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’

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

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

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

COMPARISON OF MODIFICATION SITES FORMED ON HUMAN SERUM ALBUMIN AT VARIOUS STAGES OF GLYCATION

Background—Many of the complications encountered during diabetes can be linked to the nonenzymatic glycation of proteins, including human serum albumin (HSA). However, there is little information regarding how the glycation pattern of HSA changes as the total extent of glycation is varied. The goal of this study was to identify and conduct a semi-quantitative comparison of the glycation products on HSA that are produced in the presence of various levels of glycation. Methods—Three glycated HSA samples were prepared in vitro by incubating physiological concentrations of HSA with 15 mmol/l glucose for 2 or 5 weeks, or with 30 mmol/l glucose for 4 weeks. These samples were then digested and examined by matrix-assisted laser desorption/ ionization time-of-flight mass spectrometry (MALDI-TOF MS) to identify the glycation products that were formed. Results—It was found that the glycation pattern of HSA changed with its overall extent of total glycation. Many modifications including previously-reported primary glycation sites (e.g., K199, K281, and the N-terminus) were consistently found in the tested samples. Lysines 199 and 281, as well as arginine 428, contained the most consistently identified and abundant glycation products. Lysines 93, 276, 286, 414, 439, and 524/525, as well as the N-terminus and arginines 98, 197, and 521, were also found to be modified at various degrees of HSA glycation. Conclusions—The glycation pattern of HSA was found to vary with different levels of total glycation and included modifications at the 2 major drug binding sites on this protein. This result suggests that different modified forms of HSA, both in terms of the total extent of glycation and glycation pattern, may be found at various stages of diabetes. The clinical implication of these results is that the binding of HSA to some drug may be altered at various stages of diabetes as the extent of glycation and types of modifications in this protein are varied

Protein arginine methyltransferase 6 regulates multiple aspects of gene expression

It is well established that transcription and alternative splicing events are functionally coupled during gene expression. Here, we report that protein arginine N-methyltransferase 6 (PRMT6) may play a key role in this coupling process by functioning as a transcriptional coactivator that can also regulate alternative splicing. PRMT6 coactivates the progesterone, glucocorticoid and oestrogen receptors in luciferase reporter assays in a hormone-dependent manner. In addition, small interfering RNA (siRNA) oligonucleotide duplex knockdown of PRMT6 disrupts oestrogen-stimulated transcription of endogenous GREB1 and progesterone receptor in MCF-7 breast cancer cells, demonstrating the importance of PRMT6 in hormone-dependent transcription. In contrast, the regulation of alternative splicing by PRMT6 is hormone independent. siRNA knockdown of PRMT6 increases the exon inclusion:skipping ratio of alternatively spliced exons in endogenous vascular endothelial growth factor and spleen tyrosine kinase RNA transcripts in both the presence and absence of oestrogen. These results demonstrate that PRMT6 has a dual role in regulating gene expression and that these two functions can occur independently of each other

The solution structure of the first PHD finger of autoimmune regulator in complex with non-modified histone H3 tail reveals the antagonistic role of H3R2 methylation

Plant homeodomain (PHD) fingers are often present in chromatin-binding proteins and have been shown to bind histone H3 N-terminal tails. Mutations in the autoimmune regulator (AIRE) protein, which harbours two PHD fingers, cause a rare monogenic disease, autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED). AIRE activates the expression of tissue-specific antigens by directly binding through its first PHD finger (AIRE-PHD1) to histone H3 tails non-methylated at K4 (H3K4me0). Here, we present the solution structure of AIRE-PHD1 in complex with H3K4me0 peptide and show that AIRE-PHD1 is a highly specialized non-modified histone H3 tail reader, as post-translational modifications of the first 10 histone H3 residues reduce binding affinity. In particular, H3R2 dimethylation abrogates AIRE-PHD1 binding in vitro and reduces the in vivo activation of AIRE target genes in HEK293 cells. The observed antagonism by R2 methylation on AIRE-PHD1 binding is unique among the H3K4me0 histone readers and represents the first case of epigenetic negative cross-talk between non-methylated H3K4 and methylated H3R2. Collectively, our results point to a very specific histone code responsible for non-modified H3 tail recognition by AIRE-PHD1 and describe at atomic level one crucial step in the molecular mechanism responsible for antigen expression in the thymus