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The theory of technological mediation aims to take technological artifacts seriously, recognizing the constitutive role they play in how we experience the world, act in it, and how we are constituted as (moral) subjects. Its quest for a compatible ethics has led it to Foucault’s “care of the self,” i.e., a transformation of the self by oneself through self-discipline. In this regard, technologies have been interpreted as power structures to which one can relate through Foucaultian “technologies of the self” or ascetic practices. However, this leaves unexplored how concrete technologies can actually support the process of self-care. This paper explores this possibility by examining one such technology: a gamified To-Do list app. Doing so, it first shows that despite the apparent straightforwardness of gamification, confrontation and shame play an important role in how the app motivates me to do better. Second, inspired by Ihde’s schema of human-technology relations, it presents different ways in which the app may confront me with myself. Subsequently, it accounts for the motivation and shame that this technologically mediated confrontation with myself invokes through a Levinasian account of ethical subjectivity. In so doing, it also shows how Levinas’ phenomenology implies a responsibility for self-care and how nonhuman, technological others may still call me to responsibility. It concludes with a reflection on the role of gamification in technologically mediated subjectivation and some implications for design.

Conceiving of nuclear energy as a social experiment gives rise to the question of what to do when the experiment is no longer responsible or desirable. To be able to appropriately respond to such a situation, the nuclear energy technology in question should be reversible, i.e. it must be possible to stop its further development and implementation in society, and it must be possible to undo its undesirable consequences. This paper explores these two conditions by applying them to geological disposal of high-level radioactive waste (GD). Despite the fact that considerations of reversibility and retrievability have received increased attention in GD, the analysis in this paper concludes that GD cannot be considered reversible. Firstly, it would be difficult to stop its further development and implementation, since its historical development has led to a point where GD is significantly locked-in. Secondly, the strategy it employs for undoing undesirable consequences is less-than-ideal: it relies on containment of severely radiotoxic waste rather than attempting to eliminate this waste or its radioactivity. And while it may currently be technologically impossible to turn high-level waste into benign substances, GD’s containment strategy makes it difficult to eliminate this waste’s radioactivity when the possibility would arise. In all, GD should be critically reconsidered if the inclusion of reversibility considerations in radioactive waste management has indeed become as important as is sometimes claimed.

Background Scales are mineralised exoskeletal structures that are part of the dermal skeleton. Scales have been mostly lost during evolution of terrestrial vertebrates whilst bony fish have retained a mineralised dermal skeleton in the form of fin rays and scales. Each scale is a mineralised collagen plate that is decorated with both matrix-building and resorbing cells. When removed, an ontogenetic scale is quickly replaced following differentiation of the scale pocket-lining cells that regenerate a scale. Processes promoting de novo matrix formation and mineralisation initiated during scale regeneration are poorly understood. Therefore, we performed transcriptomic analysis to determine gene networks and their pathways involved in dermal scale regeneration. Results We defined the transcriptomic profiles of ontogenetic and regenerating scales of zebrafish and identified 604 differentially expressed genes (DEGs). These were enriched for extracellular matrix, ossification, and cell adhesion pathways, but not in enamel or dentin formation processes indicating that scales are reminiscent to bone. Hypergeometric tests involving monogenetic skeletal disorders showed that DEGs were strongly enriched for human orthologues that are mutated in low bone mass and abnormal bone mineralisation diseases ( P < 2× 10 −3 ). The DEGs were also enriched for human orthologues associated with polygenetic skeletal traits, including height ( P < 6× 10 −4 ), and estimated bone mineral density (eBMD, P < 2× 10 −5 ). Zebrafish mutants of two human orthologues that were robustly associated with height ( COL11A2 , P =6× 10 −24 ) or eBMD ( SPP1 , P =6× 10 −20 ) showed both exo- and endo- skeletal abnormalities as predicted by our genetic association analyses; col11a2 Y228X/Y228X mutants showed exoskeletal and endoskeletal features consistent with abnormal growth, whereas spp1 P160X/P160X mutants predominantly showed mineralisation defects. Conclusion We show that scales have a strong osteogenic expression profile comparable to other elements of the dermal skeleton, enriched in genes that favour collagen matrix growth. Despite the many differences between scale and endoskeletal developmental processes, we also show that zebrafish scales express an evolutionarily conserved sub-population of genes that are relevant to human skeletal disease.

ObjectiveDuchenne muscular dystrophy (DMD) is characterised by progressive muscle weakness. It has recently been reported that single nucleotide polymorphisms (SNPs) located in the SPP1 and LTBP4 loci can account for some of the inter-individual variability observed in the clinical disease course. The validation of genetic association in large independent cohorts is a key process for rare diseases in order to qualify prognostic biomarkers and stratify patients in clinical trials.MethodsDuchenne patients from five European neuromuscular centres were included. Information about age at wheelchair dependence and steroid use was gathered. Melting curve analysis of PCR fragments or Sanger sequencing were used to genotype SNP rs28357094 in the SPP1 gene in 336 patients. The genotype of SNPs rs2303729, rs1131620, rs1051303 and rs10880 in the LTBP4 locus was determined in 265 patients by mass spectrometry. For both loci, a multivariate analysis was performed, using genotype/haplotype, steroid use and cohort as covariates.ResultsWe show that corticosteroid treatment and the IAAM haplotype of the LTBP4 gene are significantly associated with prolonged ambulation in patients with DMD. There was no significant association between the SNP rs28357094 in the SPP1 gene and the age of ambulation loss.ConclusionsThis study underlines the importance of replicating genetic association studies for rare diseases in large independent cohorts to identify the most robust associations. We anticipate that genotyping of validated genetic associations will become important for the design and interpretation of clinical trials.

Type 1 diabetes is a T cell-mediated autoimmune disease, and insulin is an important target of the autoimmune response associated with β cell destruction. The mechanism of destruction is still unknown. Here, we provide evidence for CD8 T cell autoreactivity associated with recurrent autoimmunity and loss of β cell function in type 1 diabetic islet transplant recipients. We first identified an insulin B chain peptide (insB10-18) with extraordinary binding affinity to HLA-A2(*0201) that is expressed by the majority of type 1 diabetes patients. We next demonstrated that this peptide is naturally processed by both constitutive and immuno proteasomes and translocated to the endoplasmic reticulum by the peptide transporter TAP1 to allow binding to HLA-A2 in the endoplasmic reticulum and cell surface presentation. Peripheral blood mononuclear cells from a healthy donor were primed in vitro with this peptide, and CD8 T cells were isolated that specifically recognize target cells expressing the insulin B chain peptide. $HLA-A2^{insB10-18}$ tetramer staining revealed a strong association between detection of autoreactive CD8 T cells and recurrent autoimmunity after islet transplantation and graft failure in type 1 diabetic patients. We demonstrate that CD8 T cell autoreactivity is associated with β cell destruction in type 1 diabetes in humans.

Under non-inflammatory conditions HLA class II is predominantly expressed on hematopoietic cells. Therefore, donor CD4 T-cells after allogeneic stem cell transplantation (alloSCT) may mediate graft-vs.-leukemia reactivity without graft-vs.-host disease (GVHD). We analyzed immune responses in four patients converting from mixed to full donor chimerism without developing GVHD upon purified CD4 donor lymphocyte infusion (DLI) from their HLA-identical sibling donor after T-cell depleted alloSCT. activated T-cells were clonally isolated after CD4 DLI. Of the alloreactive T-cell clones, 96% were CD4 positive, illustrating the dominant role of CD4 T-cells in the immune responses. We identified 9 minor histocompatibility antigens (MiHA) as targets for alloreactivity, of which 8 were novel HLA class II restricted MiHA. In all patients, MiHA specific CD4 T-cells were found that were capable to lyse hematopoietic cells and to recognize normal and malignant cells. No GVHD was induced in these patients. Skin fibroblasts forced to express HLA class II, were recognized by only two MiHA specific CD4 T-cell clones. Of the 7 clones that failed to recognize fibroblasts, two targeted MiHA were encoded by genes not expressed in fibroblasts, presentation of one MiHA was dependent on HLA-DO, which is absent in fibroblasts, and T-cells recognizing the remaining 4 MiHA had an avidity that was apparently too low to recognize fibroblasts, despite clear recognition of hematopoietic cells. In conclusion, purified CD4 DLI from HLA-identical sibling donors can induce conversion from mixed to full donor chimerism with graft-vs.-malignancy reactivity, but without GVHD, by targeting HLA class II restricted MiHA.

Background Late presentation remains a key barrier towards controlling the HIV epidemic. Indicator conditions (ICs) are those that are AIDS-defining, associated with a prevalence of undiagnosed HIV > 0.1%, or whose clinical management would be impeded if an HIV infection were undiagnosed. IC-guided HIV testing is an effective strategy in identifying undiagnosed HIV, but opportunities for earlier HIV diagnosis through IC-guided testing are being missed. We present a protocol for an interventional study to improve awareness of IC-guided testing and increase HIV testing in patients presenting with ICs in a hospital setting. Methods We designed a multicentre interventional study to be implemented at five hospitals in the region of Amsterdam, the Netherlands. Seven ICs were selected for which HIV test ratios (proportion of patients with an IC tested for HIV) will be measured: tuberculosis, cervical/vulvar cancer or high-grade cervical/vulvar dysplasia, malignant lymphoma, hepatitis B and C, and peripheral neuropathy. Prior to the intervention, a baseline assessment of HIV test ratios across ICs will be performed in eligible patients (IC diagnosed January 2015 through May 2020, ≥18 years, not known HIV positive) and an assessment of barriers and facilitators for HIV testing amongst relevant specialties will be conducted using qualitative (interviews) and quantitative methods (questionnaires). The intervention phase will consist of an educational intervention, including presentation of baseline results as competitive graphical audit and feedback combined with discussion on implementation and opportunities for improvement. The effect of the intervention will be assessed by comparing HIV test ratios of the pre-intervention and post-intervention periods. The primary endpoint is the HIV test ratio within ±3 months of IC diagnosis. Secondary endpoints are the HIV test ratio within ±6 months of diagnosis, ratio ever tested for HIV, HIV positivity percentage, proportion of late presenters and proportion with known HIV status prior to initiating treatment for their IC. Discussion This protocol presents a strategy aimed at increasing awareness of the benefits of IC-guided testing and increasing HIV testing in patients presenting with ICs in hospital settings to identify undiagnosed HIV in Amsterdam, the Netherlands. Trial registration Dutch trial registry: NL7521 . Registered 14 February 2019.