The full-text may be used and/or reproduced, and given to third parties in any format or medium, without prior permission or charge, for personal research or study, educational, or not-for-prot purposes provided that:• a full bibliographic reference is made to the original source • a link is made to the metadata record in DRO • the full-text is not changed in any way The full-text must not be sold in any format or medium without the formal permission of the copyright holders. Abstract This paper provides a geographical analysis of divestment. Drawing on two years of intensive qualitative research with households, we explore empirically the range of conduits that figure in household divestment, showing how surplus and excess things are routinely moved through specific conduits. We argue that, rather than focusing on the trajectories of things in divestment, it is practices of divestment that merit attention, and that divestment itself is also a practice. Further, we argue that divestment practices are about trying to constitute a normative around surplus and excess things; that they connect up to the reproduction of particular consumption practices and to the meta practice of consumption (Warde, 2005). The paper also considers the relation between divestment practice and the question of disposal. We argue that, as well as paying attention to conduits, connectivities and the work of the return, there is a need to focus on placings and practices, that not only have the potential to act-back but which are always acting-back.

Identification of clinically actionable molecular subtypes of pancreatic ductal adenocarcinoma (PDAC) is key to improving patient outcome. Intertumoral metabolic heterogeneity contributes to cancer survival and the balance between distinct metabolic pathways may influence PDAC outcome. We hypothesized that PDAC can be stratified into prognostic metabolic subgroups based on alterations in the expression of genes involved in glycolysis and cholesterol synthesis.Experimental Design: We performed bioinformatics analysis of genomic, transcriptomic, and clinical data in an integrated cohort of 325 resectable and nonresectable PDAC. The resectable datasets included retrospective The Cancer Genome Atlas (TCGA) and the International Cancer Genome Consortium (ICGC) cohorts. The nonresectable PDAC cohort studies included prospective COMPASS, PanGen, and BC Cancer Personalized OncoGenomics program (POG).Results: On the basis of the median normalized expression of glycolytic and cholesterogenic genes, four subgroups were identified: quiescent, glycolytic, cholesterogenic, and mixed. Glycolytic tumors were associated with the shortest median survival in resectable (log-rank test P ¼ 0.018) and metastatic settings (log-rank test P ¼ 0.027). Patients with cholesterogenic tumors had the longest median survival. KRAS and MYC-amplified tumors had higher expression of glycolytic genes than tumors with normal or lost copies of the oncogenes (Wilcoxon rank sum test P ¼ 0.015). Glycolytic tumors had the lowest expression of mitochondrial pyruvate carriers MPC1 and MPC2. Glycolytic and cholesterogenic gene expression correlated with the expression of prognostic PDAC subtype classifier genes.Conclusions: Metabolic classification specific to glycolytic and cholesterogenic pathways provides novel biological insight into previously established PDAC subtypes and may help develop personalized therapies targeting unique tumor metabolic profiles.See related commentary by Mehla and Singh, p. 6

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Developing new ways of delivering cells to diseased tissue will be a key factor in translating cell therapeutics research into clinical use. Magnetically targeting cells enables delivery of significant numbers of cells to key areas of specific organs. To demonstrate feasibility in neurological tissue, we targeted cells magnetically to the upper hemisphere of the rodent retina. Rat mesenchymal stem cells (MSCs) were magnetized using superparamagnetic iron oxide nanoparticles (SPIONs). In vitro studies suggested that magnetization with fluidMAG-D was well tolerated, that cells remained viable, and they retained their differentiation capabilities. FluidMAG-D-labeled MSCs were injected intravitreally or via the tail vein of the S334ter-4 transgenic rat model of retinal degeneration with or without placing a gold-plated neodymium disc magnet within the orbit, but outside the eye. Retinal flatmount and cryosection imaging demonstrated that after intravitreal injection cells localized to the inner retina in a tightly confined area corresponding to the position of the orbital magnet. After intravenous injection, similar retinal localization was achieved and remarkably was associated with a tenfold increase in magnetic MSC delivery to the retina. Cryosections demonstrated that cells had migrated into both the inner and outer retina. Magnetic MSC treatment with orbital magnet also resulted in significantly higher retinal concentrations of anti-inflammatory molecules interleukin-10 and hepatocyte growth factor. This suggested that intravenous MSC therapy also resulted in significant therapeutic benefit in the dystrophic retina. With minimal risk of collateral damage, these results suggest that magnetic cell delivery is the best approach for controlled delivery of cells to the outer retina-the focus for disease in age-related macular degeneration and retinitis pigmentosa.

Aniridia is a congenital and progressive panocular condition with poor visual prognosis that is associated with brain, olfactory, and pancreatic abnormalities. Development of aniridia is linked with nonsense mutations that result in paired box 6 (PAX6) haploinsufficiency. Here, we used a mouse model of aniridia to test the hypothesis that manipulation of Pax6 dosage through a mutation-independent nonsense mutation suppression strategy would limit progressive, postnatal damage in the eye. We focused on the nonsense suppression drugs 3-[5-(2-fluorophenyl)-1,2,4-oxadiazol-3-yl]benzoic acid (ataluren) and gentamicin. Remarkably, we demonstrated that nonsense suppression not only inhibited disease progression but also stably reversed corneal, lens, and retinal malformation defects and restored electrical and behavioral responses of the retina. The most successful results were achieved through topical application of the drug formulation START (0.9% sodium chloride, 1% Tween 80, 1% powdered ataluren, 1% carboxymethylcellulose), which was designed to enhance particle dispersion and to increase suspension viscosity. These observations suggest that the eye retains marked developmental plasticity into the postnatal period and remains sensitive to molecular remodeling. Furthermore, these data indicate that other neurological developmental anomalies associated with dosage-sensitive genetic mutations may be reversible through nonsense suppression therapeutics. IntroductionThe highly conserved paired box 6 (PAX6) transcription factor is pivotal to embryonic development and maintenance in the eye, brain, olfactory system, and pancreas (1). Genetic defects leading to haploinsufficiency of PAX6 cause congenital aniridia (2), a progressive panocular condition characterized by absence of iris tissue, corneal opacity, glaucoma, cataract, and foveal hypoplasia, which is also associated with brain, olfactory, and pancreatic abnormalities (3). While the genetic basis of congenital aniridia has been known for 2 decades, this has yet to be translated into preventative or corrective PAX6 treatment strategies, mainly because of PAX6 allelic heterogeneity, since more than 600 different mutations are known (4). Premature stop codons (PTCs) caused by nonsense mutations, splice-site mutations, and frameshift mutations account for 72% of all PAX6 disease-associated mutations (4); however, approximately 50% of all mutations are in-frame nonsense mutations. Therefore, we reasoned that a mutation-independent nonsense mutation suppression approach for in-frame PTCs (4) could be relevant for many patients if this could be achieved through a postnatal strategy. In this approach, during mRNA translation, a near-cognate aminoacyl tRNA is inserted into the polypeptide. Thus, as long as the PTC is not in a critical position for protein activity, then a functional protein would be produced with the potential to provide therapeutic benefit (5).We and others have previously undertaken proof-of-concept experiments showing that aminoglycosides promote readthr...