Protein kinase activity of phosphoinositide 3-kinase regulates cytokine-dependent cell survival

Extent: 14 p.The dual specificity protein/lipid kinase, phosphoinositide 3-kinase (PI3K), promotes growth factor-mediated cell survival and is frequently deregulated in cancer. However, in contrast to canonical lipid-kinase functions, the role of PI3K protein kinase activity in regulating cell survival is unknown. We have employed a novel approach to purify and pharmacologically profile protein kinases from primary human acute myeloid leukemia (AML) cells that phosphorylate serine residues in the cytoplasmic portion of cytokine receptors to promote hemopoietic cell survival. We have isolated a kinase activity that is able to directly phosphorylate Ser585 in the cytoplasmic domain of the interleukin 3 (IL-3) and granulocyte macrophage colony stimulating factor (GM-CSF) receptors and shown it to be PI3K. Physiological concentrations of cytokine in the picomolar range were sufficient for activating the protein kinase activity of PI3K leading to Ser585 phosphorylation and hemopoietic cell survival but did not activate PI3K lipid kinase signaling or promote proliferation. Blockade of PI3K lipid signaling by expression of the pleckstrin homology of Akt1 had no significant impact on the ability of picomolar concentrations of cytokine to promote hemopoietic cell survival. Furthermore, inducible expression of a mutant form of PI3K that is defective in lipid kinase activity but retains protein kinase activity was able to promote Ser585 phosphorylation and hemopoietic cell survival in the absence of cytokine. Blockade of p110α by RNA interference or multiple independent PI3K inhibitors not only blocked Ser585 phosphorylation in cytokine-dependent cells and primary human AML blasts, but also resulted in a block in survival signaling and cell death. Our findings demonstrate a new role for the protein kinase activity of PI3K in phosphorylating the cytoplasmic tail of the GM-CSF and IL-3 receptors to selectively regulate cell survival highlighting the importance of targeting such pathways in cancer.Daniel Thomas, Jason A. Powell, Benjamin D. Green, Emma F. Barry, Yuefang Ma, Joanna Woodcock, Stephen Fitter, Andrew C.W. Zannettino, Stuart M. Pitson, Timothy P. Hughes, Angel F. Lopez, Peter R. Shepherd, Andrew H. Wei, Paul G. Ekert and Mark A. Guthridg

Internal standard-based analysis of microarray data2—Analysis of functional associations between HVE-genes

In this work we apply the Internal Standard-based analytical approach that we described in an earlier communication and here we demonstrate experimental results on functional associations among the hypervariably-expressed genes (HVE-genes). Our working assumption was that those genetic components, which initiate the disease, involve HVE-genes for which the level of expression is undistinguishable among healthy individuals and individuals with pathology. We show that analysis of the functional associations of the HVE-genes is indeed suitable to revealing disease-specific differences. We show also that another possible exploit of HVE-genes for characterization of pathological alterations is by using multivariate classification methods. This in turn offers important clues on naturally occurring dynamic processes in the organism and is further used for dynamic discrimination of groups of compared samples. We conclude that our approach can uncover principally new collective differences that cannot be discerned by individual gene analysi

Measuring the value of placements to employers: A cost-benefit approach

This article explores the concept and measurement of placement value, underexplored in theory and practice to date. The article makes a theoretical contribution to the placement value discourse by examining and articulating the placement value concept. It also offers a practical contribution by exploring a piloted tool to evaluate employer placement value, developed as part of a project funded by the Higher Education Funding Council for England. It examines the immaturity of the placement value concept against contemporary value discourse, including service- and goods-dominant logic frameworks (exploring value-in-use and value-in-exchange) and calls for greater attention to be paid to placement value to support the sustainable provision of placements.N/

Remote health workforce turnover and retention: What are the policy and practice priorities?

BACKGROUND:Residents of remote communities in Australia and other geographically large countries have comparatively poorer access to high-quality primary health care. To inform ongoing policy development and practice in relation to remote area health service delivery, particularly in remote Indigenous communities, this review synthesizes the key findings of (1) a comprehensive study of workforce turnover and retention in remote Northern Territory (NT) of Australia and (2) a narrative review of relevant international literature on remote and rural health workforce retention strategies. This synthesis provides a valuable summary of the current state of international knowledge about improving remote health workforce retention. MAIN TEXT:Annual turnover rates of NT remote area nurses (148%) and Aboriginal health practitioners (80%) are very high and 12-month stability rates low (48% and 76%, respectively). In remote NT, use of agency nurses has increased substantially. Primary care costs are high and proportional to staff turnover and remoteness. Effectiveness of care decreases with higher turnover and use of short-term staff, such that higher staff turnover is always less cost-effective. If staff turnover in remote clinics were halved, the potential savings would be approximately A$32 million per annum. Staff turnover and retention were affected by management style and effectiveness, and employment of Indigenous staff. Review of the international literature reveals three broad themes: Targeted enrolment into training and appropriate education designed to produce a competent, accessible, acceptable and 'fit-for-purpose' workforce; addressing broader health system issues that ensure a safe and supportive work environment; and providing ongoing individual and family support. Key educational initiatives include prioritising remote origin and Indigenous students for university entry; maximising training in remote areas; contextualising curricula; providing financial, pedagogical and pastoral support; and ensuring clear, supported career pathways and continuing professional development. Health system initiatives include ensuring adequate funding; providing adequate infrastructure including fit-for-purpose clinics, housing, transport and information technology; offering flexible employment arrangements whilst ensuring a good 'fit' between individual staff and the community (especially with regard to cultural skills); optimising co-ordination and management of services that empower staff and create positive practice environments; and prioritising community participation and employment of locals. Individual and family supports include offering tailored financial incentives, psychological support and 'time out'. CONCLUSION:Optimal remote health workforce stability and preventing excessive 'avoidable' turnover mandates alignment of government and health authority policies with both health service requirements and individual health professional and community needs. Supportive underpinning policies include: Strong intersectoral collaboration between the health and education sectors to ensure a fit-for-purpose workforce;A funding policy which mandates the development and implementation of an equitable, needs-based formula for funding remote health services;Policies that facilitate transition to community control, prioritise Indigenous training and employment, and mandate a culturally safe work context; andAn employment policy which provides flexibility of employment conditions in order to be able to offer individually customised retention packages There is considerable extant evidence from around the world about effective retention strategies that contribute to slowing excessive remote health workforce turnover, resulting in significant cost savings and improved continuity of care. The immediate problem comprises an 'implementation gap' in translating empirical research evidence into actions designed to resolve existing problems. If we wish to ameliorate the very high turnover of staff in remote areas, in order to provide an equitable service to populations with arguably the highest health needs, we need political and executive commitment to get the policy settings right and ensure the coordinated implementation of multiple strategies, including better linking existing strategies and 'filling the gaps' where necessary.John Wakerman, John Humphreys, Deborah Russell, Steven Guthridge, Lisa Bourke, Terry Dunbar, Yuejen Zhao, Mark Ramjan, Lorna Murakami-Gold and Michael P. Jone

Assessing the Impact and Cost of Short-Term Health Workforce in Remote Indigenous Communities in Australia: A Mixed Methods Study Protocol

Background: Remote Australia is a complex environment characterized by workforce shortages, isolated practice, a large resident Indigenous population, high levels of health need, and limited access to services. In recent years, there has been an increasing trend of utilizing a short-term visiting (fly-in/fly-out) health workforce in many remote areas. However, there is a dearth of evidence relating to the impact of this transitory workforce on the existing resident workforce, consumer satisfaction, and the effectiveness of current services. Objective: This study aims to provide rigorous empirical data by addressing the following objectives: (1) to identify the impact of short-term health staff on the workload, professional satisfaction, and retention of resident health teams in remote areas; (2) to identify the impact of short-term health staff on the quality, safety, and continuity of patient care; and (3) to identify the impact of short-term health staff on service cost and effectiveness. Methods: Mixed methods will be used. Administrative data will be extracted that relates to all 54 remote clinics managed by the Northern Territory Department of Health, covering a population of 35,800. The study period will be 2010 to 2014. All 18 Aboriginal Community-Controlled Health Services in the Northern Territory will also be invited to participate. We will use these quantitative data to describe staffing stability and turnover in these communities, and then utilize multiple regression analyses to determine associations between the key independent variables of interest (resident staff turnover, stability or median survival, and socioeconomic status, community size, and per capita funding) and dependent variables related to patient care, service cost, quality, and effectiveness. The qualitative component of the study will involve in-depth interviews and focus groups with staff and patients, respectively, in six remote communities. Three communities will be high staff turnover communities and three characterized by low turnover. This will provide information on service quality, impact on resident and visiting staff, and patient satisfaction with the services. The research team will work with staff, patients, and a key stakeholder group of senior policymakers to develop workforce strategies to maintain or attain remote health workforce stability. Results: The study commenced in 2015. As of October 2016, fieldwork has been almost completed and quantitative analysis has commenced. Results are expected to be published in 2017. Conclusions: The study has commenced, but it is too early to provide results or conclusions.John Wakerman, John Humphreys, Lisa Bourke, Terry Dunbar, Michael Jones, Timothy A Carey, Steven Guthridge, Deborah Russell, David Lyle, Yuejen Zhao, Lorna Murakami-Gol

Genetic association of CD247 (CD3ζ) with SLE in a large-scale multiethnic study

A classic T-cell phenotype in systemic lupus erythematosus (SLE) is the downregulation and replacement of the CD3ζ chain that alters T-cell receptor signaling. However, genetic associations with SLE in the human CD247 locus that encodes CD3ζ are not well established and require replication in independent cohorts. Our aim was therefore to examine, localize and validate CD247-SLE association in a large multiethnic population. We typed 44 contiguous CD247 single-nucleotide polymorphisms (SNPs) in 8922 SLE patients and 8077 controls from four ethnically distinct populations. The strongest associations were found in the Asian population (11 SNPs in intron 1, 4.99 × 10(-4) < P < 4.15 × 10(-2)), where we further identified a five-marker haplotype (rs12141731-rs2949655-rs16859085-rs12144621-rs858554; G-G-A-G-A; P(hap) = 2.12 × 10(-5)) that exceeded the most associated single SNP rs858554 (minor allele frequency in controls = 13%; P = 4.99 × 10(-4), odds ratio = 1.32) in significance. Imputation and subsequent association analysis showed evidence of association (P < 0.05) at 27 additional SNPs within intron 1. Cross-ethnic meta-analysis, assuming an additive genetic model adjusted for population proportions, showed five SNPs with significant P-values (1.40 × 10(-3) < P< 3.97 × 10(-2)), with one (rs704848) remaining significant after Bonferroni correction (P(meta) = 2.66 × 10(-2)). Our study independently confirms and extends the association of SLE with CD247, which is shared by various autoimmune disorders and supports a common T-cell-mediated mechanism.National Institutes of Health grants: (UL1RR025741, K24AR002138, P602AR30692, P01AR49084, UL1TR000165, P01AI083194, RO1AR43814, P60AR053308, UL1TR000004, AR43727, R21AI070304, RO1AR057172, UL1RR025014, R01AR051545-03, UL1RR029882, P60AR062755, P30AR53483, U19AI082714, P30GM103510, U01AI101934, AI063274, AR056360, AI083194, R37AI024717, P01083194, P01AR049084, PR094002); Northwestern University Feinberg School of Medicine; University of Alabama Birmingham; National Institute of Arthritis and Musculoskeletal and Skin Diseases; University of California Los Angeles; University of California San Francisco; Hopkins University; University of Colorado School of Medicine; University of Southern California; Seattle Children's Research Institute Arthritis Foundation; Medical University of South Carolina; Oklahoma Medical Research Foundation; Cincinnati Children's Hospital Medical Center; US Departments of Defense grant: (PR094002); Veterans Affairs; Alliance for Lupus Research; Kirkland Scholar Award; Korea Healthcare technology R & D project: (A121983); Ministry for Health and Welfare; Republic of Korea; Swedish Research Council; Instituto de Salud Carlos III grant: (PS09/00129); European Union FEDER funds; Fundação para a Ciência e Tecnologia fellowships: (SFRH/BPD/29354/2006, SFRH/BPD/34648/2007)

A Comprehensive and Universal Method for Assessing the Performance of Differential Gene Expression Analyses

The number of methods for pre-processing and analysis of gene expression data continues to increase, often making it difficult to select the most appropriate approach. We present a simple procedure for comparative estimation of a variety of methods for microarray data pre-processing and analysis. Our approach is based on the use of real microarray data in which controlled fold changes are introduced into 20% of the data to provide a metric for comparison with the unmodified data. The data modifications can be easily applied to raw data measured with any technological platform and retains all the complex structures and statistical characteristics of the real-world data. The power of the method is illustrated by its application to the quantitative comparison of different methods of normalization and analysis of microarray data. Our results demonstrate that the method of controlled modifications of real experimental data provides a simple tool for assessing the performance of data preprocessing and analysis methods

Crop Updates 2000 - Pulses

This session covers fifty nine papers from different authors: 1.1999 PULSE INDUSTRY HIGHLIGHTS 2. CONTRIBUTORS 3. BACKGROUND 4. SUMMARY OF PREVIOUS RESULTS 5. 1999 REGIONAL ROUNDUP 6. Northern Agricultural Region, W. O’Neill, AGWEST 7. Central Agricultural Region J. Russell and R.J. French AGWEST 8. Great Southern and Lakes N. Brandon, C. Gaskin and N. Runciman, AGWEST 9. Esperance Mallee M. Seymour, AGWEST PULSE PRODUCTION AGRONOMY AND GENETIC IMPROVEMENT 10. Faba Bean 11. Desi chickpea Traits associated with drought resistance in chickpea, J. Berger, N.C. Turner, CLIMA and CSIRO Plant Industry, R.J. French, AGWEST, R. Carpenter, C. Ludwig and R. Kenney, CSIRO Plant Industry 12. Genotype x environment analysis of chickpea adaptation, J. Berger and N. Turner, CLIMA and CSIRO Plant Industry, and K.H.M. Siddique, AGWEST 13. Carbon fixation by chickpea pods under terminal drought, Q. Ma, CLIMA, M.H. Behboudian, Massey University, New Zealand, N.C. Turner and J.A. Palta, CLIMA, and CSIRO Plant Industry 14. Influence of terminal drought on growth and seed quality, M.H. Behboudian, Massey University, New Zealand, Q. Ma, CLIMA, N.C. Turner and J.A. Palta, CSIRO Plant Industry 15. Resistance to chilling at flowering and to budworm, H. Clarke, CLIMA Chickpea nodulation survey, J. Stott and J. Howieson, Centre for Rhizobium Studies, Murdoch University 16. Kabuli chickpea 17. Premium quality kabuli chickpea development in the ORIA, K.H.M. Siddique CLIMA and AGWEST, K.L. Regan, AGWEST, R. Shackles, AGWEST 18. International screening for Ascochyta blight resistance, K.H.M. Siddique CLIMA and AGWEST, C. Francis, CLIMA, K.L. Regan, AGWEST, N. Acikgoz and N. Atikyilmaz, AARI, Turkey and R.S. Malholtra, ICARDA, Syria 19. Agronomic evaluation of Ascochyta resistant kabuli germplasm in WA, K.H.M. Siddique CLIMA and AGWESTC. Francis, CLIMA, K.L. Regan and M. Baker, AGWEST 20. Field Pea 21. Lentil 22. ACIAR project J. Clements, K.H.M. Siddique CLIMA and AGWEST and C. Francis CLIMA 23. Vetch 24. Rust, M. Seymour, AGWEST 25. Narbon bean 26. Agronomy, M. Seymour, AGWEST 27. Lupinus species 28. Screening lupins for tolerance to alkaline/calcareous soils, C. Tang, CLIMA andUniversity of WAand J.D. Brand, WAITE, University of Adelaide 29. Lathyrus development, C. Hanbury and K.H.M. Siddique, CLIMA and AGWEST 30. Sheep feeding studies, C. White, CSIRO, Perth, C. Hanbury, CLIMA and K.H.M. Siddique, CLIMA and AGWEST 31. Lathyrus: a potential new ingredient in pig diets, B.P. Mullan, C.D. Hanbury and K.H.M. Siddique, AGWEST 32. Species comparison 33. Species for horticultural rotations, K.H.M. Siddique, AGWEST, R. Lancaster and I. Guthridge AGWEST 34. Marrow fat field pea shows promise in the southwest, K.H.M. Siddique, AGWEST, N. Runciman, AGWEST, and I. Pritchard, AGWEST, 35. Pulses on grey clay soils, P. Fisher, M. Braimbridge, J. Bignell, N. Brandon, R. Beermier, W. Bowden, AGWEST 36. Nutrient management of pulses 37. Summary of pulse nutrition studies in WA, M.D.A. Bolland, K.H.M. Siddique, G.P. Riethmuller, and R.F. Brennan, AGWEST 38. Pulse species response to phosphorus and zinc, S. Lawrence, Zed Rengel, University of WA, S.P. Loss, CSBP futurefarm, M.D.A. Bolland, .H.M. Siddique, W. Bowden, AGWEST 39. Gypsum 40. Antitranspirants seed priming DEMONSTRATION OF PULSES IN THE FARMING SYSTEM 41. Foliar and soil applied nutrients for field peas in the south coast mallee,M. Seymour, AGWEST, and P. Vedeniapine, Phosyn Ltd 42. Demonstration of pulse species at Kendenup, C. Kirkwood, Farmer, Katanning, R. Beermier, N. Runciman and N. Brandon, AGWEST 43. Kabuli chickpea demonstration at Gnowangerup, R. Beermier and N. Brandon, AGWEST 44. Lathyrus sativus demonstration at Mindarabin, N. Brandon and R. Beermier, AGWEST 45. New field pea varieties in the central eastern region, J. Russell, AGWEST DISEASE AND PEST MANAGEMENT 46. Ascochyta blight of chickpea 47. Botrytis grey mould (BGM) of chickpea 48. Fungal disease diagnostics, Pulse disease diagnostics, D. Wright, AGWEST Plant Laboratories 49. Viruses in pulses, Luteovirus infection in field pea and faba bean crops, and viruses in seed, L. Latham, CLIMA and AGWEST, R. Jones, AGWEST 50. Screening of pulse species for pea seed-borne mosaic virus, L. Latham, CLIMAand AGWEST, and R. Jones, AGWEST 51. CMV in chickpea: effect of seed-borne sources on virus spread and seed yield, R. Jones, AGWEST and L. Latham, CLIMA and AGWEST 52. Insect pests 53. Evaluation of transgenic field pea against the pea weevil,M.J. de Sousa Majer, School of Environmental Biology, Curtin University of Technology,, D. Hardie, and N.C. Turner, CSIRO Division of Plant Industry 54. Development of a molecular marker for pea weevil resistance in field pea, Oonagh Byrne, CLIMA, Darryl Hardie, AGWEST and Penny Smith, UWA 55. Aphid feeding damage to faba bean and lentil crops, Françoise Berlandier, AGWEST 56. Taxonomy and control of bruchids in pulses, N. Keals, CLIMA, D. Hardie and R. Emery, AGWEST, 57. ACKNOWLEDGMENTS 58. PUBLICATIONS BY PULSE PRODUCTIVITY PROJECT STAFF 59. VARIETIES PRODUCED AND COMMERCIALLY RELEASE

Skin infection, housing and social circumstances in children living in remote Indigenous communities: testing conceptual and methodological approaches

BACKGROUND: Poor housing conditions in remote Indigenous communities in Australia are a major underlying factor in poor child health, including high rates of skin infections. The aim of this study is to test approaches to data collection, analysis and feedback for a follow-up study of the impact of housing conditions on child health. METHODS: Participation was negotiated in three communities with community councils and individual participants. Data were collected by survey of dwelling condition, interviews, and audit health centre records of children aged under seven years. Community feedback comprised immediate report of items requiring urgent repair followed by a summary descriptive report. Multivariate models were developed to calculate adjusted incidence rate ratios (IRR) for skin infections and their association with aspects of household infrastructure. RESULTS: There was a high level of participation in all communities. Health centre records were inadequate for audit in one community. The records of 138 children were available for development of multivariate analytic models. Rates of skin infection in dwellings that lacked functioning facilities for removing faeces or which had concrete floors may be up to twice as high as for other dwellings, and the latter association appears to be exacerbated by crowding. Younger children living in older dwellings may also be at approximately two-fold higher risk. A number of socioeconomic and socio-demographic variables also appear to be directly associated with high rates of skin infections. CONCLUSION: The methods used in the pilot study were generally feasible, and the analytic approach provides meaningful results. The study provides some evidence that new and modern housing is contributing to a reduction in skin infections in Aboriginal children in remote communities, particularly when this housing leads to a reduction in crowding and the effective removal of human waste

Transancestral mapping and genetic load in systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is an autoimmune disease with marked gender and ethnic disparities. We report a large transancestral association study of SLE using Immunochip genotype data from 27,574 individuals of European (EA), African (AA) and Hispanic Amerindian (HA) ancestry. We identify 58 distinct non-HLA regions in EA, 9 in AA and 16 in HA (∼50% of these regions have multiple independent associations); these include 24 novel SLE regions (P<5 × 10-8), refined association signals in established regions, extended associations to additional ancestries, and a disentangled complex HLA multigenic effect. The risk allele count (genetic load) exhibits an accelerating pattern of SLE risk, leading us to posit a cumulative hit hypothesis for autoimmune disease. Comparing results across the three ancestries identifies both ancestry-dependent and ancestry-independent contributions to SLE risk. Our results are consistent with the unique and complex histories of the populations sampled, and collectively help clarify the genetic architecture and ethnic disparities in SLE.info:eu-repo/semantics/publishedVersio