives. La méthode de collecte de données était de mener 72 entretiens semi-structurés à différents niveaux de responsabilité politique et de typologie des entités sociales, ainsi que l'analyse documentaire des sources officielles et associatives. Les résultats montrent des différences entre l'approche et la mise en oeuvre d'initiatives conditionnées par le modèle d'intégration de chaque contexte –l'opposition du modèle républicain à Paris envers le sport communautariste– et par la situation de crise économique –fragilité des programmes par les compressions budgétaires et les subventions dans le contexte madrilène–. Les conclusions de cette thèse visent à approfondir la véritable contribution du sport à l'intégration sociale et culturelle des jeunes immigrants, et, par extension, des sociétés culturellement plurielles. ABSTRACT Sport as a social and cultural phenomenon has been widely claimed by its integrative virtues. Whether competition or recreational, sport has been claimed for some integrative values that allow a rise in social status justified in part by the success of immigrant origin players in professional sports. On the other hand, associations, and especially those generated by the migrant community, also uses sports organization as a form of solidarity and identity recognition. The aim of the thesis is double: to understand the formulation of sports programs intended for sociocultural integration designed by political and and associative entities in neighborhoods with greater presence of young immigrants and/or second generation of Paris and Madrid and to analyze the implementation of such initiatives. The method of data collection was to conduct 72 in-depth interviews to various levels of political responsibility and typology of social entities and documentary analysis of institutional and associative sources. The results show differences between the approach and implementation of initiatives conditioned by the integration model of each context –an opposition of the republican model in Paris from ethnic sports– and the situation of economic crisis –programs weakness due to budget cuts and subsidies in the Madrid–. The conclusions of this thesis aim to deepen the true contribution of sport to social and cultural integration of young immigrants, and by extension, to culturally plural societies.

Life pathways of Haitian-American young adults in South Florida

This research examines the life pathways of 1.5 and second generation Haitian immigrants in South Florida. The purpose of the research is to better understand how integration occurs for the children of Haitian immigrants as they transition from adolescence to adulthood. Building upon a prior study of second-generation immigrant adolescents between 1995 and 2000, a sub-set of the original participants was located to participate in this follow-up research. Qualitative interviews were conducted as well as in-depth ethnographic research, including participant observation. Survey instruments used with other second-generation populations were also administered, enabling comparisons with the Children of Immigrants Longitudinal Study (CILS). The results indicate that educational and occupational achievements were markedly below the participants’ original expectations as adolescents. Gender figures prominently in participants’ familial roles and relationships, with men and women distinctly incorporating both Haitian and American cultural practices within their households. Contrary to previous research, these results on the identification of participants suggest that these young adults claim attachment to both Haiti and to the United States. The unique longitudinal and ethnographic nature of this study contributes to the ongoing discussion of the integration of the children of immigrants by demonstrating significant variation from the prior integration trends observed with Haitian adolescents. The results cast doubt on existing theory on the children of immigrants for explaining the trajectory of Haitian-American integration patterns. Specifically, this research indicates that Haitians are not downwardly mobile and integrating as African Americans. They have higher education and economic standing than their parents and are continuing their education well into their thirties. The respondents have multiple identities in which they increasingly express identification with Haiti, but in some contexts are also developing racialized identifications with African Americans and others of the African diaspora.

Tangible mobile app store design for China's new generation migrant worker

China has the largest numbers of Internet users and mobile phone subscribers in the world, as well as the most extensive peacetime internal migration on the planet. Mobile phone uses play a very important role in migrant responses to alienation and discrimination. There are 150 million to 200 million migrant workers in China, 60% of them are the second-generation migrant workers. They support the nation’s manufacturing and industry. The majority of these individuals is poor and is from rural areas of the country. These young people are currently ignored by mainstream mobile device manufacturers, even though this constituency will be a growing consumptive segment in the future. Thus, my research will target the new-generation migrant workers in China, and concentrates on their mobile lives to best develop a tangible mobile devices application store that will improve their mobile experiences.

Comunicación para la inclusión social de minorías. La Clase Mágica, un modelo de intervención para el cambio social

Las minorías culturales y étnicas son con frecuencia los grupos más desfavorecidos en términos sociales y económicos debido a su falta de representación institucional. El objetivo de este artículo es proponer un modelo de intervención capaz de aumentar el poder de participación de una minoría a través de la comunicación horizontal con otras identidades mayoritarias. Los resultados del estudio de caso del programa socioeducativo La Clase Mágica, para el que se utiliza una metodología eminentemente cuantitativa a partir de cuestionario, demuestran que estos aspectos contribuyen a que los mexicanos de primera y segunda generación en el sur de California desarrollen capacidades clave para el empoderamiento y la inclusión social. Además, el programa impactó en un factor determinante para que una comunidad consiga ganar poder de acción y voz suficiente para influir en las instituciones sociales: los apoyos externos.

On the feasibility of using servo-mechanisms in wireless multimedia sensor network deployments

This paper considers the use of servo-mechanisms as part of a tightly integrated homogeneous Wireless Multi- media Sensor Network (WMSN). We describe the design of our second generation WMSN node platform, which has increased image resolution, in-built audio sensors, PIR sensors, and servo- mechanisms. These devices have a wide disparity in their energy consumption and in the information quality they return. As a result, we propose a framework that establishes a hierarchy of devices (sensors and actuators) within the node and uses frequent sampling of cheaper devices to trigger the activation of more energy-hungry devices. Within this framework, we consider the suitability of servos for WMSNs by examining the functional characteristics and by measuring the energy consumption of 2 analog and 2 digital servos, in order to determine their impact on overall node energy cost. We also implement a simple version of our hierarchical sampling framework to evaluate the energy consumption of servos relative to other node components. The evaluation results show that: (1) the energy consumption of servos is small relative to audio/image signal processing energy cost in WMSN nodes; (2) digital servos do not necessarily consume as much energy as is currently believed; and (3) the energy cost per degree panning is lower for larger panning angles.

Resorbable composite scaffolds for bone tissue engineering

Bone loss associated with trauma osteo-degenerative diseases and tumors has tremendous socioeconomic impact related to personal and occupation disability and health care costs. Bone grafting is often critical to surgical therapies. Autogenous bone is presently the preferred grafting material; however, this holds several disadvantages such as donor site morbidity. In the present climate of increasing life expectancy with an ensuing increase in bone-related injuries, orthopaedic surgery is undergoing a paradigm shift from bone-grafting to bone engineering, where a scaffold is implanted to provide adequate load bearing and enhance tissue regeneration. Our group at Queensland University of Technology (QUT) have developed, characterised and tested polycaprolactone/ tricalcium phosphate (PCL/TCP) composite scaffolds for low load-bearing bone defects. These scaffolds are being further developed for application in higher load bearing sites. Our approach emphasizes the importance of the biomaterials’ structural design, the scaffold architecture and structural and nutritional requirements for cell culture. These first-generation scaffolds made from medical grade PCL (mPCL) have been studied for more than 5 years within a clinical setting 1. This paper describes the application of second-generation scaffolds in small and large animal bone defect models and the ensuing bone regeneration as shown by histology and µCT.

The ghrelin receptor isoforms (GHS-R1a and GHS-R1b) and GPR39 : an investigation into receptor dimerisation

Prostate cancer is the second most common cause of cancer-related deaths in Western males. Current diagnostic, prognostic and treatment approaches are not ideal and advanced metastatic prostate cancer is incurable. There is an urgent need for improved adjunctive therapies and markers for this disease. GPCRs are likely to play a significant role in the initiation and progression of prostate cancer. Over the last decade, it has emerged that G protein coupled receptors (GPCRs) are likely to function as homodimers and heterodimers. Heterodimerisation between GPCRs can result in the formation of novel pharmacological receptors with altered functional outcomes, and a number of GPCR heterodimers have been implicated in the pathogenesis of human disease. Importantly, novel GPCR heterodimers represent potential new targets for the development of more specific therapeutic drugs. Ghrelin is a 28 amino acid peptide hormone which has a unique n-octanoic acid post-translational modification. Ghrelin has a number of important physiological roles, including roles in appetite regulation and the stimulation of growth hormone release. The ghrelin receptor is the growth hormone secretagogue receptor type 1a, GHS-R1a, a seven transmembrane domain GPCR, and GHS-R1b is a C-terminally truncated isoform of the ghrelin receptor, consisting of five transmembrane domains. Growing evidence suggests that ghrelin and the ghrelin receptor isoforms, GHS-R1a and GHS-R1b, may have a role in the progression of a number of cancers, including prostate cancer. Previous studies by our research group have shown that the truncated ghrelin receptor isoform, GHS-R1b, is not expressed in normal prostate, however, it is expressed in prostate cancer. The altered expression of this truncated isoform may reflect a difference between a normal and cancerous state. A number of mutant GPCRs have been shown to regulate the function of their corresponding wild-type receptors. Therefore, we investigated the potential role of interactions between GHS-R1a and GHS-R1b, which are co-expressed in prostate cancer and aimed to investigate the function of this potentially new pharmacological receptor. In 2005, obestatin, a 23 amino acid C-terminally amidated peptide derived from preproghrelin was identified and was described as opposing the stimulating effects of ghrelin on appetite and food intake. GPR39, an orphan GPCR which is closely related to the ghrelin receptor, was identified as the endogenous receptor for obestatin. Recently, however, the ability of obestatin to oppose the effects of ghrelin on appetite and food intake has been questioned, and furthermore, it appears that GPR39 may in fact not be the obestatin receptor. The role of GPR39 in the prostate is of interest, however, as it is a zinc receptor. Zinc has a unique role in the biology of the prostate, where it is normally accumulated at high levels, and zinc accumulation is altered in the development of prostate malignancy. Ghrelin and zinc have important roles in prostate cancer and dimerisation of their receptors may have novel roles in malignant prostate cells. The aim of the current study, therefore, was to demonstrate the formation of GHS-R1a/GHS-R1b and GHS-R1a/GPR39 heterodimers and to investigate potential functions of these heterodimers in prostate cancer cell lines. To demonstrate dimerisation we first employed a classical co-immunoprecipitation technique. Using cells co-overexpressing FLAG- and Myc- tagged GHS-R1a, GHS-R1b and GPR39, we were able to co-immunoprecipitate these receptors. Significantly, however, the receptors formed high molecular weight aggregates. A number of questions have been raised over the propensity of GPCRs to aggregate during co-immunoprecipitation as a result of their hydrophobic nature and this may be misinterpreted as receptor dimerisation. As we observed significant receptor aggregation in this study, we used additional methods to confirm the specificity of these putative GPCR interactions. We used two different resonance energy transfer (RET) methods; bioluminescence resonance energy transfer (BRET) and fluorescence resonance energy transfer (FRET), to investigate interactions between the ghrelin receptor isoforms and GPR39. RET is the transfer of energy from a donor fluorophore to an acceptor fluorophore when they are in close proximity, and RET methods are, therefore, applicable to the observation of specific protein-protein interactions. Extensive studies using the second generation bioluminescence resonance energy transfer (BRET2) technology were performed, however, a number of technical limitations were observed. The substrate used during BRET2 studies, coelenterazine 400a, has a low quantum yield and rapid signal decay. This study highlighted the requirement for the expression of donor and acceptor tagged receptors at high levels so that a BRET ratio can be determined. After performing a number of BRET2 experimental controls, our BRET2 data did not fit the predicted results for a specific interaction between these receptors. The interactions that we observed may in fact represent ‘bystander BRET’ resulting from high levels of expression, forcing the donor and acceptor into close proximity. Our FRET studies employed two different FRET techniques, acceptor photobleaching FRET and sensitised emission FRET measured by flow cytometry. We were unable to observe any significant FRET, or FRET values that were likely to result from specific receptor dimerisation between GHS-R1a, GHS-R1b and GPR39. While we were unable to conclusively demonstrate direct dimerisation between GHS-R1a, GHS-R1b and GPR39 using several methods, our findings do not exclude the possibility that these receptors interact. We aimed to investigate if co-expression of combinations of these receptors had functional effects in prostate cancers cells. It has previously been demonstrated that ghrelin stimulates cell proliferation in prostate cancer cell lines, through ERK1/2 activation, and GPR39 can stimulate ERK1/2 signalling in response to zinc treatments. Additionally, both GHS-R1a and GPR39 display a high level of constitutive signalling and these constitutively active receptors can attenuate apoptosis when overexpressed individually in some cell types. We, therefore, investigated ERK1/2 and AKT signalling and cell survival in prostate cancer the potential modulation of these functions by dimerisation between GHS-R1a, GHS-R1b and GPR39. Expression of these receptors in the PC-3 prostate cancer cell line, either alone or in combination, did not alter constitutive ERK1/2 or AKT signalling, basal apoptosis or tunicamycin-stimulated apoptosis, compared to controls. In summary, the potential interactions between the ghrelin receptor isoforms, GHS-R1a and GHS-R1b, and the related zinc receptor, GPR39, and the potential for functional outcomes in prostate cancer were investigated using a number of independent methods. We did not definitively demonstrate the formation of these dimers using a number of state of the art methods to directly demonstrate receptor-receptor interactions. We investigated a number of potential functions of GPR39 and GHS-R1a in the prostate and did not observe altered function in response to co-expression of these receptors. The technical questions raised by this study highlight the requirement for the application of extensive controls when using current methods for the demonstration of GPCR dimerisation. Similar findings in this field reflect the current controversy surrounding the investigation of GPCR dimerisation. Although GHS-R1a/GHS-R1b or GHS-R1a/GPR39 heterodimerisation was not clearly demonstrated, this study provides a basis for future investigations of these receptors in prostate cancer. Additionally, the results presented in this study and growing evidence in the literature highlight the requirement for an extensive understanding of the experimental method and the performance of a range of controls to avoid the spurious interpretation of data gained from artificial expression systems. The future development of more robust techniques for investigating GPCR dimerisation is clearly required and will enable us to elucidate whether GHS-R1a, GHS-R1b and GPR39 form physiologically relevant dimers.

Implementing dance in a Queensland primary school : a descriptive case study

This research documents and analyses the modes of implementation of the Dance component of The Arts Essential Learnings in a Queensland school. The research identifies what makes good practice in dance education and the multiple modes of implementation that support this practice. The primary purpose of this research is to describe the factors that influence dance education, as it is delivered, in a Queensland primary school to inform the development of further support for primary teachers and to improve the quality of dance education in Prep -7 schooling. The literature review investigates dance education both in Queensland, Australia and internationally, identifying current issues related to the delivery of dance in a primary school environment including barriers to implementation of dance, authentic learning and integrated approaches to learning. Based on Engestrom.s reformulation of Vygotsky.s theory of socially mediated learning, the implementation of dance education curriculum was explored through descriptive case study method. The case study was conducted in a regional Queensland school identified as delivering the dance curriculum in a variety of ways. The research project provided opportunities to observe, document and analyse how teachers deal with pedagogical dilemmas and solve logistical problems associated with teaching the dance component of the Arts curriculum in this school. Teachers. practices were contextualised through investigation of the whole school context of dance curriculum development. The findings revealed a range of teaching approaches that influenced teachers. interpretation and children.s experience of the dance curriculum. The features of a supportive whole school and cultural environment for dance were identified. These have been captured in a reworked version of Engestrom.s Second Generation Activity Theory that can be applied to the implementation of dance education in primary schools.

Incremental entrepreneurship : best practice professionalization across generations

This chapter will introduce Australia’s Dennis family – a case of ‘incremental entrepreneurship’ in the business transition from the first to the second generation. Following the second generation’s formal involvement and ownership in the business, Dennis Family Corporation (DFC) undertook a major professionalization process to formalize the family business and ensure its continued success. The members of the second generation have successfully sustained the entrepreneurial spirit of their family business (albeit in a different style), adding value to the firm in an ‘incremental’ manner. Throughout the chapter there will be a strong emphasis on the family element of DFC and the roles that each family member has played. Bert Dennis, as the founder and incumbent leader of the firm, has witnessed major changes to the business he built from the ground up. His children, in particular his son Grant Dennis as the primary next generation issue champion, have seen the changes from another perspective – ensuring the business remains within the family into the second generation and beyond. The professionalization process was sparked by a commitment from the second generation to continue to ‘make a real go’ of the family business rather than simply liquidating and distributing the assets. The dedication of all the family members to this objective has ensured the success of this process, and ultimately, the longevity of the firm. Although DFC has become more ‘professional’, it has not lost its entrepreneurial character; rather, it has improved the ways in which entrepreneurialism is fostered and pursued in the company. In essence, this case outlines how the implementation of appropriate governance and management practices has allowed the Dennis family to overcome the challenges and maximize the opportunities associated with owning and operating a multigenerational family fi rm. From a theoretical perspective, this case uses the concepts of entrepreneurial orientation (EO) (Lumpkin and Dess 1996) and the resource- based view (RBV) (Habbershon and Williams 1999; Barney 1991; Wernerfelt 1984) to demonstrate how the fi rm has leveraged its familiness to foster an enduring spirit of entrepreneurship and to maintain a sustained competitive advantage.

Rational design of serine protease inhibitors

Proteases regulate a spectrum of diverse physiological processes, and dysregulation of proteolytic activity drives a plethora of pathological conditions. Understanding protease function is essential to appreciating many aspects of normal physiology and progression of disease. Consequently, development of potent and specific inhibitors of proteolytic enzymes is vital to provide tools for the dissection of protease function in biological systems and for the treatment of diseases linked to aberrant proteolytic activity. The studies in this thesis describe the rational design of potent inhibitors of three proteases that are implicated in disease development. Additionally, key features of the interaction of proteases and their cognate inhibitors or substrates are analysed and a series of rational inhibitor design principles are expounded and tested. Rational design of protease inhibitors relies on a comprehensive understanding of protease structure and biochemistry. Analysis of known protease cleavage sites in proteins and peptides is a commonly used source of such information. However, model peptide substrate and protein sequences have widely differing levels of backbone constraint and hence can adopt highly divergent structures when binding to a protease’s active site. This may result in identical sequences in peptides and proteins having different conformations and diverse spatial distribution of amino acid functionalities. Regardless of this, protein and peptide cleavage sites are often regarded as being equivalent. One of the key findings in the following studies is a definitive demonstration of the lack of equivalence between these two classes of substrate and invalidation of the common practice of using the sequences of model peptide substrates to predict cleavage of proteins in vivo. Another important feature for protease substrate recognition is subsite cooperativity. This type of cooperativity is commonly referred to as protease or substrate binding subsite cooperativity and is distinct from allosteric cooperativity, where binding of a molecule distant from the protease active site affects the binding affinity of a substrate. Subsite cooperativity may be intramolecular where neighbouring residues in substrates are interacting, affecting the scissile bond’s susceptibility to protease cleavage. Subsite cooperativity can also be intermolecular where a particular residue’s contribution to binding affinity changes depending on the identity of neighbouring amino acids. Although numerous studies have identified subsite cooperativity effects, these findings are frequently ignored in investigations probing subsite selectivity by screening against diverse combinatorial libraries of peptides (positional scanning synthetic combinatorial library; PS-SCL). This strategy for determining cleavage specificity relies on the averaged rates of hydrolysis for an uncharacterised ensemble of peptide sequences, as opposed to the defined rate of hydrolysis of a known specific substrate. Further, since PS-SCL screens probe the preference of the various protease subsites independently, this method is inherently unable to detect subsite cooperativity. However, mean hydrolysis rates from PS-SCL screens are often interpreted as being comparable to those produced by single peptide cleavages. Before this study no large systematic evaluation had been made to determine the level of correlation between protease selectivity as predicted by screening against a library of combinatorial peptides and cleavage of individual peptides. This subject is specifically explored in the studies described here. In order to establish whether PS-SCL screens could accurately determine the substrate preferences of proteases, a systematic comparison of data from PS-SCLs with libraries containing individually synthesised peptides (sparse matrix library; SML) was carried out. These SML libraries were designed to include all possible sequence combinations of the residues that were suggested to be preferred by a protease using the PS-SCL method. SML screening against the three serine proteases kallikrein 4 (KLK4), kallikrein 14 (KLK14) and plasmin revealed highly preferred peptide substrates that could not have been deduced by PS-SCL screening alone. Comparing protease subsite preference profiles from screens of the two types of peptide libraries showed that the most preferred substrates were not detected by PS SCL screening as a consequence of intermolecular cooperativity being negated by the very nature of PS SCL screening. Sequences that are highly favoured as result of intermolecular cooperativity achieve optimal protease subsite occupancy, and thereby interact with very specific determinants of the protease. Identifying these substrate sequences is important since they may be used to produce potent and selective inhibitors of protolytic enzymes. This study found that highly favoured substrate sequences that relied on intermolecular cooperativity allowed for the production of potent inhibitors of KLK4, KLK14 and plasmin. Peptide aldehydes based on preferred plasmin sequences produced high affinity transition state analogue inhibitors for this protease. The most potent of these maintained specificity over plasma kallikrein (known to have a very similar substrate preference to plasmin). Furthermore, the efficiency of this inhibitor in blocking fibrinolysis in vitro was comparable to aprotinin, which previously saw clinical use to reduce perioperative bleeding. One substrate sequence particularly favoured by KLK4 was substituted into the 14 amino acid, circular sunflower trypsin inhibitor (SFTI). This resulted in a highly potent and selective inhibitor (SFTI-FCQR) which attenuated protease activated receptor signalling by KLK4 in vitro. Moreover, SFTI-FCQR and paclitaxel synergistically reduced growth of ovarian cancer cells in vitro, making this inhibitor a lead compound for further therapeutic development. Similar incorporation of a preferred KLK14 amino acid sequence into the SFTI scaffold produced a potent inhibitor for this protease. However, the conformationally constrained SFTI backbone enforced a different intramolecular cooperativity, which masked a KLK14 specific determinant. As a consequence, the level of selectivity achievable was lower than that found for the KLK4 inhibitor. Standard mechanism inhibitors such as SFTI rely on a stable acyl-enzyme intermediate for high affinity binding. This is achieved by a conformationally constrained canonical binding loop that allows for reformation of the scissile peptide bond after cleavage. Amino acid substitutions within the inhibitor to target a particular protease may compromise structural determinants that support the rigidity of the binding loop and thereby prevent the engineered inhibitor reaching its full potential. An in silico analysis was carried out to examine the potential for further improvements to the potency and selectivity of the SFTI-based KLK4 and KLK14 inhibitors. Molecular dynamics simulations suggested that the substitutions within SFTI required to target KLK4 and KLK14 had compromised the intramolecular hydrogen bond network of the inhibitor and caused a concomitant loss of binding loop stability. Furthermore in silico amino acid substitution revealed a consistent correlation between a higher frequency of formation and the number of internal hydrogen bonds of SFTI-variants and lower inhibition constants. These predictions allowed for the production of second generation inhibitors with enhanced binding affinity toward both targets and highlight the importance of considering intramolecular cooperativity effects when engineering proteins or circular peptides to target proteases. The findings from this study show that although PS-SCLs are a useful tool for high throughput screening of approximate protease preference, later refinement by SML screening is needed to reveal optimal subsite occupancy due to cooperativity in substrate recognition. This investigation has also demonstrated the importance of maintaining structural determinants of backbone constraint and conformation when engineering standard mechanism inhibitors for new targets. Combined these results show that backbone conformation and amino acid cooperativity have more prominent roles than previously appreciated in determining substrate/inhibitor specificity and binding affinity. The three key inhibitors designed during this investigation are now being developed as lead compounds for cancer chemotherapy, control of fibrinolysis and cosmeceutical applications. These compounds form the basis of a portfolio of intellectual property which will be further developed in the coming years.

Can creativity be taught? And why should it be?

CreativityMoneyLove has an important question at its core – ‘what does the education and skills system need to look like in order for people to lead fulfilled creative lives, and in order for the creative and cultural industries in the UK to thrive?’ It is a question that is currently being asked by politicians and policy makers in different ways, in respect to different sections of industry, as they search for levers to economic growth. The aim of this publication is to give creative practitioners, employers and key thinkers a platform to express their views. Creativity as a concept is not an isolated part of the education system. It has the potential to underpin the entire way we learn, in order to build more imaginative, innovative and thoughtful people who can prosper in a rapidly changing world. It is vital therefore that we ask those at the forefront of their fields how they think the system could and should be changing. We have asked people to consider education in the broadest sense, from the school curriculum to vocational training, from university teaching to informal learning. The opinions expressed here are not our own. Many are overtly political, controversial, inspirational, and contradictory. We wanted to capture those views here, at this particular moment in time, when some key decisions are being made about the future of education in the UK. As two agencies that are in a position to take some of the ideas forward, this is an important part of the process of our own strategic thinking for the future. For A New Direction and Creative & Cultural Skills, the content generated through CreativityMoneyLove will provide the stimulus for a range of conversations, interventions, projects and discussions with young people, policy makers, employers, educators and creative practitioners. The dialogue has started at www.creativitymoneylove.co.uk, where all the pieces are also published online, and the bank of opinion can be added to. Spread the word, and add your own article on the subject.

Renegades on the frontier of innovation: The shanzhai grassroots communities of Shenzhen in China's creative economy

Two Australian researchers specializing in China's creative industries examine recent developments in southern China commonly associated with the shanzhai phenomenon (e.g., production and sale of cheap local facsimiles of globally branded goods). While shanzhai is often condemned as the embodiment of China's "knock-off" industries, the authors argue that it might be more appropriately viewed as an instance of China's emerging creative economy and an example of rapid prototyping. The paper traces the evolution of shanzhai mobile phones and the materialization of the shanzhai ethos in popular culture. In arguing that shanzhai provides inputs into creative industries, the paper describes the fuzzy boundary between formal and informal culture and notes the interaction between three spheres of activity: official culture, the market, and grassroots culture.

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.