Autosomal dominant hypercholesterolemia (ADH; OMIM144400), a risk factor for coronary heart disease, is characterized by an increase in low-density lipoprotein cholesterol levels that is associated with mutations in the genes LDLR (encoding low-density lipoprotein receptor) or APOB (encoding apolipoprotein B). We mapped a third locus associated with ADH, HCHOLA3 at 1p32, and now report two mutations in the gene PCSK9 (encoding proprotein convertase subtilisin/kexin type 9) that cause ADH. PCSK9 encodes NARC-1 (neural apoptosis regulated convertase), a newly identified human subtilase that is highly expressed in the liver and contributes to cholesterol homeostasis.

A diet that is based on high-heat-treated foods increases markers associated with an enhanced risk of type 2 diabetes and cardiovascular diseases in healthy people. Replacing high-heat-treatment techniques by mild cooking techniques may help to positively modulate biomarkers associated with an increased risk of diabetes mellitus and cardiovascular diseases.

The purpose of the present study was to establish the prebiotic effect of a new xylo-oligosaccharide (XOS) and of an inulin-and-XOS mixture (INU -XOS) and to determine their effect on endotoxaemia (lipopolysaccharides (LPS)) and immune parameters. In this randomised, parallel, placebo-controlled, double-blind study, sixty healthy volunteers were randomly assigned to three groups, receiving either 5 g XOS, INU-XOS (3 g inulin þ 1 g XOS) or an equivalent weight of wheat maltodextrin (placebo) during 4 weeks. Faecal samples were collected to assess the effects of these products on microbiota, as well as SCFA composition, enzymatic activities and secretory IgA production. Circulating LPS was measured in plasma samples, and whole blood was incubated with LPS to measure cytokine expression. Consumption of XOS alone increased the faecal concentrations of Bifidobacterium and butyrate and activities of a-glucosidase and b-glucuronidase, while decreasing the concentrations of acetate and p-cresol. Consumption of XOS in combination with inulin did not decrease the concentrations of acetate and p-cresol, but increased in addition the faecal concentrations of total SCFA and propionate. Furthermore, consumption of XOS in combination with inulin decreased LPS concentrations in blood and attenuated LPS-induced increases in gene expression in IL-1b and LPS-induced decreases in gene expression in IL-13 in blood. In conclusion, consumption of XOS alone or in combination with inulin results in beneficial albeit different changes in the intestinal microbiome on a high-fat diet. In addition, consumption of XOS in combination with inulin attenuates the proinflammatory effects of a high-fat diet in the blood of healthy subjects.Key words: Xylo-oligosaccharides: Immunonutrition: Prebiotics: Lipopolysaccharides: CytokinesThe complex role of the human intestinal microbiota is emerging and its functions are now more and more established when considering energy metabolism, nutrient digestion, vitamin synthesis, epithelial defences and immune responses (1) . The composition and function of the humanassociated microbiota are considered as a partner of the host in order to fight infection and to improve inflammatory processes and conditions. There is an increasing body of evidence linking the physiopathology of metabolic diseases such as obesity or inflammatory bowel disease and the gut microbiota (2) .Through resistance to digestion in the upper gastrointestinal tract, non-digestible carbohydrates reach the colon intact to undergo a complete or partial fermentation in the large intestine. If they selectively stimulate the growth and/or the activity of the beneficial, health-promoting members of the gut microbiota, they meet the criteria of prebiotics (3 -6) . b(2 ! 1)-Fructans, which include inulin and fructo-oligosaccharides (FOS), are considered to be prebiotics, while xylo-oligosaccharides (XOS) are considered as candidate prebiotics (7) .Mice fed a high-fat diet exhibited a significant increase in plasma lipopolysaccharides (LPS)...

This investigation was pursued to test the use of intracellular antibodies (intrabodies) as a means of blocking the pathogenesis of Huntington's disease (HD). HD is characterized by abnormally elongated polyglutamine near the N terminus of the huntingtin protein, which induces pathological protein-protein interactions and aggregate formation by huntingtin or its exon 1-containing fragments. Selection from a large human phage display library yielded a single-chain Fv (sFv) antibody specific for the 17 Nterminal residues of huntingtin, adjacent to the polyglutamine in HD exon 1. This anti-huntingtin sFv intrabody was tested in a cellular model of the disease in which huntingtin exon 1 had been fused to green fluorescent protein (GFP). Expression of expanded repeat HD-polyQ-GFP in transfected cells shows perinuclear aggregation similar to human HD pathology, which worsens with increasing polyglutamine length; the number of aggregates in these transfected cells provided a quantifiable model of HD for this study. Coexpression of anti-huntingtin sFv intrabodies with the abnormal huntingtin-GFP fusion protein dramatically reduced the number of aggregates, compared with controls lacking the intrabody. Anti-huntingtin sFv fused with a nuclear localization signal retargeted huntingtin analogues to cell nuclei, providing further evidence of the anti-huntingtin sFv specificity and of its capacity to redirect the subcellular localization of exon 1. This study suggests that intrabody-mediated modulation of abnormal neuronal proteins may contribute to the treatment of neurodegenerative diseases such as HD, Alzheimer's, Parkinson's, prion disease, and the spinocerebellar ataxias. H untington's disease (HD) is a genetic disorder that derives from expanded CAG repeats in the huntingtin gene (1), which then encodes pathological huntingtin protein with abnormally long polyglutamine sequences (polyQ, or Qn). Huntingtin is expressed ubiquitously by human cells, with high levels in the brain, particularly the cortex and striatum. Murine model studies of HD have shown it occurs through dominant gain of function when a single abnormal allele is present (2-6). Polyglutamine lengths ranging up to 35 residues (Q35) are present in healthy individuals, whereas Q40 or longer are associated with HD pathogenesis (1, 7). Larger polyQ expansions are correlated with earlier onset and more severe symptoms. The polyglutamine length-dependent aggregation of huntingtin has been reported to involve interaction with other proteins as well as selfassociation. Intracellular protein aggregates are found in human HD brains at autopsy and in tissues of mice carrying transgenes with expanded-repeat huntingtin (8-11). Here we report on the use of intracellular antibodies (intrabodies) as a potential therapeutic strategy on the basis of their ability to inhibit aberrant protein aggregate formation in a cellular model for HD. This approach may be applicable to other diseases as well, because HD is a paradigm for several adult-onset neurodegenerative diseases tha...