Validation of a chloroquine-induced cell death mechanism for clinical use against malaria

An alternative antimalarial pathway of an ‘outdated’ drug, chloroquine (CQ), may facilitate its return to the shrinking list of effective antimalarials. Conventionally, CQ is believed to interfere with hemozoin formation at nanomolar concentrations, but resistant parasites are able to efflux this drug from the digestive vacuole (DV). However, we show that the DV membrane of both resistant and sensitive laboratory and field parasites is compromised after exposure to micromolar concentrations of CQ, leading to an extrusion of DV proteases. Furthermore, only a short period of exposure is required to compromise the viability of late-stage parasites. To study the feasibility of this strategy, mice malaria models were used to demonstrate that high doses of CQ also triggered DV permeabilization in vivo and reduced reinvasion efficiency. We suggest that a time-release oral formulation of CQ may sustain elevated blood CQ levels sufficiently to clear even CQ-resistant parasites

The Ethics of Engagement in an Age of Austerity: A Paradox Perspective

Our contribution in this paper is to highlight the ethical implications of workforce engagement strategies in an age of austerity. Hard or instrumentalist approaches to workforce engagement create the potential for situations where engaged employees are expected to work ever longer and harder with negative outcomes for their well-being. Our study explores these issues in an investigation of the enactment of an engagement strategy within a UK Health charity, where managers and workers face paradoxical demands to raise service quality and cut costs. We integrate insights from engagement, paradox, and ethic of care literatures, to explore these paradoxical demands—illustrating ways in which engagement experiences become infused with tensions when the workforce faces competing requirements to do 'more with less' resources. We argue that those targeted by these paradoxical engagement strategies need to be supported and cared for, embedded in an ethic of care that provides explicit workplace resources for helping workers and managers cope with and work through corresponding tensions. Our study points to the critical importance of support from senior and frontline managers for open communications and dialogue practices

Tumour necrosis factor-α converting enzyme (TACE) activity in human colonic epithelial cells1

Tumour necrosis factor (TNF)-α converting enzyme (TACE) releases biologically active, soluble TNF-α from transmembrane pro-TNF-α and has attracted interest as a specific therapeutic target in inflammatory bowel disease (IBD). Strong immunoreactivity for TACE protein was demonstrated recently in human colonic epithelium, but the function is unknown. We investigated if human colonic epithelial cells express functional TACE activity and how TACE expression is regulated in response to cytokine stimulation. TACE and TNF-α mRNA and protein expression were measured in HT-29 and DLD-1 colonic epithelial cells by reverse-transcription polymerase chain reaction, western blotting or enzyme-linked immunosorbent assay. Monocytic THP-1 cells served as positive control. Functional TACE activity was identified and quantified in detergent extracts of cell lines and freshly isolated colonocytes from 14 IBD patients and five controls by a hydrolysis assay using an oligopeptide spanning the cleavage site in pro-TNF-α. HT-29 and DLD-1 cells spontaneously expressed TACE mRNA and the active form of TACE protein at levels similar to those of monocytic cells. Functional TACE activity was demonstrated in all cell lines and in cells of controls or IBD patients irrespective of disease activity. TACE mRNA expression and functional activity remained unchanged in cell lines after stimulation with TNF-α despite clear induction of TNF-α mRNA expression and release of soluble TNF-α protein. The release of soluble TNF-α protein was almost completely abolished by CH4474, a synthetic TACE inhibitor. We conclude that functional TACE activity is constitutively expressed in human colonic epithelial cells and responsible for processing of the mature, soluble form of TNF-α in response to cytokine stimulation

Teacher professional development under the impact of internationalization in VET

This chapter addresses the professional learning needs of teachers in the vocational education and training (VET) sector under the changed circumstances of internationalization and international student mobility. International education is Australia’s largest service export, contributing over $16 billion to the national economy annually. Australian VET teachers are facing significant professional challenges to engage with pedagogical issues in teaching international students. However, there has been a lack of research on how teachers are equipped to effectively cater for international students and respond to the demands of internationalization in VET through professional development. Drawing on empirical research and positioning theory, this chapter analyzes the impact of the presence of international students on VET teachers’ professional learning needs and practices. The findings suggest the need to systemically and explicitly support substantive professional learning with regard to approaches to engaging and teaching international students. The findings in particular show teachers’ aspiration for deep and responsive capacity building and professional learning concerning three primary areas including understandings of international students’ backgrounds and motives for undertaking Australian VET, currency with research on international students, and capacity to develop pedagogies responsive to this cohort. Professional learning centered on these areas is essential to foster conditions for the generation of a more truly student-centered and international student-responsive practices among teachers

Interferon-gamma is causatively involved in experimental inflammatory bowel disease in mice

Cytokines may be crucially involved in the pathogenesis of inflammatory bowel diseases (IBD), but it remains controversial whether interferon (IFN)-γ, a typical proinflammatory cytokine, is an essential mediator to cause the disorders. In the present study, IFN-γ–/– and wild-type (WT) C57BL/6 mice were fed 2·5% dextran sodium sulphate (DSS) in drinking water for 7 days, in order to investigate DSS-induced intestinal inflammation. The DSS-treated WT mice exhibited a robust production of IFN-γ in the gut, a remarkable loss of body weight, as well as high rate of mortality (60%). In striking contrast, IFN-γ deficient mice did not develop DSS-induced colitis, as indicated by the maintenance of body weight and survival rate of 100%. Severe intestinal inflammation was demonstrated exclusively in WT animals in terms of the shortening of the bowel as well as the elevation of the disease activity index, myeloperoxidase (MPO) activity and serum haptoglobin level. Histological study of DSS-treated WT intestine revealed disruption of mucosal epithelium and massive infiltration of inflammatory cells, while the organ from IFN-γ–/– mice remained virtually normal in appearance. Enzyme-linked immunosorbent assay (ELISA) analyses indicated abundant production of three chemokines, i.e. monokine induced by interferon-γ (MIG), interferon-inducible protein 10 (IP-10) and monocyte chemoattractant protein-1 (MCP-1), in the DSS-irritated intestine of WT but not of IFN-γ–/– mice. The present results demonstrate clearly that IFN-γ plays indispensable roles in the initiation of DSS colitis, and some chemokines are produced in an IFN-γ-dependent fashion