Altered expression of microRNA in the airway wall in chronic asthma: miR-126 as a potential therapeutic target

Background: The role of microRNAs (miRNAs) in regulating gene expression is currently an area of intense interest. Relatively little is known, however, about the role of miRNAs in inflammatory and immunologically-driven disorders. In a mouse model, we have previously shown that miRNAs are potentially important therapeutic targets in allergic asthma, because inhibition of miR-126, one of a small subset of miRNAs upregulated in the airway wall, effectively suppressed Th2-driven airway inflammation and other features of asthma. In the present study, we extended investigation of the therapeutic potential of miRNA inhibition to our well-established model of chronic asthma. Methods: Female BALB/c mice were systemically sensitised with ovalbumin (OVA) and chronically challenged with low mass concentrations of aerosolised OVA for up to 6 weeks. Airway tissue was obtained by blunt dissection and RNA was isolated for miRNA profiling. On the basis of the results obtained, animals were subsequently treated with either an antagomir to miR-126 (ant-miR-126) or a scrambled control antagomir once weekly during the 6 weeks of chronic challenge, and the effects on airway inflammation and remodelling were assessed using established morphometric techniques. Results: Compared to naïve mice, there was selective upregulation of a modest number of miRNAs, notably miR-126, in the airway wall tissue of chronically challenged animals. The relative increase was maximal after 2 weeks of inhalational challenge and subsequently declined to baseline levels. Compared to treatment with the scrambled control, ant-miR-126 significantly reduced recruitment of intraepithelial eosinophils, but had no effect on the chronic inflammatory response, or on changes of airway remodelling. Conclusions: In this model of chronic asthma, there was an initial increase in expression of a small number of miRNAs in the airway wall, notably miR-126. However, this later declined to baseline levels, suggesting that sustained changes in miRNA may not be essential for perpetuation of chronic asthma. Moreover, inhibition of miR-126 by administration of an antagomir suppressed eosinophil recruitment into the airways but had no effect on chronic inflammation in the airway wall, or on changes of remodelling, suggesting that multiple miRNAs are likely to regulate the development of these lesions

Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomised placebo-controlled trial

Background: Glucagon-like peptide 1 receptor agonists differ in chemical structure, duration of action, and in their effects on clinical outcomes. The cardiovascular effects of once-weekly albiglutide in type 2 diabetes are unknown. We aimed to determine the safety and efficacy of albiglutide in preventing cardiovascular death, myocardial infarction, or stroke. Methods: We did a double-blind, randomised, placebo-controlled trial in 610 sites across 28 countries. We randomly assigned patients aged 40 years and older with type 2 diabetes and cardiovascular disease (at a 1:1 ratio) to groups that either received a subcutaneous injection of albiglutide (30–50 mg, based on glycaemic response and tolerability) or of a matched volume of placebo once a week, in addition to their standard care. Investigators used an interactive voice or web response system to obtain treatment assignment, and patients and all study investigators were masked to their treatment allocation. We hypothesised that albiglutide would be non-inferior to placebo for the primary outcome of the first occurrence of cardiovascular death, myocardial infarction, or stroke, which was assessed in the intention-to-treat population. If non-inferiority was confirmed by an upper limit of the 95% CI for a hazard ratio of less than 1·30, closed testing for superiority was prespecified. This study is registered with ClinicalTrials.gov, number NCT02465515. Findings: Patients were screened between July 1, 2015, and Nov 24, 2016. 10 793 patients were screened and 9463 participants were enrolled and randomly assigned to groups: 4731 patients were assigned to receive albiglutide and 4732 patients to receive placebo. On Nov 8, 2017, it was determined that 611 primary endpoints and a median follow-up of at least 1·5 years had accrued, and participants returned for a final visit and discontinuation from study treatment; the last patient visit was on March 12, 2018. These 9463 patients, the intention-to-treat population, were evaluated for a median duration of 1·6 years and were assessed for the primary outcome. The primary composite outcome occurred in 338 (7%) of 4731 patients at an incidence rate of 4·6 events per 100 person-years in the albiglutide group and in 428 (9%) of 4732 patients at an incidence rate of 5·9 events per 100 person-years in the placebo group (hazard ratio 0·78, 95% CI 0·68–0·90), which indicated that albiglutide was superior to placebo (p<0·0001 for non-inferiority; p=0·0006 for superiority). The incidence of acute pancreatitis (ten patients in the albiglutide group and seven patients in the placebo group), pancreatic cancer (six patients in the albiglutide group and five patients in the placebo group), medullary thyroid carcinoma (zero patients in both groups), and other serious adverse events did not differ between the two groups. There were three (<1%) deaths in the placebo group that were assessed by investigators, who were masked to study drug assignment, to be treatment-related and two (<1%) deaths in the albiglutide group. Interpretation: In patients with type 2 diabetes and cardiovascular disease, albiglutide was superior to placebo with respect to major adverse cardiovascular events. Evidence-based glucagon-like peptide 1 receptor agonists should therefore be considered as part of a comprehensive strategy to reduce the risk of cardiovascular events in patients with type 2 diabetes. Funding: GlaxoSmithKline

An integrated expression atlas of miRNAs and their promoters in human and mouse

MicroRNAs (miRNAs) are short non-coding RNAs with key roles in cellular regulation. As part of the fifth edition of the Functional Annotation of Mammalian Genome (FANTOM5) project, we created an integrated expression atlas of miRNAs and their promoters by deep-sequencing 492 short RNA (sRNA) libraries, with matching Cap Analysis Gene Expression (CAGE) data, from 396 human and 47 mouse RNA samples. Promoters were identified for 1,357 human and 804 mouse miRNAs and showed strong sequence conservation between species. We also found that primary and mature miRNA expression levels were correlated, allowing us to use the primary miRNA measurements as a proxy for mature miRNA levels in a total of 1,829 human and 1,029 mouse CAGE libraries. We thus provide a broad atlas of miRNA expression and promoters in primary mammalian cells, establishing a foundation for detailed analysis of miRNA expression patterns and transcriptional control regions

Hopeful, Harmless, and Heroic

There has been a notable increase in the public visibility of girl activists in the past ten years. In this article, I analyze media narratives about several individual girl activists to highlight key components of the newly desirable figure of the girl activist. After tracing the expansion of girl power discourses from an emphasis on individual empowerment to the invocation of girls as global saviors, I argue that girls are particularly desirable figures for public consumption because the encoding of girls as symbols of hope helps to resolve public anxieties about the future, while their more radical political views are managed through girlhood’s association with harmlessness. Ultimately, the figure of the hopeful and harmless girl activist hero is simultaneously inspirational and demobilizing

Continually RedefiningProtagonismo: The Peruvian Movement of Working Children and Political Change, 1976–2015

Activists in the Peruvian working children’s movement have been theorizing about “children’s protagonismo” for nearly 40 years. Changing political contexts and the infusion of discourses from other social movements have produced three major sets of meanings for this concept, each reflecting different dynamics in Peruvian social movement history. First, the concept, infused with ideas from liberation theology and Latin American engagements with Marxism, was primarily understood in terms of class struggle and collective organization. Second, because of opportunities and threats in the 1980s and 1990s, it became more closely associated with children’s rights frameworks. Third, since the early 2000s, the movement’s approach to protagonismo has drawn on indigenous theories of interdependence and relationality to challenge the individualism of neoliberal capitalism and governmentality. In holding these diverse ideological commitments together, the concept has allowed the movement of working children to communicate across multiple discursive communities.Los activistas del movimiento de los niños trabajadores peruanos han teorizado sobre el “protagonismo infantil” durante casi 40 años. Los cambios en el contexto político y la influencia de discursos pertenecientes a otros movimientos sociales han generado tres grandes conjuntos de significado alrededor de este concepto, cada uno de los cuales reflejando distintas dinámicas en la historia del movimiento social peruano. Primero, el concepto se entendió en términos de clase imbuidos por ideas de la teología de la liberación, así como actitudes latinoamericanas de compromiso con el marxismo y la organización colectiva. Posteriormente, a raíz de las oportunidades y amenazas de las décadas de 1980 y 90, se relacionó de manera más estrecha con el marco de los derechos del niño. Desde principios de la década del 2000, el enfoque del protagonismo se ha ligado a teorías indígenas de la interdependencia y la relacionalidad para desafiar el individualismo del capitalismo neoliberal y la gobernabilidad. Al unir tal diversidad de compromisos ideológicos, el concepto ha permitido que el movimiento de los niños trabajadores tenga voz en múltiples comunidades discursivas

The Australian special humanitarian program for the entry of Soviet Jews and Australian offshore refugee policy: 1972-1980

This thesis is a critical inquiry into the history of Australia’s Special Humanitarian Program (1980), and the implications of the development of the Special Humanitarian Program (SHP) for Australia’s offshore refugee policy. This thesis investigates why the SHP was created, how the SHP was developed, and its historical significance for Australian refugee policy. The SHP was conceived in 1980 as a policy solution to facilitate the entry and resettlement of Jews from the Soviet Union. It was expanded into a Global SHP program in 1981 for all minorities overseas who were escaping human rights abuses in their home countries and had a connection to Australia. Critically, the SHP was for people in humanitarian need who were not classified as refugees under international law for technical legal reasons. They were de facto refugees: refugees in fact and circumstances but not in legal status. This thesis argues that the SHP was a substantial addition to and expansion of Australia’s offshore refugee policy and of Australia’s protection of de facto refugees. This thesis will show that the SHP was a concept of humanitarian entry that was substantially similar to Australia’s refugee entry even though the SHP formally appeared to have different processing requirements to the refugee program. Australia was not and is not legally obliged to admit into Australia refugees who are overseas, and moreover is not bound to admit people overseas who are de facto refugees. Australia did so and acted above its legal obligations, this thesis explains, largely in response to diplomatic pressures on handling Soviet Jewish migration and interdependence with US policy. Australia also was influenced by a strong ideological imperative on international human rights that galvanised in the 1970s; human rights discourses drove Australia to act consistently with international rights to freedom of movement and to protection. This thesis makes a related argument that international human rights generated compelling duties and obligations on Australia, through political pressure, to admit refugees and de facto refugees and create responsive entry policies. The SHP is an area of Australian refugee policy that has not received scholarly attention in either legal or historical disciplines. Moreover, there is no detailed history of the development of SHP as the de facto refugee component of Australia’s overseas humanitarian intake. This thesis addresses a gap in legal scholarship on the development of Australian refugee law and policy, and in historical scholarship on immigration and refugee policy. It also extends knowledge on Soviet Jewish immigration in the field of Australian Jewish history. The thesis is informed by legal examination of international law and practice with respect to refugees. The thesis is primarily based on archival research in the Australian government archives. It also utilises Hansard parliamentary debates, Jewish organisational papers, US Presidential and organisational archives from New York, Australian and US newspapers, Australian demographic data, and some interviews. <div><br></div><div>Awards: Winner of the Mollie Holman Doctoral Medal for Excellence, Faculty of Art, Design and Architecture, 2014.</div