Inhibition of the Mitochondrial Enzyme ABAD Restores the Amyloid-β-Mediated Deregulation of Estradiol

Alzheimer's disease (AD) is a conformational disease that is characterized by amyloid-β (Aβ) deposition in the brain. Aβ exerts its toxicity in part by receptor-mediated interactions that cause down-stream protein misfolding and aggregation, as well as mitochondrial dysfunction. Recent reports indicate that Aβ may also interact directly with intracellular proteins such as the mitochondrial enzyme ABAD (Aβ binding alcohol dehydrogenase) in executing its toxic effects. Mitochondrial dysfunction occurs early in AD, and Aβ's toxicity is in part mediated by inhibition of ABAD as shown previously with an ABAD decoy peptide. Here, we employed AG18051, a novel small ABAD-specific compound inhibitor, to investigate the role of ABAD in Aβ toxicity. Using SH-SY5Y neuroblastoma cells, we found that AG18051 partially blocked the Aβ-ABAD interaction in a pull-down assay while it also prevented the Aβ42-induced down-regulation of ABAD activity, as measured by levels of estradiol, a known hormone and product of ABAD activity. Furthermore, AG18051 is protective against Aβ42 toxicity, as measured by LDH release and MTT absorbance. Specifically, AG18051 reduced Aβ42-induced impairment of mitochondrial respiration and oxidative stress as shown by reduced ROS (reactive oxygen species) levels. Guided by our previous finding of shared aspects of the toxicity of Aβ and human amylin (HA), with the latter forming aggregates in Type 2 diabetes mellitus (T2DM) pancreas, we determined whether AG18051 would also confer protection from HA toxicity. We found that the inhibitor conferred only partial protection from HA toxicity indicating distinct pathomechanisms of the two amyloidogenic agents. Taken together, our results present the inhibition of ABAD by compounds such as AG18051 as a promising therapeutic strategy for the prevention and treatment of AD, and suggest levels of estradiol as a suitable read-out

The FANCM:p.Arg658* truncating variant is associated with risk of triple-negative breast cancer

Abstract: Breast cancer is a common disease partially caused by genetic risk factors. Germline pathogenic variants in DNA repair genes BRCA1, BRCA2, PALB2, ATM, and CHEK2 are associated with breast cancer risk. FANCM, which encodes for a DNA translocase, has been proposed as a breast cancer predisposition gene, with greater effects for the ER-negative and triple-negative breast cancer (TNBC) subtypes. We tested the three recurrent protein-truncating variants FANCM:p.Arg658*, p.Gln1701*, and p.Arg1931* for association with breast cancer risk in 67,112 cases, 53,766 controls, and 26,662 carriers of pathogenic variants of BRCA1 or BRCA2. These three variants were also studied functionally by measuring survival and chromosome fragility in FANCM−/− patient-derived immortalized fibroblasts treated with diepoxybutane or olaparib. We observed that FANCM:p.Arg658* was associated with increased risk of ER-negative disease and TNBC (OR = 2.44, P = 0.034 and OR = 3.79; P = 0.009, respectively). In a country-restricted analysis, we confirmed the associations detected for FANCM:p.Arg658* and found that also FANCM:p.Arg1931* was associated with ER-negative breast cancer risk (OR = 1.96; P = 0.006). The functional results indicated that all three variants were deleterious affecting cell survival and chromosome stability with FANCM:p.Arg658* causing more severe phenotypes. In conclusion, we confirmed that the two rare FANCM deleterious variants p.Arg658* and p.Arg1931* are risk factors for ER-negative and TNBC subtypes. Overall our data suggest that the effect of truncating variants on breast cancer risk may depend on their position in the gene. Cell sensitivity to olaparib exposure, identifies a possible therapeutic option to treat FANCM-associated tumors

Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus

A locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 BRCA1 mutation carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous OC (P=9.2 × 10-20), ER-negative BC (P=1.1 × 10-13), BRCA1-associated BC (P=7.7 × 10-16) and triple negative BC (P-diff=2 × 10-5). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P=2 × 10-3) and ABHD8 (P<2 × 10-3). Chromosome conformation capture identifies interactions between four candidate SNPs and ABHD8, and luciferase assays indicate six risk alleles increased transactivation of the ADHD8 promoter. Targeted deletion of a region containing risk SNP rs56069439 in a putative enhancer induces ANKLE1 downregulation; and mRNA stability assays indicate functional effects for an ANKLE1 3′-UTR SNP. Altogether, these data suggest that multiple SNPs at 19p13 regulate ABHD8 and perhaps ANKLE1 expression, and indicate common mechanisms underlying breast and ovarian cancer risk

A case-only study to identify genetic modifiers of breast cancer risk for BRCA1/BRCA2 mutation carriers

Abstract: Breast cancer (BC) risk for BRCA1 and BRCA2 mutation carriers varies by genetic and familial factors. About 50 common variants have been shown to modify BC risk for mutation carriers. All but three, were identified in general population studies. Other mutation carrier-specific susceptibility variants may exist but studies of mutation carriers have so far been underpowered. We conduct a novel case-only genome-wide association study comparing genotype frequencies between 60,212 general population BC cases and 13,007 cases with BRCA1 or BRCA2 mutations. We identify robust novel associations for 2 variants with BC for BRCA1 and 3 for BRCA2 mutation carriers, P < 10−8, at 5 loci, which are not associated with risk in the general population. They include rs60882887 at 11p11.2 where MADD, SP11 and EIF1, genes previously implicated in BC biology, are predicted as potential targets. These findings will contribute towards customising BC polygenic risk scores for BRCA1 and BRCA2 mutation carriers

Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus

A locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 BRCA1 mutation carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous OC (P = 9.2 x 10(-20)), ER-negative BC (P = 1.1 x 10(-13)), BRCA1-associated BC (P = 7.7 x 10(-16)) and triple negative BC (P-diff = 2 x 10(-5)). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P = 2 x 10(-3)) and ABHD8 (PPeer reviewe

A case-only study to identify genetic modifiers of breast cancer risk for BRCA1/BRCA2 mutation carriers

Breast cancer (BC) risk for BRCA1 and BRCA2 mutation carriers varies by genetic and familial factors. About 50 common variants have been shown to modify BC risk for mutation carriers. All but three, were identified in general population studies. Other mutation carrier-specific susceptibility variants may exist but studies of mutation carriers have so far been underpowered. We conduct a novel case-only genome-wide association study comparing genotype frequencies between 60,212 general population BC cases and 13,007 cases with BRCA1 or BRCA2 mutations. We identify robust novel associations for 2 variants with BC for BRCA1 and 3 for BRCA2 mutation carriers, P < 10−8, at 5 loci, which are not associated with risk in the general population. They include rs60882887 at 11p11.2 where MADD, SP11 and EIF1, genes previously implicated in BC biology, are predicted as potential targets. These findings will contribute towards customising BC polygenic risk scores for BRCA1 and BRCA2 mutation carriers

Le « long » parcours des épurés de l’arrondissement judiciaire de Mons : de la déchéance au recouvrement des droits (1945-1961)

Le 15 février 1946, Léon F. est inscrit sur la liste « épuration civique » et déchu, à vie, de l’ensemble des droits prévus à l’article 123 sexies du Code pénal. On lui reproche son adhésion à Rex dans le courant de l’année 1943 alors qu’il était notoire que ce parti servait la politique de l’ennemi. Plus d’un an et demi après la libération de la Belgique, Léon F. est donc frappé de la déchéance de ses droits civils et politiques, mesure prévue par l’arrêté-loi du 19 septembre 1945, instauran..

Racisme et danse: mouvement de construction des corps d'exception

Like other sectors of society, the world of dance, which is pedagogical and choreographic, hosts a racism built around prescriptive prejudices. The racism is (re)produced at the same time by a lack of awareness of the actors-resses of this environment of the scope of the prejudices but also through different rhetorics. At the same time universalist and differentialist, making racialized dancers sometimes equals whose differences will be erased, or also some “Others” having physical or behavioural particularities specific of their gene or their culture justifying thus their being set apart. It is the construction of these other bodies, differencied, dominated in the field of the dance which will be focus of our interest here.Comme d’autres espaces de la société, le monde de la danse; pédagogique et chorégraphique, abrite un racisme construit autour de préjugés prescriptifs. Il se (re)produit à la fois par un manque de conscience des acteurs-rices de ce milieu sur la portée des préjugés mais également par le biais de différents discours. À la fois universaliste et différentialiste, faisant des danseurs-euses racisées tantôt des semblables chez qui l’on va gommer la différence, ou encore des “Autres” possédant des particularités physiques ou comportementales propres à leur gène ou à leur culture justifiant ainsi leur mise à l’écart. C'est la construction de ces corps “Autres”, altérisés, dominés dans le champ de la danse qui va nous intéresser ici.Come in altri spazi della società, nel mondo pedagogico e coreografico della danza,  risiede un razzismo basato su pregiudizi prescrittivi, che si (ri)produce tanto a causa della mancanza di coscienza, da parte di attori e attrici del settore, dell’importanza dei pregiudizi, quanto attraverso discorsi di vario tipo, universalisti ma anche differenzialisti. Tali discorsi presentano i ballerini e le ballerine razzializzati.e talvolta come dei simili, la cui differenza sarà quindi annullata, talvolta come Altri, dotati di particolarità fisiche o comportamentali di origine genetica o culturale, giustificandone in tal modo l’emarginazione. Il mio contributo si concentrerà sulla creazione di questi corpi altri, differenziati, dominati nell’ambiente della danza, analizzando il modo in cui le pratiche e i discorsi degli attori e delle attrici contribuiscono a creare questi corpi di eccezione

The contribution of learner corpora to the substantiation of fluency levels

The study reported in this paper examines whether, and to what extent, corpus data on three features contributing to (dis)fluency, namely unfilled pauses, restarts and false starts produced by 50 French-speaking learners of English, support the fluency descriptor scale of the Common European Framework of Reference for Languages (CEFR; Council of Europe 2001). The analysis shows that, except for restarts, there is no statistical difference in the mean frequency of pauses and false starts across the CEFR fluency levels represented in the data. Statistical measures did, however, show significant differences between the group of advanced learners and a comparable group of native speakers for all three categories of (dis)fluency phenomena. An investigation into the immediate environment of the three features further revealed that, rather than being used in isolation, they tend to form recurrent clusters that bear the potential of providing convincing evidence for the delineation of fluency levels