Beyond the clinic? Eluding a medical diagnosis of anorexia through narrative

The persistence and recurrence of anorexia nervosa poses a clinical challenge, and provides support for critiques of oppressive and injurious facets of society inscribed on women’s bodies. This essay illustrates how a phenomenological, linguistic anthropological approach fruitfully traverses clinical and cultural perspectives by directing attention beyond the embodied experience of patients diagnosed with anorexia nervosa to those who are not clinically diagnosed. Extending a model of illness and recovery as entailing sufferers’ emplotting of past, present, and imagined future selves, I argue that women’s accounts of their experiences do not simply reflect lived reality, but actually propel health-relevant states of being by enlivening and creating these realities in the process of their telling. In indexical interaction with public and clinical discourses, narratives’ grammar, lexicon, and plot structures modify subjects’ experiences and interpretations of the events and feelings recounted. This article builds on the insight that linear narratives of “full recovery” that adopt a clinical and feminist voice can help tellers stay recovered, whereas for those “struggling to recover,” a genre of contingent, uncertain, sideshadowing narratives alternatively renders recovery an elusive and ambivalently desired object. This essay then identifies a third narrative genre, eluding a diagnosis, which combines elements of the first two genres to paradoxically keep its teller simultaneously sheltered from, and invisible to the well-meaning clutches of medical care, leaving her suffering, yet free, to starve. This focus on narrative genres illustrates the utility of linguistic analyses for discerning and interpreting distress in subclinical populations.First author draf

Cuttlefish responses to visual orientation of substrates, water flow and a model of motion camouflage

Low-level mechanisms in vertebrate vision are sensitive to line orientation. Here we investigate orientation sensitivity in the cuttlefish Sepia pharaonis, by allowing animals to settle on stripe patterns. When camouflaging themselves cuttlefish are known to be sensitive to image parameters such as contrast and spatial scale, but we find no effect of background orientation on the patterns displayed. It is nonetheless clear that the animals see orientation, because they prefer to rest with the body-axis perpendicular to the stripes. We consider three possible mechanisms to account for this behaviour. Firstly, that the body patterns are themselves oriented, and that the cuttlefish align themselves to aid static camouflage. This is unlikely, as the patterns displayed have no dominant orientation at any spatial scale. A second possibility is that motion camouflage favours alignment of the body orthogonal to background stripes, and we suggest how this alignment can minimise motion signals produced by occlusion. Thirdly we show that cuttlefish prefer to rest with their body-axis parallel to the water flow, and it is possible that they use visual patterns such as sand ripples to determine water flow

VEGF is essential for hypoxia-inducible factor-mediated neovascularization but dispensable for endothelial sprouting

Although our understanding of the molecular regulation of adult neovascularization has advanced tremendously, vascular-targeted therapies for tissue ischemia remain suboptimal. The master regulatory transcription factors of the hypoxia-inducible factor (HIF) family are attractive therapeutic targets because they coordinately up-regulate multiple genes controlling neovascularization. Here, we used an inducible model of epithelial HIF-1 activation, the TetON-HIF-1 mouse, to test the requirement for VEGF in HIF-1 mediated neovascularization. TetON-HIF-1, K14-Cre, and VEGF^(flox/flox) alleles were combined to create TetON-HIF-1:VEGFΔ mice to activate HIF-1 and its target genes in adult basal keratinocytes in the absence of concomitant VEGF. HIF-1 induction failed to produce neovascularization in TetON-HIF-1:VEGFΔ mice despite robust up-regulation of multiple proangiogenic HIF targets, including PlGF, adrenomedullin, angiogenin, and PAI-1. In contrast, endothelial sprouting was preserved, enhanced, and more persistent, consistent with marked reduction in Dll4-Notch-1 signaling. Optical-resolution photoacoustic microscopy, which provides noninvasive, label-free, high resolution, and wide-field vascular imaging, revealed the absence of both capillary expansion and arteriovenous remodeling in serially imaged individual TetON-HIF-1:VEGFΔ mice. Impaired TetON-HIF-1:VEGFΔ neovascularization could be partially rescued by 12-O-tetradecanoylphorbol-13-acetate skin treatment. These data suggest that therapeutic angiogenesis for ischemic cardiovascular disease may require treatment with both HIF-1 and VEGF

Depletion of tRNA-halves enables effective small RNA sequencing of low-input murine serum samples

The ongoing ascent of sequencing technologies has enabled researchers to gain unprecedented insights into the RNA content of biological samples. MiRNAs, a class of small non-coding RNAs, play a pivotal role in regulating gene expression. The discovery that miRNAs are stably present in circulation has spiked interest in their potential use as minimally-invasive biomarkers. However, sequencing of blood-derived samples ( serum, plasma) is challenging due to the often low RNA concentration, poor RNA quality and the presence of highly abundant RNAs that dominate sequencing libraries. In murine serum for example, the high abundance of tRNA-derived small RNAs called 5' tRNA halves hampers the detection of other small RNAs, like miRNAs. We therefore evaluated two complementary approaches for targeted depletion of 5' tRNA halves in murine serum samples. Using a protocol based on biotinylated DNA probes and streptavidin coated magnetic beads we were able to selectively deplete 95% of the targeted 5' tRNA half molecules. This allowed an unbiased enrichment of the miRNA fraction resulting in a 6-fold increase of mapped miRNA reads and 60% more unique miRNAs detected. Moreover, when comparing miRNA levels in tumor-carrying versus tumor-free mice, we observed a three-fold increase in differentially expressed miRNAs

Genome wide expression profiling of p53 regulated miRNAs in neuroblastoma

Restoration of the antitumor activity of p53 could offer a promising approach for the treatment of neuroblastoma. MicroRNAs (miRNAs) are important mediators of p53 activity, but their role in the p53 response has not yet been comprehensively addressed in neuroblastoma. Therefore, we set out to characterize alterations in miRNA expression that are induced by p53 activation in neuroblastoma cells. Genome-wide miRNA expression analysis showed that miR-34a-5p, miR-182-5p, miR-203a, miR-222-3p, and miR-432-5p are upregulated following nutlin-3 treatment in a p53 dependent manner. The function of miR-182-5p, miR-203a, miR-222-3p, and miR-432-5p was analyzed by ectopic overexpression of miRNA mimics. We observed that these p53-regulated miRNAs inhibit the proliferation of neuroblastoma cells to varying degrees, with the most profound growth inhibition recorded for miR-182-5p. Overexpression of miR-182-5p promoted apoptosis in some neuroblastoma cell lines and induced neuronal differentiation of NGP cells. Using Chromatin Immunoprecipitation-qPCR (ChIP-qPCR), we did not observe direct binding of p53 to MIR182, MIR203, MIR222, and MIR432 in neuroblastoma cells. Taken together, our findings yield new insights in the network of p53-regulated miRNAs in neuroblastoma

Dual targeting of MDM2 and BCL2 as a therapeutic strategy in neuroblastoma

Wild-type p53 tumor suppressor activity in neuroblastoma tumors is hampered by increased MDM2 activity, making selective MDM2 antagonists an attractive therapeutic strategy for this childhood malignancy. Since monotherapy in cancer is generally not providing long-lasting clinical responses, we here aimed to identify small molecule drugs that synergize with idasanutlin (RG7388). To this purpose we evaluated 15 targeted drugs in combination with idasanutlin in three p53 wild type neuroblastoma cell lines and identified the BCL2 inhibitor venetoclax (ABT-199) as a promising interaction partner. The venetoclax/idasanutlin combination was consistently found to be highly synergistic in a diverse panel of neuroblastoma cell lines, including cells with high MCL1 expression levels. A more pronounced induction of apoptosis was found to underlie the synergistic interaction, as evidenced by caspase-3/7 and cleaved PARP measurements. Mice carrying orthotopic xenografts of neuroblastoma cells treated with both idasanutlin and venetoclax had drastically lower tumor weights than mice treated with either treatment alone. In conclusion, these data strongly support the further evaluation of dual BCL2/MDM2 targeting as a therapeutic strategy in neuroblastoma

Two deaths and a funeral: ritual inscriptions' affordances for mourning and moral personhood in Vietnam

Mortuary rituals constitute the social nature of death and mourning, often working to ease painful transitions for the deceased and bereaved. In Vietnam, such rituals involve objects, including commodified yet personalized text‐artifacts like banners and placards bearing inscriptions in various scripts that are associated with various affects and different political‐economic regimes. The material, orthographic, semantic, spatial, and temporal organization of these text‐artifacts mobilize sentiments and structure ethical relations at a funeral. Together, they act as prescriptive affordances intended to discipline mourners’ grief. Yet while these objects reflect how subjects valorize “tradition,” their affective force exceeds the bounded subjunctive world fostered by ritual, and it may retrospectively limit possibilities for moral personhood.My research was generously supported by the Social Science Research Council, the Fulbright-Hays Doctoral Dissertation Abroad Research Program, the UC Pacific-Rim Research Program, the UCLA Graduate Division and Asia Institute Wagatsuma Fellowships, and institutional grants from the Centre for Ethnography and the Social Sciences and Humanities Research Council at the University of Toronto. I am also indebted to many colleagues who over years helped me develop earlier versions for invited lectures at the University of Toronto, the College of the Holy Cross, and the University of Michigan's Center for Southeast Asian Studies, and presentations at meetings of the American Anthropological Association, the Association for Asian Studies, the Harvard East Asia Society, and the Society for Psychological Anthropology. I further benefited from extremely helpful comments from multiple American Ethnologist reviewers and editor-in-chief Niko Besnier. The tragedies that this article describes continue to leave me painfully grateful to the families in whose sorrows I share, and I remain committed, but struggling, to honor their loved ones. (Social Science Research Council; Fulbright-Hays Doctoral Dissertation Abroad Research Program; UC Pacific-Rim Research Program; UCLA Graduate Division; Asia Institute Wagatsuma Fellowships; Centre for Ethnography; Social Sciences and Humanities Research Council at the University of Toronto)https://anthrosource.onlinelibrary.wiley.com/doi/10.1111/amet.12599Accepted manuscriptPublished versio