Small-Molecule Activators of Insulin-Degrading Enzyme Discovered through High-Throughput Compound Screening

Background: Hypocatabolism of the amyloid β-protein (Aβ) by insulin-degrading enzyme (IDE) is implicated in the pathogenesis of Alzheimer disease (AD), making pharmacological activation of IDE an attractive therapeutic strategy. However, it has not been established whether the proteolytic activity of IDE can be enhanced by drug-like compounds. Methodology/Principal Findings: Based on the finding that ATP and other nucleotide polyphosphates modulate IDE activity at physiological concentrations, we conducted parallel high-throughput screening campaigns in the absence or presence of ATP and identified two compounds—designated Ia1 and Ia2—that significantly stimulate IDE proteolytic activity. Both compounds were found to interfere with the crosslinking of a photoaffinity ATP analogue to IDE, suggesting that they interact with a bona fide ATP-binding domain within IDE. Unexpectedly, we observed highly synergistic activation effects when the activity of Ia1 or Ia2 was tested in the presence of ATP, a finding that has implications for the mechanisms underlying ATP-mediated activation of IDE. Notably, Ia1 and Ia2 activated the degradation of Aβ by ∼700% and ∼400%, respectively, albeit only when Aβ was presented in a mixture also containing shorter substrates. Conclusions/Significance: This study describes the first examples of synthetic small-molecule activators of IDE, showing that pharmacological activation of this important protease with drug-like compounds is achievable. These novel activators help to establish the putative ATP-binding domain as a key modulator of IDE proteolytic activity and offer new insights into the modulatory action of ATP. Several larger lessons abstracted from this screen will help inform the design of future screening campaigns and facilitate the eventual development of IDE activators with therapeutic utility

Da racialização do sexismo ao sexismo identitário entre imigrantes na França contemporânea From racialization to identitary sexism among immigrants in contemporary France

Este texto examina a maneira como o racismo manipula a denúncia do sexismo e apresenta os efeitos desses discursos sobre as pessoas que são alvo de discriminação. Sustenta que, longe de diminuir as violências sexistas, as lógicas racistas que se escondem atrás do anti-sexismo tendem a reforçá-las. Nossa demonstração se apóia em dados recolhidos durante uma pesquisa sobre a experiência do racismo, sexualidade e a gestão dos riscos de infecção por HIV, conduzida entre 1997 e 2003 junto a 69 jovens, homens e mulheres, de idade entre 18 e 25 anos, na França.<br>This paper analyzes the way racism manipulates accusations of racism, and presents the effects of such discourses on discriminated individuals. It argues that, far from reducing sexist violence, the racist logic concealed by anti-sexism tends to reinforce it. Our theses is based on data collected in a survey on experiences of racism, sexuality and HIV-infection risks management, carried out from 1997 to 2003, among 69 young males and females, aged 18-25 years, in France

Viols et agressions sexuelles en France : premiers résultats de l’enquête Virage

Les femmes rapportent des viols et des agressions sexuelles dans des proportions très supérieures à celles des hommes. Pour elles, les violences dans le cadre des relations conjugales s’ajoutent aux violences subies dans la famille dès l’enfance et l’adolescence, ainsi qu’aux agressions sexuelles vécues tout au long de la vie dans les différents espaces de vie (travail, espace public)

Identification of a Novel BBS Gene (BBS12) Highlights the Major Role of a Vertebrate-Specific Branch of Chaperonin-Related Proteins in Bardet-Biedl Syndrome

Bardet-Biedl syndrome (BBS) is primarily an autosomal recessive ciliopathy characterized by progressive retinal degeneration, obesity, cognitive impairment, polydactyly, and kidney anomalies. The disorder is genetically heterogeneous, with 11 BBS genes identified to date, which account for ∼70% of affected families. We have combined single-nucleotide–polymorphism array homozygosity mapping with in silico analysis to identify a new BBS gene, BBS12. Patients from two Gypsy families were homozygous and haploidentical in a 6-Mb region of chromosome 4q27. FLJ35630 was selected as a candidate gene, because it was predicted to encode a protein with similarity to members of the type II chaperonin superfamily, which includes BBS6 and BBS10. We found pathogenic mutations in both Gypsy families, as well as in 14 other families of various ethnic backgrounds, indicating that BBS12 accounts for ∼5% of all BBS cases. BBS12 is vertebrate specific and, together with BBS6 and BBS10, defines a novel branch of the type II chaperonin superfamily. These three genes are characterized by unusually rapid evolution and are likely to perform ciliary functions specific to vertebrates that are important in the pathophysiology of the syndrome, and together they account for about one-third of the total BBS mutational load. Consistent with this notion, suppression of each family member in zebrafish yielded gastrulation-movement defects characteristic of other BBS morphants, whereas simultaneous suppression of all three members resulted in severely affected embryos, possibly hinting at partial functional redundancy within this protein family