Contribution of transmembrane domain V amino acids to β1l-adrenoceptor activity and affinity

There are two binding sites on the β1-adrenoceptor (AR), β1H and β1L corresponding to high and low affinity binding sites respectively, which can be activated to cause cardiostimulation (reviewed Kaumann and Molenaar, 2008). Some β-blockers that block β1AR and β2ARs can activate β1LARs at higher concentrations than those required to cause blockade. The β2AR does not form a corresponding low affinity binding site (Baker et al 2002) and therefore we postulated that heterologous amino acids are responsible for the formation of β1LAR. Our aim was to investigate whether heterologous amino acids of transmembrane domain V (TMDV) of β1AR and β2ARs contribute to β1LAR. β1ARs, β2ARs and mutant β1ARs containing all (β1(β2TMDV)AR) or single amino acids of TMDV of the β2AR were prepared and stably expressed in Chinese Hamster Ovary cells. Concentration-effect curves for cyclicAMP accumulation were carried out for (-)-CGP12177 or (-)-isoprenaline in the absence or presence of (-)-bupranolol. _______________________________________________________________________ (-)-CGP 12177 (-)-Bupranolol affinity (pKB) pEC50 vs (-)-CGP 12177 vs (-)-isoprenaline _______________________________________________________________________ β1AR 8.00 ± 0.11 (11) 7.23 ± 0.23 (5) 9.52 ± 0.28 (5) β2AR (high density) 9.24 ± 0.14 (5) 9.82 ± 0.52 (8) xPaulxxxxxxx β2AR (low density) no effect β1(β2TMV)AR 8.86 ± 0.10 (15) 8.06 ± 0.17 (8) 9.08 ± 0.22 (6) β1(V230I)AR 9.07 ± 0.07 (10) 7.64 ± 0.12 (8) 9.36 ± 0.28 (9) β1(R222Q)AR 8.09 ± 0.29 (6) 7.33 ± 0.23 (5) 9.36 ± 0.08 (6) β1(V230A)AR 7.59 ± 0.09 (6) 7.32 ± 0.24 (4) 8.62 ± 0.18 (5) _______________________________________________________________________ The potency of (-)-CGP12177 was higher at β2AR than at β1AR consistent with activation through a low affinity site at the β1AR (β1LAR) but not β2AR. The presence of V230 in β1AR accounted for the lower potency of (-)-CGP 12177. The affinity of (-)-bupranolol at β1AR and mutants was higher when determined with (-)-isoprenaline than with (-)-CGP 12177. The affinity of (-)-bupranolol determined against (-)-CGP 12177 was lower at β1AR compared to β2AR. The presence of V230 in β1AR accounted in part for the lower affinity. In conclusion V230 of the β1AR contributes in part to the low affinity binding site of β1AR. Baker JG, Hall IP, Hill SJ (2002). Pharmacological characterization of CGP12177 at the human β2-adrenoceptor. Br J Pharmacol 137, 400−408 Kaumann AJ, Molenaar P (2008) The low-affinity site of the β1-adrenoceptor and its relevance to cardiovascular pharmacology. Pharmacol Ther 118, 303-336

Business process management education in academia: Status, challenges, and recommendations

In response to the growing proliferation of Business Process Management (BPM) in industry and the demand this creates for BPM expertise, universities across the globe are at various stages of incorporating knowledge and skills in their teaching offerings. However, there are still only a handful of institutions that offer specialized education in BPM in a systematic and in-depth manner. This article is based on a global educators’ panel discussion held at the 2009 European Conference on Information Systems in Verona, Italy. The article presents the BPM programs of five universities from Australia, Europe, Africa, and North America, describing the BPM content covered, program and course structures, and challenges and lessons learned. The article also provides a comparative content analysis of BPM education programs illustrating a heterogeneous view of BPM. The examples presented demonstrate how different courses and programs can be developed to meet the educational goals of a university department, program, or school. This article contributes insights on how best to continuously sustain and reshape BPM education to ensure it remains dynamic, responsive, and sustainable in light of the evolving and ever-changing marketplace demands for BPM expertise.

Internal market orientation and market-oriented behaviours

Purpose: The purpose of this empirical paper is to investigate internal marketing from a behavioural perspective. The impact of internal marketing behaviours, operationalised as an internal market orientation (IMO), on employees’ marketing and other in-role behaviours (IRB) were examined. ---------- Design/methodology/approach: Survey data measuring IMO, market orientation and a range of constructs relevant to the nomological network in which they are embedded were collected from the UK retail managers. These were tested to establish their psychometric properties and the conceptual model was analysed using structural equations modelling, employing a partial least squares methodology. ---------- Findings: IMO has positive consequences for employees’ market-oriented and other IRB. These, in turn, influence marketing success. Research limitations/implications – The paper provides empirical support for the long-held assumption that internal and external marketing are related and that organisations should balance their external focus with some attention to employees. Future research could measure the attitudes and behaviours of managers, employees and customers directly and explore the relationships between them. ---------- Practical implications: Firm must ensure that they do not put the needs of their employees second to those of managers and shareholders; managers must develop their listening skills and organisations must become more responsive to the needs of their employees. ---------- Originality/value: The paper contributes to the scarce body of empirical support for the role of internal marketing in services organisations. For researchers, this paper legitimises the study of internal marketing as a route to external market success; for managers, the study provides quantifiable evidence that focusing on employees’ wants and needs impacts their behaviours towards the market.

Micro-family-owned businesses in hostile environment : future engine for growth?

Using panel data from the four waves of the Indonesia Family Life Survey in 1993, 1997, 2000 and 2007 we investigate the prerequisite for and contribution of micro-family-businesses to economic development. We find that family-owned firms are on average fairly profitable compared with the industrial sector profit standard. Failure rates between 1997 and 2000 are very low (about 10%), while the industrial sector experimented a massive shakeout of about 33% in the wake of the 1997 crisis (Ter Wengel & Rodriguez, 2006), with an increase in the number of family-businesses between the two years of observation. This paper contributes to the economics of entrepreneurship studies by continuing the discussion of entrepreneurship in hostile business environments (Baumol, 1990; Sobel, 2008).

Ryanodine receptor phosphorylation in human heart failure

Heart failure is a complex disorder, characterized by activation of the sympathetic nervous system, leading to dysregulated Ca2+ homeostasis in cardiac myocytes and tissue remodeling. In a variety of diseases, cardiac malfunction is associated with aberrant fluxes of Ca2+ across both the surface membrane and the internal Ca2+ store, the sarcoplasmic reticulum (SR). One prominent hypothesis residues is that in heart failure, the activity of the ryanodine receptor (RyR2) Ca2+ release channel in the SR is increased due to excess phosphorylation and that this contributes to excess SR Ca2+ leak in diastole, reduced SR Ca2+ load and decreased contractility (Huke & Bers, 2008). There is controversy over which serine residues in RyR2 are hyperphosphorylated in animal models of heart failure and whether this is via the CaMKII or the PKA-linked signaling pathway. S2808, S2814 and S2030 in RyR2 have been variously claimed to be hyperphosphorylated. Our aim was to examine the degree of phosphorylation of these residues in RyR2 from failing human hearts. The use of human tissue was approved by the Human Research Ethics Committee, The Prince Charles Hospital, EC28114. Left ventricular tissue samples were obtained from an explanted heart of a patient with endstage heart failure (Emery Dreifuss Muscular Dystrophy with cardiomyopathy) and non-failing tissue was from a patient with cystic fibrosis undergoing heart-lung transplantation with no history of heart disease. SR vesicles were prepared as described by Laver et al. (1995) and examined with SDS-Page and Western Blot. Transferred proteins were probed with antibodies to detect total protein phosphorylation, phosphorylation of RyR2 serine residues S2808, S2814, S2030 and for the key proteins calsequestrin, triadin, junctin and FKBP12.6. To avoid membrane stripping artifact, each membrane was exposed to one phosphorylation-specific antibody and signal densities quantified using Bio-Rad Quantity One software. We found no distinguishable difference between failing and healthy hearts in the protein expression levels of RyR2, triadin, junctin or calsequestrin. We found an expected upregulation of total RyR2 phosphorylation in the failing heart sample, compared to a matched amount of RyR2 (quantified using densiometry) in healthy heart. Probing with antibodies detecting only the phosphorylated form of the specific RyR2 residues showed that the increase in total RyR2 phosphorylation in the failing heart was due to hyperphosphorylation of S2808 and S2814. We found that S2030 phosphorylation levels were unchanged in human heart failure. Interestingly, we found that S2030 has a basal level of phosphorylation in the healthy human heart, different from the absence of basal phosphorylation recently reported in rodent heart (Huke & Bers, 2008). Finally, preliminary results indicate that less FKBP 12.6 is associated with RyR2 in the failing heart, possibly as a consequence of PKA activation. In conclusion, residues S2808 and S2814 are hyperphosphorylated in human heart failure, presumably due to upregulation of the CaMKII and/or PKA signaling pathway as a result of chronic activation of the sympathetic nervous system. Such changes in RyR2 phosphorylation are believed to contribute to the leaky RyR2 phenotype associated with heart failure, which increases the incidence of arrhythmia and contributes to the severely impaired contractile performance of the failing heart. Huke S & Bers DM. (2008). Ryanodine receptor phosphorylation at serine 2030, 2808 and 2814 in rat cardiomyocytes. Biochemical and Biophysical Research Communications 376, 80-85. Laver DR, Roden LD, Ahern GP, Eager KR, Junankar PR & Dulhunty AF. (1995). Cytoplasmic Ca2+ inhibits the ryanodine receptor from cardiac muscle. Journal of Membrane Biology 147, 7-22. Proceedings

Effectiveness of constructability concept in the provision of infrastructure assets

The concept of constructability is to use construction knowledge and experience during all phases of a project, particularly in the earliest phases of planning and design. It facilitates project objectives before delivery stage, and decreases unnecessary costs during construction phase. Despite the extensive use, constructability concept fails to address many issues related to Operation and Maintenance (O&M) of construction projects. Extending constructability concept, to include the O&M issues, could lead to the projects that are not fitted for construction purposes only, but also fitted for use. This study reviews the literature of constructability implementation, its benefits and shortcomings during the infrastructure life cycle, as well as the delivery success factors of infrastructure projects. This contributes to the propose need of a model to improve the effectiveness and efficiency of infrastructure project by extending the concept of constructability to include O&M. Development of such a model can facilitate post-occupancy stakeholders’ participation in a constructability program. It will help infrastructure owners eliminate project reworks, and improve O&M effectiveness and efficiency.

An interview with Professor David Held : exploring the concepts of cosmopolitanism and democracy

David Held is the Graham Wallace Chair in Political Science, and co-director of LSE Global Governance, at the London School of Economics. He is the author of many works, such as Cosmopolitanism: Ideals and Realities (2010); The Cosmopolitanism Reader (2010), with Garrett Brown; Globalisation/AntiGlobalisation (2007), Models of Democracy (2006), Global Covenant (2004) and Global Transformations: Politics, Economics and Culture (1999). Professor Held is also the co-founder, alongside Lord Professor Anthony Giddens, of Polity Press. Professor Held is widely known for his work concerning cosmopolitan theory, democracy, and social, political and economic global improvement. His Global Policy Journal endeavours to marry academic developments with practitioner realities, and contributes to the understanding and improvement of our governing systems.

Integrating the resource-based view and transaction cost economics in immigrant business performance

This paper presents a new integrated framework that integrates the resource-based view and transaction cost economics to explain the phenomenon of immigrant entrepreneurship. We extend the existing literature on immigrant entrepreneurship by identifying different types of ethnic network resources and demonstrating how these resources interact with transaction costs in the context of Chinese immigrants. Thus, our study contributes to the literature by providing a theoretical framework which identifies mechanisms immigrant entrepreneurs use to strategically deploy resources to minimize costs and maximize performance outcomes.

Chlamydial infection of immune cells : altered function and implications for disease

Chlamydia trachomatis is an obligate intracellular bacterial pathogen that infects the genital and ocular mucosa of humans, causing infections that can lead to pelvic inflammatory disease, infertility, and blinding trachoma. C. pneumoniae is a respiratory pathogen that is the cause of 12–15% of community-acquired pneumonia. Both chlamydial species were believed to be restricted to the epithelia of the genital, ocular, and respiratory mucosa; however, increasing evidence suggests that both these pathogens can be isolated from peripheral blood of both healthy individuals and patients with inflammatory conditions such as coronary artery disease and asthma. Chlamydia can also be isolated from brain tissues of patients with degenerative neurological disorders such as Alzheimer’s disease and multiple sclerosis, and also from certain lymphomas. An increasing number of in vitro studies suggest that some chlamydial species can infect immune cells, at least at low levels. These infections may alter immune cell function in a way that promotes chlamydial persistence in the host and contributes to the progression of several chronic inflammatory diseases. In this paper, we review the evidence for the growth of Chlamydia in immune cells, particularly monocytes/macrophages and dendritic cells, and describe how infection may affect the function of these cells.

A novel corepressor, BCoR-L1, represses transcription through an interaction with CtBP

Corepressors play a crucial role in negative gene regulation and are defective in several diseases. BCoR is a corepressor for the BCL6 repressor protein. Here we describe and functionally characterize BCoR-L1, a homolog of BCoR. When tethered to a heterologous promoter, BCoR-L1 is capable of strong repression. Like other corepressors, BCoR-L1 associates with histone deacetylase (HDAC) activity. Specifically, BCoR-L1 coprecipitates with the Class II HDACs, HDAC4, HDAC5, and HDAC7, suggesting that they are involved in its role as a transcriptional repressor. BCoR-L1 also interacts with the CtBP corepressor through a CtBP-interacting motif in its amino terminus. Abrogation of the CtBP binding site within BCoR-L1 partially relieves BCoR-L1-mediated transcriptional repression. Furthermore, BCoR-L1 is located on the E-cadherin promoter, a known CtBP-regulated promoter, and represses the E-cadherin promoter activity in a reporter assay. The inhibition of BCoR-L1 expression by RNA-mediated interference results in derepression of E-cadherin in cells that do not normally express E-cadherin, indicating that BCoR-L1 contributes to the repression of an authentic endogenous CtBP target.

A polymorphism in the dysbindin gene (DTNBP1) associated with multiple psychiatric disorders including schizophrenia

Background A number of studies have found associations between dysbindin (DTNBP1) polymorphisms and schizophrenia. Recently we identified a DTNBP1 SNP (rs9370822) that is strongly associated with schizophrenia. Individuals diagnosed with schizophrenia were nearly three times as likely to carry the CC genotype compared to the AA genotype. Methods To investigate the importance of this SNP in the function of DTNBP1, a number of psychiatric conditions including addictive behaviours and anxiety disorders were analysed for association with rs9370822. Results The DTNBP1 polymorphism was significantly associated with post-traumatic stress disorder (PTSD) as well as nicotine and opiate dependence but not alcohol dependence. Individuals suffering PTSD were more than three times as likely to carry the CC genotype compared to the AA genotype. Individuals with nicotine or opiate dependence were more than twice as likely to carry the CC genotype compared to the AA genotype. Conclusions This study provides further support for the importance of DTNBP1 in psychiatric conditions and suggests that there is a common underlying molecular defect involving DTNBP1 that contributes to the development of several anxiety and addictive disorders that are generally recognised as separate clinical conditions. These disorders may actually be different expressions of a single metabolic pathway perturbation. As our participant numbers are limited our observations should be viewed with caution until they are independently replicated.

Hierarchical Bayesian models for estimating the extent of plant pest invasions

Plant biosecurity requires statistical tools to interpret field surveillance data in order to manage pest incursions that threaten crop production and trade. Ultimately, management decisions need to be based on the probability that an area is infested or free of a pest. Current informal approaches to delimiting pest extent rely upon expert ecological interpretation of presence / absence data over space and time. Hierarchical Bayesian models provide a cohesive statistical framework that can formally integrate the available information on both pest ecology and data. The overarching method involves constructing an observation model for the surveillance data, conditional on the hidden extent of the pest and uncertain detection sensitivity. The extent of the pest is then modelled as a dynamic invasion process that includes uncertainty in ecological parameters. Modelling approaches to assimilate this information are explored through case studies on spiralling whitefly, Aleurodicus dispersus and red banded mango caterpillar, Deanolis sublimbalis. Markov chain Monte Carlo simulation is used to estimate the probable extent of pests, given the observation and process model conditioned by surveillance data. Statistical methods, based on time-to-event models, are developed to apply hierarchical Bayesian models to early detection programs and to demonstrate area freedom from pests. The value of early detection surveillance programs is demonstrated through an application to interpret surveillance data for exotic plant pests with uncertain spread rates. The model suggests that typical early detection programs provide a moderate reduction in the probability of an area being infested but a dramatic reduction in the expected area of incursions at a given time. Estimates of spiralling whitefly extent are examined at local, district and state-wide scales. The local model estimates the rate of natural spread and the influence of host architecture, host suitability and inspector efficiency. These parameter estimates can support the development of robust surveillance programs. Hierarchical Bayesian models for the human-mediated spread of spiralling whitefly are developed for the colonisation of discrete cells connected by a modified gravity model. By estimating dispersal parameters, the model can be used to predict the extent of the pest over time. An extended model predicts the climate restricted distribution of the pest in Queensland. These novel human-mediated movement models are well suited to demonstrating area freedom at coarse spatio-temporal scales. At finer scales, and in the presence of ecological complexity, exploratory models are developed to investigate the capacity for surveillance information to estimate the extent of red banded mango caterpillar. It is apparent that excessive uncertainty about observation and ecological parameters can impose limits on inference at the scales required for effective management of response programs. The thesis contributes novel statistical approaches to estimating the extent of pests and develops applications to assist decision-making across a range of plant biosecurity surveillance activities. Hierarchical Bayesian modelling is demonstrated as both a useful analytical tool for estimating pest extent and a natural investigative paradigm for developing and focussing biosecurity programs.

Analysing queer student media using a combined queer theoretical and media studies approach

Australian queer (GLBTIQ) university student media is an important site of cultural and political self-representation. These groups exist within university student unions and the unions provide them with space, financial support and resources. Community media is a significant site for the development of queer identity, community and a key part of queer politics. This paper reviews my research into queer community media which is grounded in a Queer Theoretical perspective of identity performativity. Cover argues that Queer Theoretical approaches that study media products fail to consider the material contexts which contribute to their construction. I use an ethnographic approach combined with discourse analysis in order to reveal queer student activists’ media representations of queer, and the production contexts which shape them. My research contributes to queer media scholarship by using a methodology to address the gap that Cover identifies.

Queers doing theory : Australian queer student activist print media’s representations of capitalism

Queer university student print media often represents capitalism in a framework which could be classified as Marxism. However, at the same time, queer student media extensively publishes ideas which could be classified as academic queer theory. This chapter features analysis of these representations from the 2003, 2004 and 2006 editions of national queer student publication, Querelle, and from a sample of queer student media from four Australian universities. The perspectives of Marxism and academic queer theory are often argued to be contradictory (See for example, Hennessy 1994; Morton 1996b; Kirsch 2007), and thus the students’ application of these theories in tandem could be considered problematic. McKee asks ‘Who gets to be an intellectual?’ (2004) and suggests that the intellectualising undertaken by mainstream and alternative cultural creators is just as valid as that undertaken by university academics. He also raises concerns that the concept of theory is seen to be kept separate from everyday culture (McKee 2002). This chapter argues that in the construction and representation of their politics in this manner the queer student activists are creating their own version of queer theory. This analysis of queer student media contributes to research on queer communities and queer theory, demonstrating how one specific cultural subset theorises queerness and queer politics, thereby contributing to the genealogy of queer.

Workforce gender diversity: Is it a source of competitive advantage?

Research on workforce diversity at the organisational level gained momentum in the 1990s, because of the growing trend in HR research to link HR practices with organisational performance. The new parallel wave of research focused on the business case for diversity, in which diversity was linked to organisational performance. However, the results of these studies, mainly focusing on linear diversity-performance relationships, have been inconsistent. Based on contrasting theories, this paper proposes three competing predictions of the gender diversity-performance relationship at the organisational level: a positive linear relationship derived from the resource-based view of the firm, a negative linear relationship derived from self-categorisation and social identity theories, and a U-shaped curvilinear relationship derived from the integration of the resource-based view of the firm with self-categorisation and social identity theories. The U-shaped relationship accounts for the inconsistent findings in past research, because different proportions of men and women produce different social dynamics that have different effects on organisational performance. Further, the proposed U-shaped relationship can have different slopes in the manufacturing and services industries. The paper contributes to the field of diversity by strengthening its weak theoretical foundations and by highlighting the industry differences.