Prediction of transcriptional regulatory interactions in bacteria : a comparative genomics approach

Exponential growth of genomic data in the last two decades has made manual analyses impractical for all but trial studies. As genomic analyses have become more sophisticated, and move toward comparisons across large datasets, computational approaches have become essential. One of the most important biological questions is to understand the mechanisms underlying gene regulation. Genetic regulation is commonly investigated and modelled through the use of transcriptional regulatory network (TRN) structures. These model the regulatory interactions between two key components: transcription factors (TFs) and the target genes (TGs) they regulate. Transcriptional regulatory networks have proven to be invaluable scientific tools in Bioinformatics. When used in conjunction with comparative genomics, they have provided substantial insights into the evolution of regulatory interactions. Current approaches to regulatory network inference, however, omit two additional key entities: promoters and transcription factor binding sites (TFBSs). In this study, we attempted to explore the relationships among these regulatory components in bacteria. Our primary goal was to identify relationships that can assist in reducing the high false positive rates associated with transcription factor binding site predictions and thereupon enhance the reliability of the inferred transcription regulatory networks. In our preliminary exploration of relationships between the key regulatory components in Escherichia coli transcription, we discovered a number of potentially useful features. The combination of location score and sequence dissimilarity scores increased de novo binding site prediction accuracy by 13.6%. Another important observation made was with regards to the relationship between transcription factors grouped by their regulatory role and corresponding promoter strength. Our study of E.coli ��70 promoters, found support at the 0.1 significance level for our hypothesis | that weak promoters are preferentially associated with activator binding sites to enhance gene expression, whilst strong promoters have more repressor binding sites to repress or inhibit gene transcription. Although the observations were specific to �70, they nevertheless strongly encourage additional investigations when more experimentally confirmed data are available. In our preliminary exploration of relationships between the key regulatory components in E.coli transcription, we discovered a number of potentially useful features { some of which proved successful in reducing the number of false positives when applied to re-evaluate binding site predictions. Of chief interest was the relationship observed between promoter strength and TFs with respect to their regulatory role. Based on the common assumption, where promoter homology positively correlates with transcription rate, we hypothesised that weak promoters would have more transcription factors that enhance gene expression, whilst strong promoters would have more repressor binding sites. The t-tests assessed for E.coli �70 promoters returned a p-value of 0.072, which at 0.1 significance level suggested support for our (alternative) hypothesis; albeit this trend may only be present for promoters where corresponding TFBSs are either all repressors or all activators. Nevertheless, such suggestive results strongly encourage additional investigations when more experimentally confirmed data will become available. Much of the remainder of the thesis concerns a machine learning study of binding site prediction, using the SVM and kernel methods, principally the spectrum kernel. Spectrum kernels have been successfully applied in previous studies of protein classification [91, 92], as well as the related problem of promoter predictions [59], and we have here successfully applied the technique to refining TFBS predictions. The advantages provided by the SVM classifier were best seen in `moderately'-conserved transcription factor binding sites as represented by our E.coli CRP case study. Inclusion of additional position feature attributes further increased accuracy by 9.1% but more notable was the considerable decrease in false positive rate from 0.8 to 0.5 while retaining 0.9 sensitivity. Improved prediction of transcription factor binding sites is in turn extremely valuable in improving inference of regulatory relationships, a problem notoriously prone to false positive predictions. Here, the number of false regulatory interactions inferred using the conventional two-component model was substantially reduced when we integrated de novo transcription factor binding site predictions as an additional criterion for acceptance in a case study of inference in the Fur regulon. This initial work was extended to a comparative study of the iron regulatory system across 20 Yersinia strains. This work revealed interesting, strain-specific difierences, especially between pathogenic and non-pathogenic strains. Such difierences were made clear through interactive visualisations using the TRNDifi software developed as part of this work, and would have remained undetected using conventional methods. This approach led to the nomination of the Yfe iron-uptake system as a candidate for further wet-lab experimentation due to its potential active functionality in non-pathogens and its known participation in full virulence of the bubonic plague strain. Building on this work, we introduced novel structures we have labelled as `regulatory trees', inspired by the phylogenetic tree concept. Instead of using gene or protein sequence similarity, the regulatory trees were constructed based on the number of similar regulatory interactions. While the common phylogentic trees convey information regarding changes in gene repertoire, which we might regard being analogous to `hardware', the regulatory tree informs us of the changes in regulatory circuitry, in some respects analogous to `software'. In this context, we explored the `pan-regulatory network' for the Fur system, the entire set of regulatory interactions found for the Fur transcription factor across a group of genomes. In the pan-regulatory network, emphasis is placed on how the regulatory network for each target genome is inferred from multiple sources instead of a single source, as is the common approach. The benefit of using multiple reference networks, is a more comprehensive survey of the relationships, and increased confidence in the regulatory interactions predicted. In the present study, we distinguish between relationships found across the full set of genomes as the `core-regulatory-set', and interactions found only in a subset of genomes explored as the `sub-regulatory-set'. We found nine Fur target gene clusters present across the four genomes studied, this core set potentially identifying basic regulatory processes essential for survival. Species level difierences are seen at the sub-regulatory-set level; for example the known virulence factors, YbtA and PchR were found in Y.pestis and P.aerguinosa respectively, but were not present in both E.coli and B.subtilis. Such factors and the iron-uptake systems they regulate, are ideal candidates for wet-lab investigation to determine whether or not they are pathogenic specific. In this study, we employed a broad range of approaches to address our goals and assessed these methods using the Fur regulon as our initial case study. We identified a set of promising feature attributes; demonstrated their success in increasing transcription factor binding site prediction specificity while retaining sensitivity, and showed the importance of binding site predictions in enhancing the reliability of regulatory interaction inferences. Most importantly, these outcomes led to the introduction of a range of visualisations and techniques, which are applicable across the entire bacterial spectrum and can be utilised in studies beyond the understanding of transcriptional regulatory networks.

Ultrafiltration rate is a poor indicator of haemodialysis nursing quality. Commentary on Lindberg and Ludvigsen (2012)

In their paper Lindberg and Ludvigsen (2012) have correctly identified the lack of evidence-based nurse-sensitive indicators measuring the quality of haemodialysis nursing care. The authors suggest that the intradialytic ultrafiltration rate (UFR) (total fluid removed divided by the total time in a single dialysis treatment, measured in litres per hour) may be one such indicator. Importantly it is best practice to minimise high UFRs as they are associated with higher risk of cardiovascular events and vascular access complications (Curatola et al., 2011). However, this does not justify UFR to qualify as a nurse-sensitive indicator of quality in the haemodialysis context. The aim of this response is to voice our concerns over the proposal to use haemodialysis treatment UFR as a haemodialysis nurse-sensitive quality indicator...

Frame-rate stereopsis using non-parametric transforms and programmable logic

A frame-rate stereo vision system, based on non-parametric matching metrics, is described. Traditional metrics, such as normalized cross-correlation, are expensive in terms of logic. Non-parametric measures require only simple, parallelizable, functions such as comparators, counters and exclusive-or, and are thus very well suited to implementation in reprogrammable logic.

Increased sedation requirements in patients receiving extracorporeal membrane oxygenation for respiratory and cardiorespiratory failure

Critically ill patients receiving extracorporeal membrane oxygenation (ECMO) are often noted to have increased sedation requirements. However, data related to sedation in this complex group of patients is limited. The aim of our study was to characterise the sedation requirements in adult patients receiving ECMO for cardiorespiratory failure. A retrospective chart review was performed to collect sedation data for 30 consecutive patients who received venovenous or venoarterial ECMO between April 2009 and March 2011. To test for a difference in doses over time we used a regression model. The dose of midazolam received on ECMO support increased by an average of 18 mg per day (95% confidence interval 8, 29 mg, P=0.001), while the dose of morphine increased by 29 mg per day (95% confidence interval 4, 53 mg, P=0.021) The venovenous group received a daily midazolam dose that was 157 mg higher than the venoarterial group (95% confidence interval 53, 261 mg, P=0.005). We did not observe any significant increase in fentanyl doses over time (95% confidence interval 1269, 4337 µg, P=0.94). There is a significant increase in dose requirement for morphine and midazolam during ECMO. Patients on venovenous ECMO received higher sedative doses as compared to patients on venoarterial ECMO. Future research should focus on mechanisms behind these changes and also identify drugs that are most suitable for sedation during ECMO.

Fatalism, superstition, religion, and culture : road user beliefs and behaviour in Pakistan

Road traffic crashes have emerged as a major health problem around the world. Road crash fatalities and injuries have been reduced significantly in developed countries, but they are still an issue in low and middle-income countries. The World Health Organization (WHO, 2009) estimates that the death toll from road crashes in low- and middle-income nations is more than 1 million people per year, or about 90% of the global road toll, even though these countries only account for 48% of the world's vehicles. Furthermore, it is estimated that approximately 265,000 people die every year in road crashes in South Asian countries and Pakistan stands out with 41,494 approximately deaths per year. Pakistan has the highest rate of fatalities per 100,000 population in the region and its road crash fatality rate of 25.3 per 100,000 population is more than three times that of Australia's. High numbers of road crashes not only cause pain and suffering to the population at large, but are also a serious drain on the country's economy, which Pakistan can ill-afford. Most studies identify human factors as the main set of contributing factors to road crashes, well ahead of road environment and vehicle factors. In developing countries especially, attention and resources are required in order to improve things such as vehicle roadworthiness and poor road infrastructure. However, attention to human factors is also critical. Human factors which contribute to crashes include high risk behaviours like speeding and drink driving, and neglect of protective behaviours such as helmet wearing and seat belt wearing. Much research has been devoted to the attitudes, beliefs and perceptions which contribute to these behaviours and omissions, in order to develop interventions aimed at increasing safer road use behaviours and thereby reducing crashes. However, less progress has been made in addressing human factors contributing to crashes in developing countries as compared to the many improvements in road environments and vehicle standards, and this is especially true of fatalistic beliefs and behaviours. This is a significant omission, since in different cultures in developing countries there are strong worldviews in which predestination persists as a central idea, i.e. that one's life (and death) and other events have been mapped out and are predetermined. Fatalism refers to a particular way in which people regard the events that occur in their lives, usually expressed as a belief that an individual does not have personal control over circumstances and that their lives are determined through a divine or powerful external agency (Hazen & Ehiri, 2006). These views are at odds with the dominant themes of modern health promotion movements, and present significant challenges for health advocates who aim to avert road crashes and diminish their consequences. The limited literature on fatalism reveals that it is not a simple concept, with religion, culture, superstition, experience, education and degree of perceived control of one's life all being implicated in accounts of fatalism. One distinction in the literature that seems promising is the distinction between empirical and theological fatalism, although there are areas of uncertainty about how well-defined the distinction between these types of fatalism is. Research into road safety in Pakistan is scarce, as is the case for other South Asian countries. From the review of the literature conducted, it is clear that the descriptions given of the different belief systems in developing countries including Pakistan are not entirely helpful for health promotion purposes and that further research is warranted on the influence of fatalism, superstition and other related beliefs in road safety. Based on the information available, a conceptual framework is developed as a means of structuring and focusing the research and analysis. The framework is focused on the influence of fatalism, superstition, religion and culture on beliefs about crashes and road user behaviour. Accordingly, this research aims to provide an understanding of the operation of fatalism and related beliefs in Pakistan to assist in the development and implementation of effective and culturally appropriate interventions. The research examines the influence of fatalism, superstition, religious and cultural beliefs on risky road use in Pakistan and is guided by three research questions: 1. What are the perceptions of road crash causation in Pakistan, in particular the role of fatalism, superstition, religious and cultural beliefs? 2. How does fatalism, superstition, and religious and cultural beliefs influence road user behaviour in Pakistan? 3. Do fatalism, superstition, and religious and cultural beliefs work as obstacles to road safety interventions in Pakistan? To address these questions, a qualitative research methodology was developed. The research focused on gathering data through individual in-depth interviewing using a semi-structured interview format. A sample of 30 participants was interviewed in Pakistan in the cities of Lahore, Rawalpindi and Islamabad. The participants included policy makers (with responsibility for traffic law), experienced police officers, religious orators, professional drivers (truck, bus and taxi) and general drivers selected through a combination of purposive, criterion and snowball sampling. The transcripts were translated from Urdu and analysed using a thematic analysis approach guided by the conceptual framework. The findings were divided into four areas: attribution of crash causation to fatalism; attribution of road crashes to beliefs about superstition and malicious acts; beliefs about road crash causation linked to popular concepts of religion; and implications for behaviour, safety and enforcement. Fatalism was almost universally evident, and expressed in a number of ways. Fate was used to rationalise fatal crashes using the argument that the people killed were destined to die that day, one way or another. Related to this was the sense of either not being fully in control of the vehicle, or not needing to take safety precautions, because crashes were predestined anyway. A variety of superstitious-based crash attributions and coping methods to deal with road crashes were also found, such as belief in the role of the evil eye in contributing to road crashes and the use of black magic by rivals or enemies as a crash cause. There were also beliefs related to popular conceptions of religion, such as the role of crashes as a test of life or a source of martyrdom. However, superstitions did not appear to be an alternative to religious beliefs. Fate appeared as the 'default attribution' for a crash when all other explanations failed to account for the incident. This pervasive belief was utilised to justify risky road use behaviour and to resist messages about preventive measures. There was a strong religious underpinning to the statement of fatalistic beliefs (this reflects popular conceptions of Islam rather than scholarly interpretations), but also an overlap with superstitious and other culturally and religious-based beliefs which have longer-standing roots in Pakistani culture. A particular issue which is explored in more detail is the way in which these beliefs and their interpretation within Pakistani society contributed to poor police reporting of crashes. The pervasive nature of fatalistic beliefs in Pakistan affects road user behaviour by supporting continued risk taking behaviour on the road, and by interfering with public health messages about behaviours which would reduce the risk of traffic crashes. The widespread influence of these beliefs on the ways that people respond to traffic crashes and the death of family members contribute to low crash reporting rates and to a system which appears difficult to change. Fate also appeared to be a major contributing factor to non-reporting of road crashes. There also appeared to be a relationship between police enforcement and (lack of) awareness of road rules. It also appears likely that beliefs can influence police work, especially in the case of road crash investigation and the development of strategies. It is anticipated that the findings could be used as a blueprint for the design of interventions aimed at influencing broad-spectrum health attitudes and practices among the communities where fatalism is prevalent. The findings have also identified aspects of beliefs that have complex social implications when designing and piloting driver intervention strategies. By understanding attitudes and behaviours related to fatalism, superstition and other related concepts, it should be possible to improve the education of general road users, such that they are less likely to attribute road crashes to chance, fate, or superstition. This study also underscores the understanding of this issue in high echelons of society (e.g., policy makers, senior police officers) as their role is vital in dispelling road users' misconceptions about the risks of road crashes. The promotion of an evidence or scientifically-based approach to road user behaviour and road safety is recommended, along with improved professional education for police and policy makers.

A waste management system for small and medium enterprises engaged in office building retrofit projects

Waste management and minimisation is considered to be an important issue for achieving sustainability in the construction industry. Retrofit projects generate less waste than demolitions and new builds, but they possess unique features and require waste management approaches that are different to traditional new builds. With the increasing demand for more energy efficient and environmentally sustainable office spaces, the office building retrofit market is growing in capital cities around Australia with a high level of refurbishment needed for existing aging properties. Restricted site space and uncertain delivery process in these projects make it a major challenge to manage waste effectively. The labour-intensive nature of retrofit projects creates the need for the involvement of small and medium enterprises (SMEs) as subcontractors in on-site works. SMEs are familiar with on-site waste generation but are not as actively motivated and engaged in waste management activities as the stakeholders in other construction projects in the industry. SMEs’ responsibilities for waste management in office building retrofit projects need to be identified and adapted to the work delivery processes and the waste management system supported by project stakeholders. The existing literature provides an understanding of how to manage construction waste that is already generated and how to increase the waste recovery rate for office building retrofit projects. However, previous research has not developed theories or practical solutions that can guide project stakeholders to understand the specific waste generation process and effectively plan for and manage waste in ongoing project works. No appropriate method has been established for the potential role and capability of SMEs to manage and minimise waste from their subcontracting works. This research probes into the characteristics of office building retrofit project delivery with the aim to develop specific tools to manage waste and incorporate SMEs in this process in an appropriate and effective way. Based on an extensive literature review, the research firstly developed a questionnaire survey to identify the critical factors of on-site waste generation in office building retrofit projects. Semi-structured interviews were then utilised to validate the critical waste factors and establish the interrelationships between the factors. The interviews served another important function of identifying the current problems of waste management in the industry and the performance of SMEs in this area. Interviewees’ opinions on remedies to the problems were also collected. On the foundation of the findings from the questionnaire survey and semi-structured interviews, two waste planning and management strategies were identified for the dismantling phase and fit-out phase of office building retrofit projects, respectively. Two models were then established to organize SMEs’ waste management activities, including a work process-based integrated waste planning model for the dismantling phase and a system dynamics model for the fit-out phase. In order to apply the models in real practice, procedures were developed to guide SMEs’ work flow in on-site waste planning and management. In addition, a collaboration framework was established for SMEs and other project stakeholders for effective waste planning and management. Furthermore, an organisational engagement strategy was developed to improve SME waste management practices. Three case studies were conducted to validate and finalise the research deliverables. This research extends the current literature that mostly covers waste management plans in new build projects, by presenting the knowledge and understanding of addressing waste problems in retrofit projects. It provides practical tools and guidance for industry practitioners to effectively manage the waste generation processes in office building retrofit projects. It can also promote industry-level recognition of the role of SMEs and their performance in on-site waste management.

Molecular and structural requirements of the ß1L-adrenoceptor

Noradrenaline which occurs naturally in the body binds to beta-adrenoceptors on the heart, causing the heart to beat faster and with greater force in response to increased demand. This enables the heart to provide oxygenated blood to vital organs. Prolonged overstimulation by noradrenaline can be harmful to the heart and lead to the progression of heart disease. In these circumstances beta-adrenoceptors are blocked with drugs called beta-blockers. Beta-blockers block the effects of noradrenaline by binding to the same site on the beta-adrenoceptor. Some beta-blockers such as CGP12177 can also cause increases in heart rate. Therefore it was proposed that CGP12177 could bind in a different place to noradrenaline. The aim of this study was to determine where CGP12177 binds to on the beta-adrenoceptor. The results have revealed a separate binding site named beta-1-low. These results may lead to the development of improved -blockers for the management of heart conditions.

Role of resting metabolic rate and energy expenditure in hunger and appetite control : a new formulation

A long-running issue in appetite research concerns the influence of energy expenditure on energy intake. More than 50 years ago, Otto G. Edholm proposed that "the differences between the intakes of food [of individuals] must originate in differences in the expenditure of energy". However, a relationship between energy expenditure and energy intake within any one day could not be found, although there was a correlation over 2 weeks. This issue was never resolved before interest in integrative biology was replaced by molecular biochemistry. Using a psychobiological approach, we have studied appetite control in an energy balance framework using a multi-level experimental system on a single cohort of overweight and obese human subjects. This has disclosed relationships between variables in the domains of body composition [fat-free mass (FFM), fat mass (FM)], metabolism, gastrointestinal hormones, hunger and energy intake. In this Commentary, we review our own and other data, and discuss a new formulation whereby appetite control and energy intake are regulated by energy expenditure. Specifically, we propose that FFM (the largest contributor to resting metabolic rate), but not body mass index or FM, is closely associated with self-determined meal size and daily energy intake. This formulation has implications for understanding weight regulation and the management of obesity.

Resting metabolic rate is associated with hunger, self-determined meal size, and daily energy intake and may represent a marker for appetite

Background: There are strong logical reasons why energy expended in metabolism should influence the energy acquired in food-intake behavior. However, the relation has never been established, and it is not known why certain people experience hunger in the presence of large amounts of body energy. Objective: We investigated the effect of the resting metabolic rate (RMR) on objective measures of whole-day food intake and hunger. Design: We carried out a 12-wk intervention that involved 41 overweight and obese men and women [mean ± SD age: 43.1 ± 7.5 y; BMI (in kg/m2): 30.7 ± 3.9] who were tested under conditions of physical activity (sedentary or active) and dietary energy density (17 or 10 kJ/g). RMR, daily energy intake, meal size, and hunger were assessed within the same day and across each condition. Results: We obtained evidence that RMR is correlated with meal size and daily energy intake in overweight and obese individuals. Participants with high RMRs showed increased levels of hunger across the day (P < 0.0001) and greater food intake (P < 0.00001) than did individuals with lower RMRs. These effects were independent of sex and food energy density. The change in RMR was also related to energy intake (P < 0.0001). Conclusions: We propose that RMR (largely determined by fat-free mass) may be a marker of energy intake and could represent a physiologic signal for hunger. These results may have implications for additional research possibilities in appetite, energy homeostasis, and obesity. This trial was registered under international standard identification for controlled trials as ISRCTN47291569.

Approaches to designing for older adults' intuitive interaction with complex devices

Many older people have difficulties using modern consumer products due to increased product complexity both in terms of functionality and interface design. Previous research has shown that older people have more difficulty in using complex devices intuitively when compared to the younger. Furthermore, increased life expectancy and a falling birth rate have been catalysts for changes in world demographics over the past two decades. This trend also suggests a proportional increase of older people in the work-force. This realisation has led to research on the effective use of technology by older populations in an effort to engage them more productively and to assist them in leading independent lives. Ironically, not enough attention has been paid to the development of interaction design strategies that would actually enable older users to better exploit new technologies. Previous research suggests that if products are designed to reflect people's prior knowledge, they will appear intuitive to use. Since intuitive interfaces utilise domain-specific prior knowledge of users, they require minimal learning for effective interaction. However, older people are very diverse in their capabilities and domain-specific prior knowledge. In addition, ageing also slows down the process of acquiring new knowledge. Keeping these suggestions and limitations in view, the aim of this study was set to investigate possible approaches to developing interfaces that facilitate their intuitive use by older people. In this quest to develop intuitive interfaces for older people, two experiments were conducted that systematically investigated redundancy (the use of both text and icons) in interface design, complexity of interface structure (nested versus flat), and personal user factors such as cognitive abilities, perceived self-efficacy and technology anxiety. All of these factors could interfere with intuitive use. The results from the first experiment suggest that, contrary to what was hypothesised, older people (65+ years) completed the tasks on the text only based interface design faster than on the redundant interface design. The outcome of the second experiment showed that, as expected, older people took more time on a nested interface. However, they did not make significantly more errors compared with younger age groups. Contrary to what was expected, older age groups also did better under anxious conditions. The findings of this study also suggest that older age groups are more heterogeneous in their capabilities and their intuitive use of contemporary technological devices is mediated more by domain-specific technology prior knowledge and by their cognitive abilities, than chronological age. This makes it extremely difficult to develop product interfaces that are entirely intuitive to use. However, by keeping in view the cognitive limitations of older people when interfaces are developed, and using simple text-based interfaces with flat interface structure, would help them intuitively learn and use complex technological products successfully during early encounter with a product. These findings indicate that it might be more pragmatic if interfaces are designed for intuitive learning rather than for intuitive use. Based on this research and the existing literature, a model for adaptable interface design as a strategy for developing intuitively learnable product interfaces was proposed. An adaptable interface can initially use a simple text only interface to help older users to learn and successfully use the new system. Over time, this can be progressively changed to a symbols-based nested interface for more efficient and intuitive use.

Dimensions of the venture creation process : amount, dynamics, and sequences of action in nascent entrepreneurship

This research examines the entrepreneurship phenomenon, and the question: Why are some venture attempts more successful than others? This question is not a new one. Prior research has answered this by describing those that engage in nascent entrepreneurship. Yet, this approach yielded little consensus and offers little comfort for those newly considering venture creation (Gartner, 1988). Rather, this research considers the process of venture creation, by focusing on the actions of nascent entrepreneurs. However, the venture creation process is complex (Liao, Welsch, & Tan, 2005), and multi-dimensional (Davidsson, 2004). The process can vary in the amount of action engaged by the entrepreneur; the temporal dynamics of how action is enacted (Lichtenstein, Carter, Dooley, and Gartner 2007); or the sequence in which actions are undertaken. And little is known about whether any, or all three, of these dimensions matter. Further, there exists scant general knowledge about how the venture creation process influences venture creation outcomes (Gartner & Shaver, 2011). Therefore, this research conducts a systematic study of what entrepreneurs do as they create a new venture. The primary goal is to develop general principles so that advice may be offered on how to ‘proceed’, rather than how to ‘be’. Three integrated empirical studies were conducted that separately focus on each of the interrelated dimensions. The basis for this was a randomly sampled, longitudinal panel, of nascent ventures. Upon recruitment these ventures were in the process of being created, but yet to be established as new businesses. The ventures were tracked one year latter to follow up on outcomes. Accordingly, this research makes the following original contributions to knowledge. First, the findings suggest that all three of the dimensions play an important role: action, dynamics, and sequence. This implies that future research should take a multi-dimensional view of the venture creation process. Failing to do so can only result in a limited understanding of a complex phenomenon. Second, action is the fundamental means through which venture creation is achieved. Simply put, more active venture creation efforts are more likely more successful. Further, action is the medium which allows resource endowments their effect upon venture outcomes. Third, the dynamics of how venture creation plays out over time is also influential. Here, a process with a high rate of action which increases in intensity will more likely achieve positive outcomes. Forth, sequence analysis, suggests that the order in which actions are taken will also drive outcomes. Although venture creation generally flows in sequence from discovery toward exploitation (Shane & Venkataraman, 2000; Eckhardt & Shane, 2003; Shane, 2003), processes that actually proceed in this way are less likely to be realized. Instead, processes which specifically intertwine discovery and exploitation action together in symbiosis more likely achieve better outcomes (Sarasvathy, 2001; Baker, Miner, & Eesley, 2003). Further, an optimal venture creation order exists somewhere between these sequential and symbiotic process archetypes. A process which starts out as symbiotic discovery and exploitation, but switches to focus exclusively on exploitation later on is most likely to achieve venture creation. These sequence findings are unique, and suggest future integration between opposing theories for order in venture creation.

A framework of promoting stakeholder mutual benefits for sustainable housing implementation

Strong regulatory pressure and rising public awareness on environmental issues will continue to influence the market demand for sustainable housing for years to come. Despite this potential, the voluntary uptake rate of sustainable practices is not as high as expected within the new built housing industry. This is in contrast to the influx of emerging building technologies, new materials and innovative designs as showcased in office buildings and exemplar homes worldwide. One of the possible reasons for this under-performance is that key stakeholders such as developers, builders and consumers do not fully understand and appreciate the related challenges, risks and opportunities of pursuing sustainability. Therefore, in their professional and business activities, they may not be able to see the tangible and mutual benefits that sustainable housing may bring. This research investigates the multiple challenges to achieving benefits (CABs) from sustainable housing development, and links these factors to the characteristics of key stakeholders in the housing supply chain. It begins with a comparative survey study among seven stakeholder groups in the Australian housing industry, in order to examine the importance and interrelationships of CABs. In-depth interviews then further explore the survey findings with a focus on stakeholder diversity, which leads to the identification of 12 critical mutual-benefit factors and their interrelationship. Based on such a platform, a mutual-benefit framework is developed with the aid of Interpretive Structure Modelling, to identify the patterns of stakeholder benefit materialisation, suggest the priority of critical factors and provide related stakeholder-specific action guidelines for sustainable housing implementation. The study concludes with a case study of two real-life housing projects to test the application of the mutual-benefit framework for improvement. This framework will lead to a shared value of sustainability among stakeholders and improved stakeholder collaboration, which in turn help to break the "circle of blame" for the current under-performance of sustainable housing implementation.