Hypoxia-inducible factor-1α-dependent induction of miR122 enhances hepatic ischemia tolerance

Hepatic ischemia and reperfusion (IR) injury contributes to the morbidity and mortality associated with liver transplantation. microRNAs (miRNAs) constitute a family of noncoding RNAs that regulate gene expression at the posttranslational level through the repression of specific target genes. Here, we hypothesized that miRNAs could be targeted to enhance hepatic ischemia tolerance. A miRNA screen in a murine model of hepatic IR injury pointed us toward the liver-specific miRNA miR122. Subsequent studies in mice with hepatocyte-specific deletion of miR122 (miR122loxP/loxP Alb-Cre+ mice) during hepatic ischemia and reperfusion revealed exacerbated liver injury. Transcriptional studies implicated hypoxia-inducible factor-1α (HIF1α) in the induction of miR122 and identified the oxygen-sensing prolyl hydroxylase domain 1 (PHD1) as a miR122 target. Further studies indicated that HIF1α-dependent induction of miR122 participated in a feed-forward pathway for liver protection via the enhancement of hepatic HIF responses through PHD1 repression. Moreover, pharmacologic studies utilizing nanoparticle-mediated miR122 overexpression demonstrated attenuated liver injury. Finally, proof-of-principle studies in patients undergoing orthotopic liver transplantation showed elevated miR122 levels in conjunction with the repression of PHD1 in post-ischemic liver biopsies. Taken together, the present findings provide molecular insight into the functional role of miR122 in enhancing hepatic ischemia tolerance and suggest the potential utility of pharmacologic interventions targeting miR122 to dampen hepatic injury during liver transplantation

Ethnographic understandings of ethnically diverse neighbourhoods to inform urban design practice

The aim of this paper is to inform urban design practice through deeper understanding and analysis of the social dynamics of public outdoor space in ethnically diverse neighbourhoods. We hypothesise that findings from ethnographic research can provide a resource that improves cultural literacy and supports social justice in professional practice. The primary method is a meta-synthesis literature review of 24 ethnographic research papers, all of which explore some dimensions of public open space use and values in UK urban contexts characterised by ethnic and racial diversity. We summarise thematic understandings and significance of neighbourhood places of shared activity, parks, spaces of passing-by and of retreat. We evaluate the implications for intercultural social dynamics, exploring the spatial and temporal dimensions of conviviality and racism in public open space. We then argue that it is possible to develop principles for urban design practice informed by this work, and propose four for discussion: maximising straightforward participation, legitimising diversity of activity, designing in micro-retreats of nearby quietness and addressing structural inequalities of open space provision. We conclude that ethnographic research can provide detailed insights into the use of the public realm and also inform a more nuanced understanding of outdoor sociality relevant for an increasingly diverse society. The challenge is two-fold: for ethnographers to become less cautious in engaging with decisions and priorities regarding how cities change, and for urban designers to explicitly embed informed understandings of difference into their broad desire for inclusive public space