Fighting for a neoliberal Europe: Swiss business associations and the UNICE, 1970–1978

The 1970s were a defining moment for the European business associations, which were faced with the most important social upheavals of the post-war period, a major economic crisis and the British process of accession to the EEC. This article aims to broaden our knowledge of how Swiss business leaders contributed, during this tumultuous period, to lead the European institutions towards further economic liberalisation. This article intends to demonstrate that their main strategy to promote their own interests was to rely on and even accentuate the contradictions between the main European business circles. Moreover, this article aims to highlight the gradual emergence, during the period, of a bloc of European employers and to investigate the role of the main Swiss trade association in what has been known as the ‘neoliberal turn’

Three-dimensional hybrid radial Cartesian echo planar imaging for functional MRI

Functional magnetic resonance imaging (fMRI) has provided neuroscientists with a powerful tool to non-invasively study brain function. Typically, fMRI data acquisition is performed using the well-established multi-slice two-dimensional echo planar imaging (2D EPI) technique. While 2D EPI has the considerable advantage of robustness, it is relatively SNR inefficient, particularly at high spatial resolution. Three dimensional (3D) sampling approaches, such as multi-shot 3D EPI provide a theoretical SNR gain compared to 2D EPI and can utilize parallel imaging acceleration along multiple dimensions, leading to the potential for higher spatial and temporal resolution. However, these multi-shot acquisitions span several seconds, making them susceptible to physiological fluctuations. In particular, subject motion is a major source of image degradation. This thesis aims to characterise and improve fMRI acquisition techniques based on 3D EPI approaches. We explored the temporal SNR characteristics of standard segmented 3D EPI for different spatial resolutions and acceleration factors. Specifically, we studied how physiological noise affects the optimal choice of imaging parameters, such as the amount of acceleration. To address some of the shortcomings of conventional 3D EPI, we implemented a hybrid radial-Cartesian 3D EPI trajectory, called TURBINE. This scheme collects EPI "blades" which are rotated about the phase-encoding axis using a golden angle rotation increment, allowing reconstruction at flexible temporal resolution. The self-navigating properties of the sequence are used to determine motion estimates from high temporal resolution navigator images and correct for subject motion as part of the image reconstruction process. We demonstrated that this scheme reduces the impact of motion on fMRI data in the presence of subtle and large subject motions. The techniques developed in this thesis aim to increase the flexibility and robustness of fMRI acquisitions. Ultimately, this research may help increase the utility of fMRI in difficult subjects or patient populations

Attenuation of lung fibrosis in mice with a clinically relevant inhibitor of glutathione-S-transferase π

Idiopathic pulmonary fibrosis (IPF) is a debilitating lung disease characterized by excessive collagen production and fibrogenesis. Apoptosis in lung epithelial cells is critical in IPF pathogenesis, as heightened loss of these cells promotes fibroblast activation and remodeling. Changes in glutathione redox status have been reported in IPF patients. S-glutathionylation, the conjugation of glutathione to reactive cysteines, is catalyzed in part by glutathione-S-transferase π (GSTP). To date, no published information exists linking GSTP and IPF to our knowledge. We hypothesized that GSTP mediates lung fibrogenesis in part through FAS S-glutathionylation, a critical event in epithelial cell apoptosis. Our results demonstrate that GSTP immunoreactivity is increased in the lungs of IPF patients, notably within type II epithelial cells. The FAS-GSTP interaction was also increased in IPF lungs. Bleomycin- and AdTGFβ-induced increases in collagen content, α-SMA, FAS S-glutathionylation, and total protein S-glutathionylation were strongly attenuated in Gstp(–/–) mice. Oropharyngeal administration of the GSTP inhibitor, TLK117, at a time when fibrosis was already apparent, attenuated bleomycin- and AdTGFβ-induced remodeling, α-SMA, caspase activation, FAS S-glutathionylation, and total protein S-glutathionylation. GSTP is an important driver of protein S-glutathionylation and lung fibrosis, and GSTP inhibition via the airways may be a novel therapeutic strategy for the treatment of IPF

WNT signalling control by KDM5C during development affects cognition

Although KDM5C is one of the most frequently mutated genes in X-linked intellectual disability, the exact mechanisms that lead to cognitive impairment remain unknown. Here we use human patient-derived induced pluripotent stem cells and Kdm5c knockout mice to conduct cellular, transcriptomic, chromatin and behavioural studies. KDM5C is identified as a safeguard to ensure that neurodevelopment occurs at an appropriate timescale, the disruption of which leads to intellectual disability. Specifically, there is a developmental window during which KDM5C directly controls WNT output to regulate the timely transition of primary to intermediate progenitor cells and consequently neurogenesis. Treatment with WNT signalling modulators at specific times reveal that only a transient alteration of the canonical WNT signalling pathway is sufficient to rescue the transcriptomic and chromatin landscapes in patient-derived cells and to induce these changes in wild-type cells. Notably, WNT inhibition during this developmental period also rescues behavioural changes of Kdm5c knockout mice. Conversely, a single injection of WNT3A into the brains of wild-type embryonic mice cause anxiety and memory alterations. Our work identifies KDM5C as a crucial sentinel for neurodevelopment and sheds new light on KDM5C mutation-associated intellectual disability. The results also increase our general understanding of memory and anxiety formation, with the identification of WNT functioning in a transient nature to affect long-lasting cognitive function

CD5 Expression by Dendritic Cells Directs T Cell Immunity and Sustains Immunotherapy Responses

The induction of proinflammatory T cells by dendritic cell (DC) subtypes is critical for antitumor responses and effective immune checkpoint blockade (ICB) therapy. Here, we show that human CD1c+CD5+ DCs are reduced in melanoma-affected lymph nodes, with CD5 expression on DCs correlating with patient survival. Activating CD5 on DCs enhanced T cell priming and improved survival after ICB therapy. CD5+ DC numbers increased during ICB therapy, and low interleukin-6 (IL-6) concentrations promoted their de novo differentiation. Mechanistically, CD5 expression by DCs was required to generate optimally protective CD5hi T helper and CD8+ T cells; further, deletion of CD5 from T cells dampened tumor elimination in response to ICB therapy in vivo. Thus, CD5+ DCs are an essential component of optimal ICB therapy

The Roles of Glycated Albumin as Intermediate Glycation Index and Pathogenic Protein

The conventional glycemic indices used in management of diabetic patients includes A1c, fructosamine, 1,5-anhydroglucitol, and glycated albumin (GA). Among these indices, A1c is currently used as the gold standard. However, A1c cannot reflect the glycemic change over a relatively short period of time, and its accuracy is known to decrease when abnormalities in hemoglobin metabolism, such as anemia, coexist. When considering these weaknesses, there have been needs for finding a novel glycemic index for diagnosing and managing diabetes, as well as for predicting diabetic complications properly. Recently, several studies have suggested the potential of GA as an intermediate-term glycation index in covering the short-term effect of treatment. Furthermore, its role as a pathogenic protein affecting the worsening of diabetes and occurrence of diabetic complications is receiving attention as well. Therefore, in this article, we wanted to review the recent status of GA as a glycemic index and as a pathogenic protein