Genome-wide analysis in a murine Dnmt1 knockdown model identifies epigenetically silenced genes in primary human pituitary tumors

DNA methylation at promoter CpG islands (CGI) is an epigenetic modification associated with inappropriate gene silencing in multiple tumor types. In the absence of a human pituitary tumor cell line, small interfering RNA-mediated knockdown of the maintenance methyltransferase DNA methyltransferase (cytosine 5)-1 (Dnmt1) was used in the murine pituitary adenoma cell line AtT-20. Sustained knockdown induced reexpression of the fully methylated and normally imprinted gene neuronatin (Nnat) in a time-dependent manner. Combined bisulfite restriction analysis (COBRA) revealed that reexpression of Nnat was associated with partial CGI demethylation, which was also observed at the H19 differentially methylated region. Subsequent genome-wide microarray analysis identified 91 genes that were significantly differentially expressed in Dnmt1 knockdown cells (10% false discovery rate). The analysis showed that genes associated with the induction of apoptosis, signal transduction, and developmental processes were significantly overrepresented in this list (P < 0.05). Following validation by reverse transcription-PCR and detection of inappropriate CGI methylation by COBRA, four genes (ICAM1, NNAT, RUNX1, and S100A10) were analyzed in primary human pituitary tumors, each displaying significantly reduced mRNA levels relative to normal pituitary (P < 0.05). For two of these genes, NNAT and S100A10, decreased expression was associated with increased promoter CGI methylation. Induced expression of Nnat in stable transfected AtT-20 cells inhibited cell proliferation. To our knowledge, this is the first report of array-based "epigenetic unmasking" in combination with Dnmt1 knockdown and reveals the potential of this strategy toward identifying genes silenced by epigenetic mechanisms across species boundaries.

Modelling the dynamics of Plasmodium falciparum histidine-rich protein 2 in human malaria to better understand malaria rapid diagnostic test performance

BACKGROUND: Effective diagnosis of malaria is a major component of case management. Rapid diagnostic tests (RDTs) based on Plasmodium falciparumhistidine-rich protein 2 (PfHRP2) are popular for diagnosis of this most virulent malaria infection. However, concerns have been raised about the longevity of the PfHRP2 antigenaemia following curative treatment in endemic regions. METHODS: A model of PfHRP2 production and decay was developed to mimic the kinetics of PfHRP2 antigenaemia during infections. Data from two human infection studies was used to fit the model, and to investigate PfHRP2 kinetics. Four malaria RDTs were assessed in the laboratory to determine the minimum detectable concentration of PfHRP2. RESULTS: Fitting of the PfHRP2 dynamics model indicated that in malaria naive hosts, P. falciparum parasites of the 3D7 strain produce 1.4 x 10(-)(1)(3) g of PfHRP2 per parasite per replication cycle. The four RDTs had minimum detection thresholds between 6.9 and 27.8 ng/mL. Combining these detection thresholds with the kinetics of PfHRP2, it is predicted that as few as 8 parasites/muL may be required to maintain a positive RDT in a chronic infection. CONCLUSIONS: The results of the model indicate that good quality PfHRP2-based RDTs should be able to detect parasites on the first day of symptoms, and that the persistence of the antigen will cause the tests to remain positive for at least seven days after treatment. The duration of a positive test result following curative treatment is dependent on the duration and density of parasitaemia prior to treatment and the presence and affinity of anti-PfHRP2 antibodies.

Geographical distribution of human Schistosoma japonicum infection in the Philippines : tools to support disease control and further elimination

S. japonicum infection is believed to be endemic in 28 of the 80 provinces of the Philippines and the most recent data on schistosomiasis prevalence have shown considerable variability between provinces. In order to increase the efficient allocation of parasitic disease control resources in the country, we aimed to describe the small scale spatial variation in S. japonicum prevalence across the Philippines, quantify the role of the physical environment in driving the spatial variation of S. japonicum, and develop a predictive risk map of S. japonicum infection. Data on S. japonicum infection from 35,754 individuals across the country were geo-located at the barangay level and included in the analysis. The analysis was then stratified geographically for Luzon, the Visayas and Mindanao. Zero-inflated binomial Bayesian geostatistical models of S. japonicum prevalence were developed and diagnostic uncertainty was incorporated. Results of the analysis show that in the three regions, males and individuals aged ≥ 20 years had significantly higher prevalence of S. japonicum compared with females and children <5 years. The role of the environmental variables differed between regions of the Philippines. S. japonicum infection was widespread in the Visayas whereas it was much more focal in Luzon and Mindanao. This analysis revealed significant spatial variation in prevalence of S. japonicum infection in the Philippines. This suggests that a spatially targeted approach to schistosomiasis interventions, including mass drug administration, is warranted. When financially possible, additional schistosomiasis surveys should be prioritized to areas identified to be at high risk, but which were underrepresented in our dataset.

Correlates of perceiving human resource management as a 'problem' in smaller firms

In this paper we investigate factors likely to correlate with human resource management (HRM) being perceived as a problem in smaller firms. The owner-manager and firm characteristics identified recognise that managerial ‘problems’ can result from a firm’s phase of growth, as well as the way in which an owner-manager’s capacity and characteristics affect their interpretation of such. From a survey of 1200 smaller firms in south east Melbourne (Australia), we use logistic regression on data from 428 respondents to assess organisational and individual factors correlating with perceiving HRM, broadly defined, to be a problem. The highest odds of this occurring were associated with being a larger manufacturing firm which was in a phase of growth other than diversification and which had a long-tenured manager who based the firm’s competitive success on factors other than the quality of staff. Knowing these correlates means assistance to help solve the perceived ‘problem’ with HRM can be more effectively targeted.

Introduction : At the Intersection of Entrepreneurship and Human Resource Management

In recent years there has been a growing literature on human resource management (HRM) and smaller firms which has also encompassed firms that are growing and entrepreneurial. For example we have seen a special edition of Entrepreneurship Theory and Practice (Katz et al., 2000), two of Human Resource Management Review (Baron, 2003; Barrett and Mayson, 2006) and one of Human Resource Management (Huselid, 2003; Tansky and Heneman, 2003), with another of Human Resource Management (to be edited by Ribeiro, Roig and Tansky) scheduled for publication in 2010. In addition, symposia on the topic have been undertaken at the Academy of Management in 2005 (organized by Mayson) and in 2004 (organized by Hayton). Papers dealing with issues of HRM for new, small, growing and/or entrepreneurial firms have been presented at a range of different conferences, whether they are management oriented such as the Academy of Management (AoM) and its regional variants (for example, the British Academy of Management (BAM) or the Australian and New Zealand Academy of Management (ANZAM)), entrepreneurially focused ones like the Babson College Entrepreneurship Research conference or ones focused specifically on smaller firms such as the conferences of the Institute for Small Business and Entrepreneurship (ISBE) in the UK or the International Council for Small Business (ICSB) and its regional affiliates. With all these papers and all this discussion is there anything left to say? Well yes, we think there is and we are...

Human resource management and entrepreneurship : building theory at the intersection

In 2008 we brought together much work at the intersection of entrepreneurship and human resource management (HRM) (Barrett & Mayson, 2008), after calls for more research (Baron, 2003; Katz, Aldrich, Welbourne & Williams, 2000; Tansky & Heneman, 2003). More has been collated since (Soriano, Dobon & Tansky, 2010; Tansky, Soriano & Dobon, 2010). We think it is now time again to regroup, pull conversational threads together and have a critical look at recent research at the intersection of HRM and Entrepreneurship. As editors of International Handbook of Entrepreneurship and HRM (Barrett & Mayson, 2008) we were privileged to collect 23 wonderfully diverse chapters from scholars around the globe addressing a range of issues at the intersection of the two pertinent disciplines or fields: HRM and entrepreneurship. This edition represented a coalescing of ideas that had been swirling about for some time. In three sections, the first dealt with theory and research methods, the second with the nature of HRM in small and entrepreneurial firms and the third with the functional aspects of HRM. At the time we were aware that the handbook did not cover the entire field and many topics were left unexplored. For example, the topic of regulation was generally absent while issues such as career advancement, performance management, organisational change and gender, diversity and ethnicity were also missing. In essence, the majority of those contributions sought to develop an understanding of the context in which particular aspects of HRM can be played out.

Non-invasive techniques for imaging in-vivo human corneal sub basal nerve mapping and migration rate in diabetic neuropathy

Purpose Corneal confocal microscopy (CCM) is a rapid non-invasive ophthalmic technique, which has been shown to diagnose and stratify the severity of diabetic neuropathy. Current morphometric techniques assess individual static images of the subbasal nerve plexus; this work explores the potential for non-invasive assessment of the wide-field morphology and dynamic changes of this plexus in vivo. Methods In this pilot study, laser scanning CCM was used to acquire maps (using a dynamic fixation target and semi-automated tiling software) of the central corneal sub-basal nerve plexus in 4 diabetic patients with and 6 without neuropathy and in 2 control subjects. Nerve migration was measured in an additional 7 diabetic patients with neuropathy, 4 without neuropathy and in 2 control subjects by repeating a modified version of the mapping procedure within 2-8 weeks, thus facilitating re-identification of distinctive nerve landmarks in the 2 montages. The rate of nerve movement was determined from these data and normalised to a weekly rate (µm/week), using customised software. Results Wide-field corneal nerve fibre length correlated significantly with the Neuropathy Disability Score (r = -0.58, p < 0.05), vibration perception (r = -0.66, p < 0.05) and peroneal conduction velocity (r = 0.67, p < 0.05). Central corneal nerve fibre length did not correlate with any of these measures of neuropathy (p > 0.05 for all). The rate of corneal nerve migration was 14.3 ± 1.1 µm/week in diabetic patients with neuropathy, 19.7 ± 13.3µm/week in diabetic patients without neuropathy, and 24.4 ± 9.8µm/week in control subjects; however, these differences were not significantly different (p = 0.543). Conclusions Our data demonstrate that it is possible to capture wide-field images of the corneal nerve plexus, and to quantify the rate of corneal nerve migration by repeating this procedure over a number of weeks. Further studies on larger sample sizes are required to determine the utility of this approach for the diagnosis and monitoring of diabetic neuropathy.

Human CD141(+) (BDCA-3)(+) dendritic cells (DCs) represent a unique myeloid DC subset that cross-presents necrotic cell antigens

The characterization of human dendritic cell (DC) subsets is essential for the design of new vaccines. We report the first detailed functional analysis of the human CD141(+) DC subset. CD141(+) DCs are found in human lymph nodes, bone marrow, tonsil, and blood, and the latter proved to be the best source of highly purified cells for functional analysis. They are characterized by high expression of toll-like receptor 3, production of IL-12p70 and IFN-beta, and superior capacity to induce T helper 1 cell responses, when compared with the more commonly studied CD1c(+) DC subset. Polyinosine-polycytidylic acid (poly I:C)-activated CD141(+) DCs have a superior capacity to cross-present soluble protein antigen (Ag) to CD8(+) cytotoxic T lymphocytes than poly I:C-activated CD1c(+) DCs. Importantly, CD141(+) DCs, but not CD1c(+) DCs, were endowed with the capacity to cross-present viral Ag after their uptake of necrotic virus-infected cells. These findings establish the CD141(+) DC subset as an important functionally distinct human DC subtype with characteristics similar to those of the mouse CD8 alpha(+) DC subset. The data demonstrate a role for CD141(+) DCs in the induction of cytotoxic T lymphocyte responses and suggest that they may be the most relevant targets for vaccination against cancers, viruses, and other pathogens.

Profiling human resource management practices in innovative firms

It has been argued that different bundles or configurations of human resource practices can improve innovation performance, but there is little empirically-based research that provides details of the practices utilised by different types of innovative firms. This study aimed to identify how different types of firms vary their HR practices to build organisation-specific innovation capabilities. The paper presents findings from a qualitative study of 26 innovative Danish firms categorised as technology-based, knowledge-intensive, or hybrid in their industry orientation. The findings highlight that knowledge-intensive firms have notably different profiles of HRM practices to technology-based firms, suggesting that firms utilise different practices to build innovation capacity depending on the core capabilities required for success in their respective industries. This paper contributes by demonstrating how HR practices differ across types of firms rather than relying on a universal perspective or one best way to design and implement HR practices.

Assessment of Geogenic Contaminants in Water Co-Produced with Coal Seam Gas Extraction in Queensland, Australia : Implications for Human Health Risk

Organic compounds in Australian coal seam gas produced water (CSG water) are poorly understood despite their environmental contamination potential. In this study, the presence of some organic substances is identified from government-held CSG water-quality data from the Bowen and Surat Basins, Queensland. These records revealed the presence of polycyclic aromatic hydrocarbons (PAHs) in 27% of samples of CSG water from the Walloon Coal Measures at concentrations <1 µg/L, and it is likely these compounds leached from in situ coals. PAHs identified from wells include naphthalene, phenanthrene, chrysene and dibenz[a,h]anthracene. In addition, the likelihood of coal-derived organic compounds leaching to groundwater is assessed by undertaking toxicity leaching experiments using coal rank and water chemistry as variables. These tests suggest higher molecular weight PAHs (including benzo[a]pyrene) leach from higher rank coals, whereas lower molecular weight PAHs leach at greater concentrations from lower rank coal. Some of the identified organic compounds have carcinogenic or health risk potential, but they are unlikely to be acutely toxic at the observed concentrations which are almost negligible (largely due to the hydrophobicity of such compounds). Hence, this study will be useful to practitioners assessing CSG water related environmental and health risk.

Organisational culture, change readiness and retention : a human services perspective

The Third Sector is experiencing unprecedented change as nonprofit organisations pursue their mission, organisational excellence and sustainability. This research collected data from employees of Australian nonprofit human service organisations. Instruments to measure organisational culture and change readiness were validated. The relationships between perceptions of organisational cultures, change readiness, job satisfaction and intentions to leave were explored. Findings indicate flexible organisational cultures influence employee attitudes more positively than control cultures. It identified that leaders have a significant role to play in developing and fostering change readiness and job satisfaction. This improves employees' adaptation to change, increases staff retention and organisational sustainability.

Human Fly

Human Fly, originally choreographed as a trio existed as one section of a larger work titled Élet [the Hungarian word for Life). Informed by the lyrics of six songs performed by French cover band Nouvelle Vague, Élet [Life] was created to be absorbed and interpreted openly by each individual. In the reworking of Human Fly I have endeavored to keep to the original intent; embracing aspects of promiscuity and seduction.

A tissue-engineered humanised xenograft model of human breast cancer-induced bone metastasis and bone colonisation

This thesis focuses on the development of a humanised mouse model to investigate human breast cancer metastasis to bone, an incurable disease presenting a major medical challenge in our society. The method is based on tissue-engineered constructs with human cells that generate a human bone-like organ within mice. This novel platform is further applied to mimic human-specific mechanisms of breast cancer metastasis and growth in human bone, and in particular the role of specific cell adhesion molecules in this process is closely investigated.