Kallikrein-related peptidase 4 activation of protease-activated receptor family members and association with prostate cancer

Two areas of particular importance in prostate cancer progression are primary tumour development and metastasis. These processes involve a number of physiological events, the mediators of which are still being discovered and characterised. Serine proteases have been shown to play a major role in cancer invasion and metastasis. The recently discovered phenomenon of their activation of a receptor family known as the protease activated receptors (PARs) has extended their physiological role to that of signaling molecule. Several serine proteases are expressed by malignant prostate cancer cells, including members of the kallikreinrelated peptidase (KLK) serine protease family, and increasingly these are being shown to be associated with prostate cancer progression. KLK4 is highly expressed in the prostate and expression levels increase during prostate cancer progression. Critically, recent studies have implicated KLK4 in processes associated with cancer. For example, the ectopic over-expression of KLK4 in prostate cancer cell lines results in an increased ability of these cells to form colonies, proliferate and migrate. In addition, it has been demonstrated that KLK4 is a potential mediator of cellular interactions between prostate cancer cells and osteoblasts (bone forming cells). The ability of KLK4 to influence cellular behaviour is believed to be through the selective cleavage of specific substrates. Identification of relevant in vivo substrates of KLK4 is critical to understanding the pathophysiological roles of this enzyme. Significantly, recent reports have demonstrated that several members of the KLK family are able to activate PARs. The PARs are relatively new members of the seven transmembrane domain containing G protein coupled receptor (GPCR) family. PARs are activated through proteolytic cleavage of their N-terminus by serine proteases, the resulting nascent N-terminal binds intramolecularly to initiate receptor activation. PARs are involved in a number of patho-physiological processes, including vascular repair and inflammation, and a growing body of evidence suggests roles in cancer. While expression of PAR family members has been documented in several types of cancers, including prostate, the role of these GPCRs in prostate cancer development and progression is yet to be examined. Interestingly, several studies have suggested potential roles in cellular invasion through the induction of cytoskeletal reorganisation and expression of basement membrane-degrading enzymes. Accordingly, this program of research focussed on the activation of the PARs by the prostate cancer associated enzyme KLK4, cellular processing of activated PARs and the expression pattern of receptor and agonist in prostate cancer. For these studies KLK4 was purified from the conditioned media of stably transfected Sf9 insect cells expressing a construct containing the complete human KLK4 coding sequence in frame with a V5 epitope and poly-histidine encoding sequences. The first aspect of this study was the further characterisation of this recombinant zymogen form of KLK4. The recombinant KLK4 zymogen was demonstrated to be activatable by the metalloendopeptidase thermolysin and amino terminal sequencing indicated that thermolysin activated KLK4 had the predicted N-terminus of mature active KLK4 (31IINED). Critically, removal of the pro-region successfully generated a catalytically active enzyme, with comparable activity to a previously published recombinant KLK4 produced from S2 insect cells. The second aspect of this study was the activation of the PARs by KLK4 and the initiation of signal transduction. This study demonstrated that KLK4 can activate PAR-1 and PAR-2 to mobilise intracellular Ca2+, but failed to activate PAR-4. Further, KLK4 activated PAR-1 and PAR-2 over distinct concentration ranges, with KLK4 activation and mobilisation of Ca2+ demonstrating higher efficacy through PAR-2. Thus, the remainder of this study focussed on PAR-2. KLK4 was demonstrated to directly cleave a synthetic peptide that mimicked the PAR-2 Nterminal activation sequence. Further, KLK4 mediated Ca2+ mobilisation through PAR-2 was accompanied by the initiation of the extra-cellular regulated kinase (ERK) cascade. The specificity of intracellular signaling mediated through PAR-2 by KLK4 activation was demonstrated by siRNA mediated protein depletion, with a reduction in PAR-2 protein levels correlating to a reduction in KLK4 mediated Ca2+mobilisation and ERK phosphorylation. The third aspect of this study examined cellular processing of KLK4 activated PAR- 2 in a prostate cancer cell line. PAR-2 was demonstrated to be expressed by five prostate derived cell lines including the prostate cancer cell line PC-3. It was also demonstrated by flow cytometry and confocal microscopy analyses that activation of PC-3 cell surface PAR-2 by KLK4 leads to internalisation of this receptor in a time dependent manner. Critically, in vivo relevance of the interaction between KLK4 and PAR-2 was established by the observation of the co-expression of receptor and agonist in primary prostate cancer and prostate cancer bone lesion samples by immunohistochemical analysis. Based on the results of this study a number of exciting future studies have been proposed, including, delineating differences in KLK4 cellular signaling via PAR-1 and PAR-2 and the role of PAR-1 and PAR-2 activation by KLK4 in prostate cancer cells and bone cells in prostate cancer progression.

Are country and cultural values interchangeable? : a case example using occupational stress and coping

Cross-cultural research in occupational stress and coping has produced a wealth of knowledge. Although advancement has been made, there are still problems to be solved. One of these problems is the confusion generated in the literature by researchers claiming nation or country as representing cultural values, and the use of the two terms interchangeably. It remains unclear whether this practice is correct. The present paper reported on this by using 511 full time employees from Australia, Singapore and Sri Lanka to study occupational stress and coping. Results revealed that cultural value paradigm (i.e., Individualism-Collectivism) was distributed across the three nations, such that over 60% of participants across the three nations were either high or low in both I-C paradigms. The findings also indicated that the relationship between cultural value paradigm and country impacted on stress and coping differently. The study shows that significant differences exist within country, as well as between countries, such that any attempt to equate ‘culture’ with ‘country’ becomes problematic. Therefore, these findings establish that country or nation was not the same as culture values and could not be used interchangeably.

Optimal monitoring in family-owned companies? Evidence from Asia

Manuscript Type: Empirical Research Issue: We propose that high levels of monitoring are not always in the best interests of minority shareholders. In family-owned companies the optimal level of board monitoring required by minority shareholders is expected to be lower than that of other companies. This is because the relative benefits and costs of monitoring are different in family-owned companies. Research Findings: At moderate levels of board monitoring, we find concave relationships between board monitoring variables and firm performance for family-owned companies but not for other companies. The optimal level of board monitoring for our sample of Asian family-owned companies equates to board independence of 38%, separation of the Chairman and CEO positions and establishment of audit and remuneration committees. Additional testing shows that the optimal level of board monitoring is sensitive to the magnitude of the agency conflict between the family group and minority shareholders and the presence of substitute monitoring. Practitioner/Policy Implications: For policymakers, the results show that more monitoring is not always in the best interests of minority shareholders. Therefore, it may be inappropriate for regulators to advise all companies to follow the same set of corporate governance guidelines. However, our results also indicate that the board governance practices of family-owned companies are still well below the identified optimal levels. Keywords: Corporate Governance, Board Independence, Board of Directors, Family Firms, Monitoring.

Dealing with Post-GFC stress disorder : Bwembya Chikolwa quoted by Christine Retschlag for Property Australia magazine 4th March 2010

Has the GFC really changed the thinking of the property industry? Or are investment managers suffering from post-GFC stress disorder fated to repeat the mistakes of the past? Christine Retschlag reports on the mindset of the market.

The promoting adult resilience (PAR) program : the effectiveness of the second, shorter pilot of a workplace prevention program

This article details the second, successful pilot of the Promoting Adult Resilience (PAR) program in the human-services departments of a local government organization. The PAR program is a strengths-based resilience building program that integrates Interpersonal and CBT perspectives and this pilot use a shorter, 7-week version of the program. Pre, post and follow-up measures on PAR participants from a resource-sector company were compared with a non-intervention matched comparison group. Post-test, PAR participants reported greater self-efficacy, more family satisfaction, greater f\work-life fit and balance and less negative family to work spillover than the comparison group. At the 6-month follow-up, these gains were maintained to a lesser degree, although work-life balance was strengthened, and negative spillover in both directions reduced. Participants also reported greater optimism for the future, greater work satisfaction and promisingly for human service workers, exhaustion was reduced and more vigour, important for human services as burnout, exhaustion is part of this is a serious work hazard

Social support and fires in the workplace : a preliminary investigation

Workers who experience fire in the workplace are faced with disruption to their work routine, as well as the emotional strain of the fire. In the broader occupational stress literature, researchers have suggested that social support will be most effective at reducing the negative effects of stressors on strain when the type of support matches the type of stressor being experienced (either instrumental or emotional). This study was a preliminary investigation into employee responses to less routine stressors, such as workplace fires, and the role of different sources of social support in predicting coping effectiveness. This study also was a first attempt at considering the influence of the social context (in terms of group identification) on the effectiveness of social support as a predictor of coping effectiveness. Specifically, it was predicted that social support would be more effective when it came from multiple sources within the organization, that it would be especially effective when provided from a group that workers identified more strongly with, and that simply feeling part of a group would improve adjustment. Both quantitative and qualitative data were collected from 33 employees who had recently experienced a significant fire in their workplace. Results suggested that the type of stressors experienced and the type of support were mismatched, but despite this, coping effectiveness was generally moderate to high. There was mixed support for predictions about the effects of social support–no moderating effect of group identification on coping effectiveness was observed for measures of workplace support, although it did moderate the effects of family support on this adjustment indicator.

A new family of multi-output DC-DC converter topologies to supply an asymmetrical four-level diode-clamped inverter

Purpose Multi-level diode-clamped inverters have the challenge of capacitor voltage balancing when the number of DC-link capacitors is three or more. On the other hand, asymmetrical DC-link voltage sources have been applied to increase the number of voltage levels without increasing the number of switches. The purpose of this paper is to show that an appropriate multi-output DC-DC converter can resolve the problem of capacitor voltage balancing and utilize the asymmetrical DC-link voltages advantages. Design/methodology/approach A family of multi-output DC-DC converters is presented in this paper. The application of these converters is to convert the output voltage of a photovoltaic (PV) panel to regulate DC-link voltages of an asymmetrical four-level diode-clamped inverter utilized for domestic applications. To verify the versatility of the presented topology, simulations have been directed for different situations and results are presented. Some related experiments have been developed to examine the capabilities of the proposed converters. Findings The three-output voltage-sharing converters presented in this paper have been mathematically analysed and proven to be appropriate to improve the quality of the residential application of PV by means of four-level asymmetrical diode-clamped inverter supplying highly resistive loads. Originality/value This paper shows that an appropriate multi-output DC-DC converter can resolve the problem of capacitor voltage balancing and utilize the asymmetrical DC-link voltages advantages and that there is a possibility of operation at high-modulation index despite reference voltage magnitude and power factor variations.

The Revised Transactional Model (RTM) of occupational stress and coping : an improved process approach

Despite more than three decades of research, there is a limited understanding of the transactional processes of appraisal, stress and coping. This has led to calls for more focused research on the entire process that underlies these variables. To date, there remains a paucity of such research. The present study examined Lazarus and Folkman’s (1984) transactional model of stress and coping. One hundred and twenty nine Australian participants with full time employment (i.e. nurses and administration employees) were recruited. There were 49 male (age mean = 34, SD = 10.51) and 80 female (age mean = 36, SD = 10.31) participants. The analysis of three path models indicated that in addition to the original paths, which were found in Lazarus and Folkman’s transactional model (primary appraisal-->secondary appraisal-->stress-->coping), there were also direct links between primary appraisal and stress level time one and between stress level time one to stress level time two. This study has provided additional insights into the transactional process which will extend our understanding of how individuals appraise, cope and experience occupational stress.

Food insecurity in Brisbane : the single mother’s struggle

Using a feminist reflexive approach this paper reports on interviews with single mother’s in the Brisbane area about their experiences with food shopping and household food security. Preliminary findings suggest that most experience significant stress around the amount of money they have available for food. As the price of food and other costs of living increase, the only budget item that is flexible – groceries - is squeezed tighter. All women expressed a reluctance to ask for help from strangers at agencies instead relying on the support of family and friends to keep them food secure. Sometimes family and friends had no spare resources to help or were not aware of the extent their friend or relative might be struggling. The increased risks of poverty and food insecurity mean many go without as feeding the children takes precedence. The quality of their diets is variable with many reporting on aiming for quantity rather than being concerned with nutritional balance. Exhaustion and stress from being over-committed doing three roles, mother, father and housekeeper was self-identified as a key factor leading to mental health conditions such as depression, burnout and break down. Female single parent households are vulnerable to reducing welfare benefits as children grow or child support changes. Current policy forces single parents out to work but many can only manage part-time work for lower wages and are barely able to cope with this extra burden often resenting the reduction in benefits it brings. Public perceptions, derision and the notions of choice surrounding single parenting leave the cohort divided and silent for fear of reprisals. In my investigation issues arise about welfare policy that keep benefits low and workplace patriarchal power that can contribute to systemic poverty and the widening of the gender gap in poverty. So far analysis suggests a better support system around community food security including some hands on home help services, nutritional information, cooking classes, community gardening and other social capital building activities are needed for these women in order to avoid long-term health problems and help them better care for the next generation.

Micro-family-owned business : transitory survival mechanism or long term wealth creator?

Principal Topic: Entrepreneurship is key to employment, innovation and growth (Acs & Mueller, 2008), and as such, has been the subject of tremendous research in both the economic and management literatures since Solow (1957), Schumpeter (1934, 1943), and Penrose (1959). The presence of entrepreneurs in the economy is a key factor in the success or failure of countries to grow (Audretsch and Thurik, 2001; Dejardin, 2001). Further studies focus on the conditions of existence of entrepreneurship, influential factors invoked are historical, cultural, social, institutional, or purely economic (North, 1997; Thurik 1996 & 1999). Of particular interest, beyond the reasons behind the existence of entrepreneurship, are entrepreneurial survival and good ''performance'' factors. Using cross-country firm data analysis, La Porta & Schleifer (2008) confirm that informal micro-businesses provide on average half of all economic activity in developing countries. They find that these are utterly unproductive compared to formal firms, and conclude that the informal sector serves as a social security net ''keep[ing] millions of people alive, but disappearing over time'' (abstract). Robison (1986), Hill (1996, 1997) posit that the Indonesian government under Suharto always pointed to the lack of indigenous entrepreneurship , thereby motivating the nationalisation of all industries. Furthermore, the same literature also points to the fact that small businesses were mostly left out of development programmes because they were supposed less productive and having less productivity potential than larger ones. Vial (2008) challenges this view and shows that small firms represent about 70% of firms, 12% of total output, but contribute to 25% of total factor productivity growth on average over the period 1975-94 in the industrial sector (Table 10, p.316). ---------- Methodology/Key Propositions: A review of the empirical literature points at several under-researched questions. Firstly, we assess whether there is, evidence of small family-business entrepreneurship in Indonesia. Secondly, we examine and present the characteristics of these enterprises, along with the size of the sector, and its dynamics. Thirdly, we study whether these enterprises underperform compared to the larger scale industrial sector, as it is suggested in the literature. We reconsider performance measurements for micro-family owned businesses. We suggest that, beside productivity measures, performance could be appraised by both the survival probability of the firm, and by the amount of household assets formation. We compare micro-family-owned and larger industrial firms' survival probabilities after the 1997 crisis, their capital productivity, then compare household assets of families involved in business with those who do not. Finally, we examine human and social capital as moderators of enterprises' performance. In particular, we assess whether a higher level of education and community participation have an effect on the likelihood of running a family business, and whether it has an impact on households' assets level. We use the IFLS database compiled and published by RAND Corporation. The data is a rich community, households, and individuals panel dataset in four waves: 1993, 1997, 2000, 2007. We now focus on the waves 1997 and 2000 in order to investigate entrepreneurship behaviours in turbulent times, i.e. the 1997 Asian crisis. We use aggregate individual data, and focus on households data in order to study micro-family-owned businesses. IFLS data covers roughly 7,600 households in 1997 and over 10,000 households in 2000, with about 95% of 1997 households re-interviewed in 2000. Households were interviewed in 13 of the 27 provinces as defined before 2001. Those 13 provinces were targeted because accounting for 83% of the population. A full description of the data is provided in Frankenberg and Thomas (2000), and Strauss et alii (2004). We deflate all monetary values in Rupiah with the World Development Indicators Consumer Price Index base 100 in 2000. ---------- Results and Implications: We find that in Indonesia, entrepreneurship is widespread and two thirds of households hold one or several family businesses. In rural areas, in 2000, 75% of households run one or several businesses. The proportion of households holding both a farm and a non farm business is higher in rural areas, underlining the reliance of rural households on self-employment, especially after the crisis. Those businesses come in various sizes from very small to larger ones. The median business production value represents less than the annual national minimum wage. Figures show that at least 75% of farm businesses produce less than the annual minimum wage, with non farm businesses being more numerous to produce the minimum wage. However, this is only one part of the story, as production is not the only ''output'' or effect of the business. We show that the survival rate of those businesses ranks between 70 and 82% after the 1997 crisis, which contrasts with the 67% survival rate for the formal industrial sector (Ter Wengel & Rodriguez, 2006). Micro Family Owned Businesses might be relatively small in terms of production, they also provide stability in times of crisis. For those businesses that provide business assets figures, we show that capital productivity is fairly high, with rates that are ten times higher for non farm businesses. Results show that households running a business have larger family assets, and households are better off in urban areas. We run a panel logit model in order to test the effect of human and social capital on the existence of businesses among households. We find that non farm businesses are more likely to appear in households with higher human and social capital situated in urban areas. Farm businesses are more likely to appear in lower human capital and rural contexts, while still being supported by community participation. The estimation of our panel data model confirm that households are more likely to have higher family assets if situated in urban area, the higher the education level, the larger the assets, and running a business increase the likelihood of having larger assets. This is especially true for non farm businesses that have a clearly larger and more significant effect on assets than farm businesses. Finally, social capital in the form of community participation also has a positive effect on assets. Those results confirm the existence of a strong entrepreneurship culture among Indonesian households. Investigating survival rates also shows that those businesses are quite stable, even in the face of a violent crisis such as the 1997 one, and as a result, can provide a safety net. Finally, considering household assets - the returns of business to the household, rather than profit or productivity - the returns of business to itself, shows that households running a business are better off. While we demonstrate that uman and social capital are key to business existence, survival and performance, those results open avenues for further research regarding the factors that could hamper growth of those businesses in terms of output and employment.