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"Graham, Anne"
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mRNA therapy restores euglycemia and prevents liver tumors in murine model of glycogen storage disease
Glycogen Storage Disease 1a (GSD1a) is a rare, inherited metabolic disorder caused by deficiency of glucose 6-phosphatase (G6Pase-α). G6Pase-α is critical for maintaining interprandial euglycemia. GSD1a patients exhibit life-threatening hypoglycemia and long-term liver complications including hepatocellular adenomas (HCAs) and carcinomas (HCCs). There is no treatment for GSD1a and the current standard-of-care for managing hypoglycemia (Glycosade
®
/modified cornstarch) fails to prevent HCA/HCC risk. Therapeutic modalities such as enzyme replacement therapy and gene therapy are not ideal options for patients due to challenges in drug-delivery, efficacy, and safety. To develop a new treatment for GSD1a capable of addressing both the life-threatening hypoglycemia and HCA/HCC risk, we encapsulated engineered mRNAs encoding human G6Pase-α in lipid nanoparticles. We demonstrate the efficacy and safety of our approach in a preclinical murine model that phenotypically resembles the human condition, thus presenting a potential therapy that could have a significant therapeutic impact on the treatment of GSD1a.
Glycogen Storage Disease 1a (Gsd1a) is an inherited disorder caused by glucose 6-phosphatase (G6Pase-α) deficiency and characterized by hypoglycaemia and high risk of liver cancer. Here the authors develop a mRNA-based G6Pase-α delivery therapy that is efficacious and safe in a mouse model of GSD1a.
Journal Article
A cascade of DNA-binding proteins for sexual commitment and development in Plasmodium
Malaria parasites must produce gametocytes for transmission to the mosquito vector, although the molecular mechanisms underlying commitment to gametocyte production remain unclear; here this process is found to be controlled by PbAP2-G, a member of the ApiAP2 family of DNA-binding proteins, in the rodent-infecting
Plasmodium berghei
parasite.
Malarial virulence factor primed for action
For malaria parasites to be transmitted to the mosquito vector they must undergo sexual development and produce gametocytes. The molecular mechanisms underlying the commitment to gametocyte development have been unclear. Two complementary manuscripts now show that AP2-G, a member of the apicomplexan AP2 family of transcription factors, is a master regulator of sexual development in the malaria parasite, acting as a developmental switch by triggering the transcription of early gametocyte genes. Abhinav Sinha
et al
. worked with the rodent malaria parasite
Plasmodium berghei
, and Björn Kafsack
et al
. with the human pathogen
P. falciparum
. AP2-G activity in human infectious malaria parasites could be a potential target for antimalarials designed to interfere with gametocyte formation.
Commitment to and completion of sexual development are essential for malaria parasites (protists of the genus
Plasmodium
) to be transmitted through mosquitoes
1
. The molecular mechanism(s) responsible for commitment have been hitherto unknown. Here we show that PbAP2-G, a conserved member of the apicomplexan AP2 (ApiAP2) family of DNA-binding proteins, is essential for the commitment of asexually replicating forms to sexual development in
Plasmodium berghei
, a malaria parasite of rodents. PbAP2-G was identified from mutations in its encoding gene, PBANKA_143750, which account for the loss of sexual development frequently observed in parasites transmitted artificially by blood passage. Systematic gene deletion of conserved ApiAP2 genes in
Plasmodium
confirmed the role of PbAP2-G and revealed a second ApiAP2 member (PBANKA_103430, here termed PbAP2-G2) that significantly modulates but does not abolish gametocytogenesis, indicating that a cascade of ApiAP2 proteins are involved in commitment to the production and maturation of gametocytes. The data suggest a mechanism of commitment to gametocytogenesis in
Plasmodium
consistent with a positive feedback loop involving PbAP2-G that could be exploited to prevent the transmission of this pernicious parasite.
Journal Article
Leading during digital technology change and disruption in a further education and training (FET) environment: Within and beyond the pandemic
Evolving social and industry practices, standards and expectations make it clear that the further education and training (FET) sector must help students acquire the knowledge, skills and attitudes that enhance their competency and prepare them for an increasingly complex and digital world. This phenomenological study shares leaders’ experiences of managing digital technology change throughout the COVID-19 pandemic that led to the acquisition of the digital skills, qualities and dispositions necessary to support the development of an educator digital mindset for some individuals, but not for all. We also reveal novel insights into how these leaders positioned their organisations for successful strategic change by supporting their educators’ engagement in the creative and effective use of digital technology in their chosen discipline, craft or professional area of expertise. We conclude that successful technology change can lead to constructive peer support and resources, create learning spaces that strengthen digital mindsets and professional identity, promote student retention and create successful digital technology-practitioners.
Journal Article
Shaping acoustic fields as a toolset for microfluidic manipulations in diagnostic technologies
Ultrasonics offers the possibility of developing sophisticated fluid manipulation tools in lab-on-a-chip technologies. Here we demonstrate the ability to shape ultrasonic fields by using phononic lattices, patterned on a disposable chip, to carry out the complex sequence of fluidic manipulations required to detect the rodent malaria parasite Plasmodium berghei in blood. To illustrate the different tools that are available to us, we used acoustic fields to produce the required rotational vortices that mechanically lyse both the red blood cells and the parasitic cells present in a drop of blood. This procedure was followed by the amplification of parasitic genomic sequences using different acoustic fields and frequencies to heat the sample and perform a real-time PCR amplification. The system does not require the use of lytic reagents nor enrichment steps, making it suitable for further integration into lab-on-a-chip point-of-care devices. This acoustic sample preparation and PCR enables us to detect ca. 30 parasites in a microliter-sized blood sample, which is the same order of magnitude in sensitivity as lab-based PCR tests. Unlike other lab-on-a-chip methods, where the sample moves through channels, here we use our ability to shape the acoustic fields in a frequency-dependent manner to provide different analytical functions. The methods also provide a clear route toward the integration of PCR to detect pathogens in a single handheld system.
Journal Article
A Canadian girl in South Africa : a teacher's experiences in the South African War, 1899 1902
\"As the South African War reached its grueling end in 1902, colonial interests at the highest levels of the British Empire hand-picked teachers from across the Commonwealth to teach the thousands of Afrikaner women, children, and non-combatants held in concentration camps. Highly educated, hard working, and often opinionated, E. Maud Graham joined the Canadian contingent of forty teachers. Her account reveals the complexity of relations and tensions at a controversial period in Britain's history. Graham presents a lively historical travel memoir, and the editors have provided rich political and historical context to her narrative in the Introduction and generous annotations. This is a rare primary source for experts in Colonial Studies, Women's Studies, and Canadian, South African, and British Imperial History.\"-- Provided by publisher.
Book
Wellbeing in schools : Examining the policy-practice nexus
National concern regarding the social and emotional wellbeing of children and young people is now strongly reflected in a wide range of Australian policy initiatives. A considerable number of these target schools and point firmly to the role education is perceived to play in promoting student wellbeing. Given that wellbeing can be difficult to define and complex to measure, closer attention needs to be paid to whether and how the current wellbeing policy environment provides conceptual clarity and intelligible implementation pathways. This article explores some of the current policy ambiguity by drawing on findings from a large-scale, mixed methods study exploring student wellbeing at school. These findings emerged from an extensive analysis of wellbeing-related policy, together with policy-related data from in-depth interviews with teachers and principals. They suggest that approaches to supporting student wellbeing are constrained by an ad hoc policy environment characterised by competing discourses and a consequential lack of clarity regarding how wellbeing is understood and best facilitated within the context of schools. The implications of these findings are discussed with particular attention to the interface between policy and practice with regard to student wellbeing in schools in Australia. [Author abstract]
Journal Article