| 1. |
- Teslovich, Tanya M., et al.
(författare)
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Biological, clinical and population relevance of 95 loci for blood lipids
- 2010
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 466:7307, s. 707-713
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Tidskriftsartikel (refereegranskat)abstract
- Plasma concentrations of total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and triglycerides are among the most important risk factors for coronary artery disease (CAD) and are targets for therapeutic intervention. We screened the genome for common variants associated with plasma lipids in >100,000 individuals of European ancestry. Here we report 95 significantly associated loci (P<5 x 10(-8)), with 59 showing genome-wide significant association with lipid traits for the first time. The newly reported associations include single nucleotide polymorphisms (SNPs) near known lipid regulators (for example, CYP7A1, NPC1L1 and SCARB1) as well as in scores of loci not previously implicated in lipoprotein metabolism. The 95 loci contribute not only to normal variation in lipid traits but also to extreme lipid phenotypes and have an impact on lipid traits in three non-European populations (East Asians, South Asians and African Americans). Our results identify several novel loci associated with plasma lipids that are also associated with CAD. Finally, we validated three of the novel genes-GALNT2, PPP1R3B and TTC39B-with experiments in mouse models. Taken together, our findings provide the foundation to develop a broader biological understanding of lipoprotein metabolism and to identify new therapeutic opportunities for the prevention of CAD.
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| 2. |
- Kaplan, Bernhard, 1984-, et al.
(författare)
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Anisotropic connectivity implements motion-basedprediction in a spiking neural network
- 2013
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Ingår i: Frontiers in Computational Neuroscience. - : Frontiers Media SA. - 1662-5188.
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Tidskriftsartikel (refereegranskat)abstract
- Predictive coding hypothesizes that the brain explicitly infers upcoming sensory inputto establish a coherent representation of the world. Although it is becoming generallyaccepted, it is not clear on which level spiking neural networks may implementpredictive coding and what function their connectivity may have. We present a networkmodel of conductance-based integrate-and-fire neurons inspired by the architectureof retinotopic cortical areas that assumes predictive coding is implemented throughnetwork connectivity, namely in the connection delays and in selectiveness for the tuningproperties of source and target cells. We show that the applied connection pattern leadsto motion-based prediction in an experiment tracking a moving dot. In contrast to ourproposed model, a network with random or isotropic connectivity fails to predict the pathwhen the moving dot disappears. Furthermore, we show that a simple linear decodingapproach is sufficient to transform neuronal spiking activity into a probabilistic estimatefor reading out the target trajectory.
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| 4. |
- Laurent-Matha, Valerie, et al.
(författare)
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Proteolysis of cystatin C by cathepsin D in the breast cancer microenvironment
- 2012
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Ingår i: FASEB Journal. - : Wiley. - 1530-6860 .- 0892-6638. ; 26:12, s. 5172-5181
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Tidskriftsartikel (refereegranskat)abstract
- The aspartic protease cathepsin D, a poor prognostic indicator of breast cancer, is abundantly secreted as procathepsin D by human breast cancer cells and self-activates at low pH in vitro, giving rise to catalytically active cathepsin D. Due to a lower extracellular pH in tumor microenvironments compared to normal tissues, cathepsin D may cleave pathophysiological substrates contributing to cancer progression. Here, we show by yeast 2-hybrid and degradomics analyses that cystatin C, the most potent natural secreted inhibitor of cysteine cathepsins, both binds to and is a substrate of extracellular procathepsin D. The amount of cystatin C in the extracellular environment is reduced in the secretome of mouse embryonic fibroblasts stably transfected with human cathepsin D. Cathepsin D extensively cleaved cystatin C in vitro at low pH. Cathepsin D secreted by breast cancer cells also processed cystatin C at the pericellular pH of tumors and so enhancing extracellular proteolytic activity of cysteine cathepsins. Thus, tumor derived cathepsin D assists breast cancer progression by reducing cystatin C activity, which, in turn, enhances cysteine cathepsin proteolytic activity, revealing a new link between protease classes in the protease web.-Laurent-Matha, V., Huesgen, P. F., Masson, O., Derocq, D., Prebois, C., Gary-Bobo, M., Lecaille, F., Rebiere, B., Meurice, G., Orear, C., Hollingsworth, R. E., Abrahamson, M., Lalmanach, G., Overall, C. M., Liaudet-Coopman, E. Proteolysis of cystatin C by cathepsin D in the breast cancer microenvironment. FASEB J. 26, 5172-5181 (2012). www.fasebj.org
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