Structure-based virtual screening allows the identification of efficient modulators of E-cadherin-mediated cell-cell adhesion

Cadherins are a large family of transmembrane calcium-dependent cell adhesion proteins that orchestrate adherens junction formation and are crucially involved in tissue morphogenesis. Due to their important role in cancer development and metastasis, cadherins can be considered attractive targets for drug discovery. A recent crystal structure of the complex of a cadherin extracellular portion and a small molecule inhibitor allowed the identification of a druggable interface, thus providing a viable strategy for the design of cadherin dimerization modulators. Here, we report on a structure-based virtual screening approach that led to the identification of efficient and selective modulators of E-cadherin-mediated cell-cell adhesion. Of all the putative inhibitors that were identified and experimentally tested by cell adhesion assays using human pancreatic tumor BxPC-3 cells expressing both E-cadherin and P-cadherin, two compounds turned out to be effective in inhibiting stable cell-cell adhesion at micromolar concentrations. Moreover, at the same concentrations, one of them also showed anti-invasive properties in cell invasion assays. These results will allow further development of novel and selective cadherin-mediated cell-cell adhesion modulators for the treatment of a variety of cadherin-expressing solid tumors and for improving the efficiency of drug delivery across biological barriers

Human Placenta Aneurysm Model for Training Neurosurgeons in Vascular Microsurgery

BACKGROUND: Neurosurgery, a demanding specialty, involves many microsurgical procedures that require complex skills, including open surgical treatment of intracranial aneurysms. Simulation or practice models may be useful for acquiring these skills before trainees perform surgery on human patients. OBJECTIVE: To describe a human placenta model for the creation and clipping of aneurysms. METHODS: Placental vessels from 40 human placentas that were dimensionally comparable to the sizes of appropriate cerebral vessels were isolated to create aneurysms of different shapes. The placentas were then prepared for vascular microsurgery exercises. Sylvian fissure-like dissection technique and clipping of large- and small-necked aneurysms were practiced on human placentas with and without pulsatile flow. A surgical field designed to resemble a real craniotomy was reproduced in the model. RESULTS: The human placenta has a plethora of vessels that are of the proper dimensions to allow the creation of aneurysms with dome and neck dimensions similar to those of human saccular and fusiform cerebral aneurysms. These anatomic scenarios allowed aneurysm inspection, manipulation, and clipping practice. Technical microsurgical procedures include simulation of sylvian fissure dissection, unruptured aneurysm clipping, ruptured aneurysm clipping, and wrapping; all were reproduced with high fidelity to the haptics of live human surgery. Skill-training exercises realistically reproduced aneurysm clipping. CONCLUSION: Human placenta provides an inexpensive, widely available, convenient biological tissue that can be used to create models of cerebral aneurysms of different morphologies. Neurosurgical trainees may benefit from the preoperative use of a realistic model to gain familiarity and practice with critical surgical techniques for treating aneurysms

Dense sampling of bird diversity increases power of comparative genomics

Whole-genome sequencing projects are increasingly populating the tree of life and characterizing biodiversity(1-4). Sparse taxon sampling has previously been proposed to confound phylogenetic inference(5), and captures only a fraction of the genomic diversity. Here we report a substantial step towards the dense representation of avian phylogenetic and molecular diversity, by analysing 363 genomes from 92.4% of bird families-including 267 newly sequenced genomes produced for phase II of the Bird 10,000 Genomes (B10K) Project. We use this comparative genome dataset in combination with a pipeline that leverages a reference-free whole-genome alignment to identify orthologous regions in greater numbers than has previously been possible and to recognize genomic novelties in particular bird lineages. The densely sampled alignment provides a single-base-pair map of selection, has more than doubled the fraction of bases that are confidently predicted to be under conservation and reveals extensive patterns of weak selection in predominantly non-coding DNA. Our results demonstrate that increasing the diversity of genomes used in comparative studies can reveal more shared and lineage-specific variation, and improve the investigation of genomic characteristics. We anticipate that this genomic resource will offer new perspectives on evolutionary processes in cross-species comparative analyses and assist in efforts to conserve species. A dataset of the genomes of 363 species from the Bird 10,000 Genomes Project shows increased power to detect shared and lineage-specific variation, demonstrating the importance of phylogenetically diverse taxon sampling in whole-genome sequencing.Peer reviewe