Sharon La Fontaine

This conceptual paper introduces the ‘Stepping Stone’ concept, an evidence-based and practitioner-led approach to embedded career education implemented at a large Australian metropolitan university. In response to growing policy and market pressures on higher education providers to support graduate employability, the approach acknowledges the increasing diversity of the student population and the need for personalised, flexible and contextually embedded career development interventions. Grounded in career development theory and practice wisdom, the concept takes a ‘just-in-time’ approach by enabling students to leverage their current paid work into more career-relevant work while they study. Embedded within a scaffolded, course-wide program, the Stepping Stone concept supports students’ transitions into the workforce by aligning career education with their individual goals and circumstances. The paper highlights the value of collaboration across the higher education workforce to design and support relevant, timely and industry-engaged career development interventions and calls for broader recognition of practice wisdom in higher education policy and strategy.

The strongest genetic risk factor for late‐onset Alzheimer's disease (AD) is allelic variation of the APOE gene, with the following risk structure: ε4 > ε3 > ε2. The biochemical basis for this risk profile is unclear. Here, we reveal a new role for the APOE gene product, apolipoprotein E (ApoE) in regulating cellular copper homeostasis, which is perturbed in the AD brain. Exposure of ApoE target replacement (TR) astrocytes (immortalised astrocytes from APOE knock‐in mice) to elevated copper concentrations resulted in exacerbated copper accumulation in ApoE4‐ compared to ApoE2‐ and ApoE3‐TR astrocytes. This effect was also observed in SH‐SY5Y neuroblastoma cells treated with conditioned medium from ApoE4‐TR astrocytes. Increased intracellular copper levels in the presence of ApoE4 may be explained by reduced levels and delayed trafficking of the copper transport protein, copper‐transporting ATPase 1 (ATP7A/Atp7a), potentially leading to impaired cellular copper export. This new role for ApoE in copper regulation lends further biochemical insight into how APOE genotype confers risk for AD and reveals a potential contribution of ApoE4 to the copper dysregulation that is a characteristic pathological feature of the AD brain. image

Work integrated learning (WIL), particularly placement-based WIL (P-WIL), has gained momentum in Higher Education over the last decade as an educational strategy for enhancing student employability. However, there is very limited guidance on effective ways to embed and scaffold WIL assessments across courses (degree programs). We present the findings from an action-research study, purposed with building academic confidence to review and re-design existing assessments to have intentional and explicit employability foci. Key to the study was the sharing of existing WIL frameworks to build practitioner expertise. What arose was a notable intersection of similar, but unplanned assessments focused on career development learning, authentic assessment, and/or demonstrations of theory-to-practice performance during WIL activities. What was lacking was a means for designing an intentional holistic schema that tagged a suite of assessments dedicated to the development and demonstration of student employability across the course. An outcome was the creation of a novel meta-assessment WIL framework (WAM-F) that supported and purposefully integrated previously independent items: 1) career development learning; 2) transferable skills development; 3) reflections from professional practice theory-to-practice WIL experiences; and explicitly tethered these to the discipline orientation of the course. The overt tethering of discipline-specific learning outcomes to a range of WIL activities, via a course-wide approach, not only assures the regulatory requirement for all WIL experiences to contribute to, scaffold and develop the learning outcomes of a course, but also makes sense of emerging educational approaches for STEM teaching teams not always familiar or confident with how to embed fit-for-purpose employability learning.

Grx1, a cytosolic thiol–disulfide oxidoreductase, actively maintains cellular redox homeostasis using glutathione substrates (reduced, GSH, and oxidized, GSSG). Here, the crystallization of reduced Grx1 from the yeast Saccharomyces cerevisiae (yGrx1) in space group P 2 ₁ 2 ₁ 2 ₁ and its structure solution and refinement to 1.22 Å resolution are reported. To study the structure–function relationship of yeast Grx1, the crystal structure of reduced yGrx1 was compared with the existing structures of the oxidized and glutathionylated forms. These comparisons revealed structural differences in the conformations of residues neighbouring the Cys27–Cys30 active site which accompany alterations in the redox status of the protein.

We have generated an Atp7a conditional knock in mouse model of dHMNX expressingAtp7a^T985I, the orthologue of the humanATP7A^T994Iidentified in dHMNX patients.

Glutathione (GSH) is a tripeptide often considered to be the master antioxidant in cells. GSH plays an integral role in cellular redox regulation and is also known to have a role in mammalian copper homeostasis. In vitro evidence suggests that GSH is involved in copper uptake, sequestration and efflux. This study was undertaken to further investigate the roles that GSH plays in neuronal copper homeostasis in vivo, using the model organism Drosophila melanogaster. RNA interference‐mediated knockdown of the Glutamate‐cysteine ligase catalytic subunit gene (Gclc) that encodes the rate‐limiting enzyme in GSH biosynthesis was utilised to genetically deplete GSH levels. When Gclc was knocked down in all neurons, this caused lethality, which was partially rescued by copper supplementation and was exacerbated by additional knockdown of the copper uptake transporter Ctr1A, or over‐expression of the copper efflux transporter ATP7. Furthermore, when Gclc was knocked down in a subset of neuropeptide‐producing cells, this resulted in adult progeny with unexpanded wings, a phenotype previously associated with copper dyshomeostasis. In these cells, Gclc suppression caused a decrease in axon branching, a phenotype further enhanced by ATP7 over‐expression. Therefore, we conclude that GSH may play an important role in regulating neuronal copper levels and that reduction in GSH may lead to functional copper deficiency in neurons in vivo. image We provide genetic evidence that glutathione (GSH) levels influence Cu content or distribution in vivo, in Drosophila neurons. GSH could be required for binding Cu imported by Ctr1A and distributing it to chaperones, such as Mtn, CCS and Atox1. Alternatively, GSH could modify the copper‐binding and transport activities of Atox1 and the ATP7 efflux protein via glutathionylation of copper‐binding cysteines.

This themed issue of Metallomics showcases recent progress in mammalian and bacterial copper biology made possible by the seminal discoveries of three pioneers

COPPER IS INDISPENSABLE for development and function of the central nervous system (CNS). This is dramatically illustrated by the severe neuropathological deficits in Menkes disease, an X-linked copper deficiency disorder resulting from mutation of the gene that encodes an essential copper transporting P1B-type ATPase, ATP7A. Since its discovery over two decades ago, the role of ATP7A in copper transport and homeostasis has been inextricably linked to satisfying systemic and CNS requirements for copper. In a recent issue of American Journal of Physiology-Cell Physiology, Hodgkinson et al. (8) describe an important body of work, which for the first time distinguishes the CNS requirement for ATP7A from the CNS requirement for copper

Mitochondrial dysfunction, ubiquitin-proteasomal system impairment and excitotoxicity occur during the injury and death of neurons in neurodegenerative conditions. The aim of this work was to elucidate the cellular mechanisms that are universally altered by these conditions. Through overlapping expression profiles of rotenone-, lactacystin- and N-methyl-d-aspartate-treated cortical neurons, we have identified three affected biological processes that are commonly affected; oxidative stress, dysfunction of calcium signalling and inhibition of the autophagic–lysosomal pathway. These data provides many opportunities for therapeutic intervention in neurodegenerative conditions, where mitochondrial dysfunction, proteasomal inhibition and excitotoxicity are evident.