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Efficient and targeted delivery of therapeutic agents remains a bottleneck in modern medicine. Here, biochemical engineering approaches to advance the repurposing of extracellular vesicles (EVs) as drug delivery vehicles are explored. Targeting ligands such as the sugar GalNAc are displayed on the surface of EVs using a HaloTag‐fused to a protein anchor that is enriched on engineered EVs. These EVs are successfully targeted to human primary hepatocytes. In addition, the authors are able to decorate EVs with an antibody that recognizes a GLP1 cell surface receptor by using an Fc and Fab region binding moiety fused to an anchor protein, and they show that this improves EV targeting to cells that overexpress the receptor. The authors also use two different protein‐engineering approaches to improve the loading of Cre recombinase into the EV lumen and demonstrate that functional Cre protein is delivered into cells in the presence of chloroquine, an endosomal escape enhancer. Lastly, engineered EVs are well tolerated upon intravenous injection into mice without detectable signs of liver toxicity. Collectively, the data show that EVs can be engineered to improve cargo loading and specific cell targeting, which will aid their transformation into tailored drug delivery vehicles. [ABSTRACT FROM AUTHOR]

Public acceptance is central to the success of a transition agenda but with the increasing uptake of renewable energy technology, achieving and sustaining the public legitimacy for accelerating the energy transition is at risk. This study provides an updated account of the energy transition development in Germany and Australia with a focus on institutional legitimation. Drawing on the distinction between input and output legitimacy, we query how enabling community participation can enhance the legitimacy of policy instruments. We employ two case studies of energy transitions - those of Germany and Australia - to explain where and how community participation has supported the legitimacy of policy interventions. While input legitimacy remains high in both Germany and Australia, both examples illustrate how policy instruments can lack legitimacy if decision-makers lose sight of or never properly consider the output dimension of legitimacy. [ABSTRACT FROM AUTHOR]

Hydrops fetalis describes fluid accumulation in at least 2 fetal compartments, including abdominal cavities, pleura, and pericardium, or in body tissue. The majority of hydrops fetalis cases are nonimmune conditions that present with generalized edema of the fetus, and approximately 15% of these nonimmune cases result from a lymphatic abnormality. Here, we have identified an autosomal dominant, inherited form of lymphatic-related (nonimmune) hydrops fetalis (LRHF). Independent exome sequencing projects on 2 families with a history of in utero and neonatal deaths associated with nonimmune hydrops fetalis uncovered 2 heterozygous missense variants in the gene encoding Eph receptor B4 (EPHB4). Biochemical analysis determined that the mutant EPHB4 proteins are devoid of tyrosine kinase activity, indicating that loss of EPHB4 signaling contributes to LRHF pathogenesis. Further, inactivation of Ephb4 in lymphatic endothelial cells of developing mouse embryos led to defective lymphovenous valve formation and consequent subcutaneous edema. Together, these findings identify EPHB4 as a critical regulator of early lymphatic vascular development and demonstrate that mutations in the gene can cause an autosomal dominant form of LRHF that is associated with a high mortality rate., Introduction Hydrops fetalis is defined as excessive fluid accumulation or edema in at least 2 fetal compartments. Nonimmune hydrops fetalis is the cause in more than 85% of cases, of [...]

The rise of a community engagement movement offers a range of possibilities for universities to function as "sites of citizenship". These include contributing to community social and economic infrastructure, supporting equity and diversity within higher education, and education for democratic citizenship. This article provides an overview of the findings of a recent study of engagement practices and policies in Australian universities. The article then goes on to discuss some of the possibilities and problems surrounding community engagement as a site of citizenship. It is suggested that while university-community engagement contributes to the public good, it also reflects a changed economic and social context in which concepts of "community" have superseded broader notions of the social. (Contains 1 table and 6 notes.)

Lipid nanoparticles (LNPs) are currently used to transport functional mRNAs, such as COVID‐19 mRNA vaccines. The delivery of angiogenic molecules, such as therapeutic VEGF‐A mRNA, to ischemic tissues for producing new blood vessels is an emerging strategy for the treatment of cardiovascular diseases. Here, the authors deliver VEGF‐A mRNA via LNPs and study stoichiometric quantification of their uptake kinetics and how the transport of exogenous LNP‐mRNAs between cells is functionally extended by cells' own vehicles called extracellular vesicles (EVs). The results show that cellular uptake of LNPs and their mRNA molecules occurs quickly, and that the translation of exogenously delivered mRNA begins immediately. Following the VEGF‐A mRNA delivery to cells via LNPs, a fraction of internalized VEGF‐A mRNA is secreted via EVs. The overexpressed VEGF‐A mRNA is detected in EVs secreted from three different cell types. Additionally, RNA‐Seq analysis reveals that as cells' response to LNP‐VEGF‐A mRNA treatment, several overexpressed proangiogenic transcripts are packaged into EVs. EVs are further deployed to deliver VEGF‐A mRNA in vitro and in vivo. Upon equal amount of VEGF‐A mRNA delivery via three EV types or LNPs in vitro, EVs from cardiac progenitor cells are the most efficient in promoting angiogenesis per amount of VEGF‐A protein produced. Intravenous administration of luciferase mRNA shows that EVs could distribute translatable mRNA to different organs with the highest amounts of luciferase detected in the liver. Direct injections of VEGF‐A mRNA (via EVs or LNPs) into mice heart result in locally produced VEGF‐A protein without spillover to liver and circulation. In addition, EVs from cardiac progenitor cells cause minimal production of inflammatory cytokines in cardiac tissue compared with all other treatment types. Collectively, the data demonstrate that LNPs transform EVs as functional extensions to distribute therapeutic mRNA between cells, where EVs deliver this mRNA differently than LNPs. [ABSTRACT FROM AUTHOR]

To authenticate to the full-text of this article, please visit this link: http://dx.doi.org/10.1111/j.1467-8500.2008.00611.x Byline: Brooke McDonald-Wilmsen (*), Sandra M. Gifford (*), Kim Webster ([dagger]), John Wiseman ([double dagger]), Sue Casey (s.) Keywords: Commonwealth government refugee and humanitarian policy; refugee resettlement; rural and regional resettlement; Australia's refugee program; Victorian case studies Abstract: Conscious policy and program support for the resettlement of refugees in regional and rural areas is a relatively recent trend in Australia. Resettlement is a complex process that hinges on the establishment of viable communities. This review suggests that its outcomes, especially for refugee communities, are potentially mixed. However, an appropriately resourced, well managed and well planned refugee resettlement program can potentially provide beneficial outcomes for refugees and host communities. This article draws on existing empirical data and contributions made at a VicHealth Roundtable in late 2007 to thematically explore the challenges facing rural and regional resettlement programs. Given that settlement is a dynamic process and the approaches to rural and regional settlement are evolving, this article provides 12 propositions for a more effective and integrated approach to policy and practice. Author Affiliation: (*)La Trobe University ([dagger])Victorian Health Promotion Foundation ([double dagger])University of Melbourne (s.)Victorian Foundation for Survivors of Torture