Dynamic axial ligand-site exchange in facially discriminated ruthenium(II) carbonyl and rhodium(III) halide metalloporphyrins

For a series of six-coordinate Ru(II)(CO)L or Rh(III)(X–)L porphyrins which are facially differentiated by having a naphthoquinol- or hydroquinol-containing strap across one face, we show that ligand migration from one face to the other can occur under mild conditions, and that ligand site preference is dependent on the nature of L and X–. For bulky nitrogen-based ligands, the strap can be displaced sideways to accommodate the ligand on the same side as the strap. For the ligand pyrazine, we show 1 H NMR evidence for monodentate and bidentate binding modes on both faces, dependent on ligand concentration and metalloporphyrin structure, and that inter-facial migration is rapid under normal conditions. For monodentate substituted pyridine ligands there is a site dependence on structure, and we show clear evidence of dynamic ligand migration through a series of ligand exchange reactions.

Proteasome inhibitors trigger NOXA-mediated apoptosis in melanoma and myeloma cells

Patients with metastatic melanoma or multiple myeloma have a dismal prognosis because these aggressive malignancies resist conventional treatment. A promising new oncologic approach uses molecularly targeted therapeutics that overcomes apoptotic resistance and, at the same time, achieves tumor selectivity. The unexpected selectivity of proteasome inhibition for inducing apoptosis in cancer cells, but not in normal cells, prompted us to define the mechanism of action for this class of drugs, including Food and Drug Administration-approved bortezomib. In this report, five melanoma cell lines and a myeloma cell line are treated with three different proteasome inhibitors (MG-132, lactacystin, and bortezomib), and the mechanism underlying the apoptotic pathway is defined. Following exposure to proteasome inhibitors, effective killing of human melanoma and myeloma cells, but not of normal proliferating melanocytes, was shown to involve p53-independent induction of the BH3-only protein NOXA. Induction of NOXA at the protein level was preceded by enhanced transcription of NOXA mRNA. Engagement of mitochondrial-based apoptotic pathway involved release of cytochrome c, second mitochondria-derived activator of caspases, and apoptosis-inducing factor, accompanied by a proteolytic cascade with processing of caspases 9, 3, and 8 and poly(ADP)-ribose polymerase. Blocking NOXA induction using an antisense (but not control) oligonucleotide reduced the apoptotic response by 30% to 50%, indicating a NOXA-dependent component in the overall killing of melanoma cells. These results provide a novel mechanism for overcoming the apoptotic resistance of tumor cells, and validate agents triggering NOXA induction as potential selective cancer therapeutics for life-threatening malignancies such as melanoma and multiple myeloma.

Action inquiry into the use of standardized evaluation tools for music therapy : a real life journey within a parent-child community program

Sing & Grow is an early intervention music therapy project that provides community group music therapy programs to families with young children who encounter risk factors that may impact on parenting and optimal child develop variety of evaluation tools were devised and used over the first 3 years of the project. Upon the subsequent funding and expansion of the project at the end of this period, it was necessary to find, test and devise more rigorous, valid and reliable measures to withstand the scrutiny of researchers, and to combat the concerns and criticisms associated with the previous methods of data collection. An action inquiry project was therefore undertaken with two groups of project participants to trial the use of the Parenting Stress Index and Depression, Anxiety and Stress Scales, both recommended by leading psychologists. Key findings that will be discussed include the friction between the deficit-focussed nature of many psychometric tools and the strengths-based approach taken in service delivery, the level of difficulty in terms of literacy and comprehension for vulnerable respondents, and the lack of one tool with the ability to comprehensively measure all aspects of a broad scoping program. Keywords: music therapy, evaluation, PSI, DASS, action inquiry.

Having a yarn about smoking : using action research to develop a 'no smoking' policy within an Aboriginal health organisation

Objectives: This article reports on a culturally appropriate process of development of a smoke-free workplace policy within the peak Aboriginal Controlled Community Health Organisation in Victoria, Australia. Smoking is acknowledged as being responsible for at least 20% of all deaths in Aboriginal communities in Australia, and many Aboriginal health workers smoke. Methods: The smoke-free workplace policy was developed using the iterative, discursive and experience-based methodology of Participatory Action Research, combined with the culturally embedded concept of ‘having a yarn’. Results: Staff members initially identified smoking as a topic to be avoided within workplace discussions. This was due, in part, to grief (everyone had suffered a smoking related bereavement). Further, there was anxiety that discussing smoking would result in culturally difficult conflict. The use of yarning opened up a safe space for discussion and debate,enabling development of a policy that was accepted across the organisation. Conclusions: Within Aboriginal organisations, it is not sufficient to focus on the outcomes of policy development. Rather, due attention must be paid to the process employed in development of policy, particularly when that policy is directly related to an emotionally and communally weighted topic such as smoking.

Exploring the parameter space of a rabbit ventricular action potential model to investigate the effect of variation on action potential and calcium transients

Computational models for cardiomyocyte action potentials (AP) often make use of a large parameter set. This parameter set can contain some elements that are fitted to experimental data independently of any other element, some elements that are derived concurrently with other elements to match experimental data, and some elements that are derived purely from phenomenological fitting to produce the desired AP output. Furthermore, models can make use of several different data sets, not always derived for the same conditions or even the same species. It is consequently uncertain whether the parameter set for a given model is physiologically accurate. Furthermore, it is only recently that the possibility of degeneracy in parameter values in producing a given simulation output has started to be addressed. In this study, we examine the effects of varying two parameters (the L-type calcium current (I(CaL)) and the delayed rectifier potassium current (I(Ks))) in a computational model of a rabbit ventricular cardiomyocyte AP on both the membrane potential (V(m)) and calcium (Ca(2+)) transient. It will subsequently be determined if there is degeneracy in this model to these parameter values, which will have important implications on the stability of these models to cell-to-cell parameter variation, and also whether the current methodology for generating parameter values is flawed. The accuracy of AP duration (APD) as an indicator of AP shape will also be assessed.