Differential Modulation of TCF/LEF-1 Activity by the Soluble LRP6-ICD

The canonical Wnt/β-catenin (Wnt) pathway is a master transcriptional regulatory signaling pathway that controls numerous biological processes including proliferation and differentiation. As such, transcriptional activity of the Wnt pathway is tightly regulated and/or modulated by numerous proteins at the level of the membrane, cytosol and/or nucleus. In the nucleus, transcription of Wnt target genes by TCF/LEF-1 is repressed by the long Groucho/TLE co-repressor family. However, a truncated member of the Groucho/TLE family, amino terminal enhancer of Split (AES) can positively modulate TCF/LEF-1 activity by antagonizing long Groucho/TLE members in a dominant negative manner. We have previously shown the soluble intracellular domain of the LRP6 receptor, a receptor required for activation of the Wnt pathway, can positively regulate transcriptional activity within the Wnt pathway. In the current study, we show the soluble LRP6 intracellular domain (LRP6-ICD) can also translocate to the nucleus in CHO and HEK 293T cells and in contrast to cytosolic LRP6-ICD; nuclear LRP6-ICD represses TCF/LEF-1 activity. In agreement with previous reports, we show AES enhances TCF/LEF-1 mediated reporter transcription and further we demonstrate that AES activity is spatially regulated in HEK 293T cells. LRP6-ICD interacts with AES exclusively in the nucleus and represses AES mediated TCF/LEF-1 reporter transcription. These results suggest that LRP6-ICD can differentially modulate Wnt pathway transcriptional activity depending upon its subcellular localization and differential protein-protein interactions

Targeting Huntington’s disease through histone deacetylases

Huntington’s disease (HD) is a debilitating neurodegenerative condition with significant burdens on both patient and healthcare costs. Despite extensive research, treatment options for patients with this condition remain limited. Aberrant post-translational modification (PTM) of proteins is emerging as an important element in the pathogenesis of HD. These PTMs include acetylation, phosphorylation, methylation, sumoylation and ubiquitination. Several families of proteins are involved with the regulation of these PTMs. In this review, I discuss the current evidence linking aberrant PTMs and/or aberrant regulation of the cellular machinery regulating these PTMs to HD pathogenesis. Finally, I discuss the evidence suggesting that pharmacologically targeting one of these protein families the histone deacetylases may be of potential therapeutic benefit in the treatment of HD

An end-to-end geometric deficiencies elimination algorithm for 3D meshes

The 3D mesh is an important representation of geometric data. It is widely used in computer graphics and has attracted more attention in computer vision community recently. However, in the generation of mesh data, geometric deficiencies (e.g., duplicate elements, degenerate faces, isolated vertices, self-intersection, and inner faces) are unavoidable. Geometric deficiencies may violate the topology structure of an object and affect the use of 3D meshes. In this paper, we propose an end-to-end algorithm to eliminate geometric deficiencies effectively and efficiently for 3D meshes in a specific and reasonable order. Specifically, duplicate elements can be first eliminated by assessing appear times of vertices or faces. Then, degenerate faces can be removed according to the outer product of two edges. Next, since isolated vertices do not appear in any face vertices, they can be deleted directly. Afterward, self-intersecting faces are detected and remeshed by using an AABB tree. Finally, we detect and remove an inner face according to whether multiple random rays shooted from a face can reach infinity. Experiments on ModelNet40 dataset illustrate that our method can eliminate the deficiencies of 3D meshes thoroughly