11 research outputs found

    Genetic Differences in the Immediate Transcriptome Response to Stress Predict Risk-Related Brain Function and Psychiatric Disorders

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    Depression risk is exacerbated by genetic factors and stress exposure; however, the biological mechanisms through which these factors interact to confer depression risk are poorly understood. One putative biological mechanism implicates variability in the ability of cortisol, released in response to stress, to trigger a cascade of adaptive genomic and non-genomic processes through glucocorticoid receptor (GR) activation. Here, we demonstrate that common genetic variants in long-range enhancer elements modulate the immediate transcriptional response to GR activation in human blood cells. These functional genetic variants increase risk for depression and co-heritable psychiatric disorders. Moreover, these risk variants are associated with inappropriate amygdala reactivity, a transdiagnostic psychiatric endophenotype and an important stress hormone response trigger. Network modeling and animal experiments suggest that these genetic differences in GR-induced transcriptional activation may mediate the risk for depression and other psychiatric disorders by altering a network of functionally related stress-sensitive genes in blood and brain

    Cyclophilin A as a molecular switch regulating prolactin receptor mediated signaling, mammary tumorigenesis and metastasis

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    Prolactin (PRL) and its receptor (PRLr) have been implicated in the development and progression of human breast cancer. PRL activates its receptor and induces activation of proximal Janus kinase 2 (Jak2) for signal transduction. Here, we sought to determine the role of PRLr-associated peptidyl-prolyl isomerase, cyclophilin A (CypA), in modulating structure/function relationships of the PRLr. It was demonstrated that CypA mediated PRL-induced conformational change of the CFP- and -YFP tagged forms of the PRLr cytoplasmic-tail, whereas CypA inhibition by NIM811 (N-methyl-4-isoleucine cyclosporin) or knockdown blocked the conformational change of the PRLr assessed by Fluorescence Resonance Energy Transfer (FRET) signal or efficiency. To further investigate the consequences of CypA inhibition or knockdown on the PRLr/Jak2 complex mediated signaling/functions, analyses of phospho-tyrosine residues that are believed to be important for interactions/signaling were investigated. It was found that NIM811 inhibition or CypA shRNA knockdown significantly reduced prolactin-stimulated phosphorylation of PRLr/Jak2 intermediates and their association with the PRLr in breast cancer cells. A microarray analysis revealed that NIM811 inhibited approximately 66% of the top 50 PRL-induced genes. NIM811 inhibited breast cancer cell proliferation, survival, migration and anchorage-independent growth. Subsequent NIM811 treatment of a triple negative breast cancer xenograft inhibited primary tumor growth, outgrowth of macro-metastasis and induced central tumor necrosis. Furthermore, loss of CypA in the MMTV-PyMT mouse model demonstrated inhibition of tumorigenesis with significant reduction in lung and lymph node metastasis. Overall, CypA modulates PRL-induced conformational change of the C-terminus of the PRLr through its isomerase activity, altering PRLr/Jak2 complex signaling/functions in breast/mammary tumorigenesis and metastasis

    The virtual museum: virtualisation of real historical environments and artifacts and three-dimensional shape-based searching

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    An intuitive technique for managing three-dimensional objects by shape is presented. This technique is applied to the Virtual Museum in the framework of heritage applications. The Virtual Museum is a virtual reality-based museum that allows the public to visualise, compare, manipulate and search the collection with an intuitive query by shape paradigm. The artefacts and the museum are virtualised with laser scanners and photogrammetric techniques. A high degree of realism can be attained by those techniques and the context in which the artefacts were discovered or were used can be recreated.Dans cet article, nous pr\ue9sentons une technique intuitive de gestion d'objets tridimensionnels d'apr\ue8s leur forme. Cette technique est appliqu\ue9e au mus\ue9e virtuel, dans le cadre des applications patrimoniales. Le mus\ue9e virtuel est un mus\ue9e \ue0 base de r\ue9alit\ue9 virtuelle qui permet au public de visualiser, de comparer, de manipuler et de chercher des objets dans sa collection, gr\ue2ce \ue0 un mod\ue8le intuitif de recherche par forme. Les artefacts et le mus\ue9e sont virtualis\ue9s au moyen de scanners laser et de techniques photogramm\ue9triques. Ces techniques permettent d'obtenir un degr\ue9 \ue9lev\ue9 de r\ue9alisme, et de recr\ue9er le contexte dans lequel les artefacts ont \ue9t\ue9 d\ue9couverts ou \ue9taient utilis\ue9s.Peer reviewed: YesNRC publication: Ye

    Virtual Heritage: The cases of the Byzantine Crypt of Santa Cristina and Temple C of Selinunte

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    This paper presents a summary of the 3-D modelling work that was accomplished in preparing multimedia products for cultural heritage interpretation and entertainment. The two cases presented are the Byzantine Crypt of Santa Cristina, Apulia and temple C of Selinunte, Sicily. The core of the approach is based upon high-resolution photo-realistic texture mapping onto 3-D models generated from range images. It is shown that three-dimensional modelling from range imaging is an effective way to present the spatial information about those two environments. The integration of both photogrammetric and CAD modeling complements this approach. Results on a CDROM, a DVD, virtual 3-D theatre, holograms and video animations are presented for these projects.Le pr\ue9sent article contient un r\ue9sum\ue9 des travaux de mod\ue9lisation tridimensionnelle r\ue9alis\ue9s lors de l'\ue9laboration de produits multim\ue9dias d'interpr\ue9tation du patrimoine culturel et de loisir. Les deux cas pr\ue9sent\ue9s sont celui de la crypte byzantine de Sainte-Christine, en Apulie, et celui du temple C de S\ue9linonte, en Sicile. La mod\ue9lisation est bas\ue9e sur le placage d'une texture photor\ue9aliste \ue0 haute r\ue9solution sur des mod\ue8les 3D g\ue9n\ue9r\ue9s \ue0 partir d'images t\ue9l\ue9m\ue9triques. Nous montrons que la mod\ue9lisation tridimensionnelle \ue0 partir d'imagerie t\ue9l\ue9m\ue9trique constitue un moyen efficace de pr\ue9senter l'information spatiale de ces deux environnements. L'int\ue9gration de la mod\ue9lisation par photogramm\ue9trie et par CAO compl\ue8te cette m\ue9thodologie. Nous pr\ue9sentons les c\ue9d\ue9roms, le DVD, les th\ue9\ue2tres virtuels 3D, les hologrammes et les animations vid\ue9o produits pour ces projets.NRC publication: Ye
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