Replenishment of type VII collagen and re-epithelialization of chronically ulcerated skin after intradermal administration of allogeneic mesenchymal stromal cells in two patients with recessive dystrophic epidermolysis bullosa

In animal models it has been shown that mesenchymal stromal cells (MSC) contribute to skin regeneration and accelerate wound healing. We evaluated whether allogeneic MSC administration resulted in an improvement in the skin of two patients with recessive dystrophic epidermolysis bullosa (RDEB; OMIM 226600). Patients had absent type VII collagen immunohistofluorescence and since birth had suffered severe blistering and wounds that heal with scarring. Vehicle or 0.5 × 10⁶ MSC were infused intradermally in intact and chronic ulcerated sites. One week after intervention, in MSC-treated skin type VII collagen was detected along the basement membrane zone and the dermal–epidermal junction was continuous. Re-epithelialization of chronic ulcerated skin was observed only near MSC administration sites. In both patients the observed clinical benefit lasted for 4 months. Thus intradermal administration of allogeneic MSC associates with type VII collagen replenishment at the dermal–epidermal junction, prevents blistering and improves wound healing in unconditioned patients with RDEB.     

Integrating gene expression and GO classification for PCA by preclustering

Background  

Gene expression data can be analyzed by summarizing groups of individual gene expression profiles based on GO annotation information. The mean expression profile per group can then be used to identify interesting GO categories in relation to the experimental settings. However, the expression profiles present in GO classes are often heterogeneous, i.e., there are several different expression profiles within one class. As a result, important experimental findings can be obscured because the summarizing profile does not seem to be of interest. We propose to tackle this problem by finding homogeneous subclasses within GO categories: preclustering.     

The case for Survivin as mitotic regulator

Survivin has been proposed to inhibit apoptosis and to regulate cell division. However, controversy still exists as to whether Survivin can indeed execute these distinct functions and if Survivin somehow coordinates apoptosis and (abnormal) cell division. Recent evidence has demonstrated that Survivin acts as a subunit of the chromosomal passenger complex, which is essential for proper chromosome segregation and cytokinesis. Within this complex, the mitotic kinase Aurora B acts as the enzymatic core, whereas Survivin dictates chromosomal passenger complex localization. This function of Survivin appears to be conserved throughout evolution. Although these findings do not exclude a role for Survivin as apoptosis inhibitor, they make a very strong case for Survivin as mitotic regulator.     

Phenyl ureas of creatinine as mGluR5 antagonists. A structure-activity relationship study of fenobam analogues

Fenobam (1) was developed by McNeil Laboratories as an anxiolytic agent with an unknown molecular target in the late 1970s. In a recent publication, it was revealed that fenobam is a non-competitive mGluR5 antagonist. Herein, we present the structure-activity relationship of fenobam and its analogues and similarities between the SAR of mGluR5 antagonism and the SAR of CNS properties originally reported by McNeil are discussed.     

Encounter success of free-ranging marine predator movements across a dynamic prey landscape

Movements of wide-ranging top predators can now be studied effectively using satellite and archival telemetry. However, the motivations underlying movements remain difficult to determine because trajectories are seldom related to key biological gradients, such as changing prey distributions. Here, we use a dynamic prey landscape of zooplankton biomass in the north-east Atlantic Ocean to examine active habitat selection in the plankton-feeding basking shark Cetorhinus maximus. The relative success of shark searches across this landscape was examined by comparing prey biomass encountered by sharks with encounters by random-walk simulations of 'model' sharks. Movements of transmitter-tagged sharks monitored for 964 days (16754 km estimated minimum distance) were concentrated on the European continental shelf in areas characterized by high seasonal productivity and complex prey distributions. We show movements by adult and sub-adult sharks yielded consistently higher prey encounter rates than 90% of random-walk simulations. Behavioural patterns were consistent with basking sharks using search tactics structured across multiple scales to exploit the richest prey areas available in preferred habitats. Simple behavioural rules based on learned responses to previously encountered prey distributions may explain the high performances. This study highlights how dynamic prey landscapes enable active habitat selection in large predators to be investigated from a trophic perspective, an approach that may inform conservation by identifying critical habitat of vulnerable species.     

Structural basis of ubiquitin recognition by the deubiquitinating protease USP2

Deubiquitinating proteases reverse protein ubiquitination and rescue their target proteins from destruction by the proteasome. USP2, a cysteine protease and a member of the ubiquitin specific protease family, is overexpressed in prostate cancer and stabilizes fatty acid synthase, which has been associated with the malignancy of some aggressive prostate cancers. Here, we report the structure of the human USP2 catalytic domain in complex with ubiquitin. Ubiquitin uses two major sites for the interaction with the protease. Both sites are required simultaneously, as shown by USP2 inhibition assays with peptides and ubiquitin mutants. In addition, a layer of ordered water molecules mediates key interactions between ubiquitin and USP2. As several of those molecules are found at identical positions in the previously solved USP7/ubiquitin-aldehyde complex structure, we suggest a general mechanism of water-mediated ubiquitin recognition by USPs.     

Membrane topology of the transporter associated with antigen processing (TAP1) within an assembled functional peptide-loading complex

The transporter associated with antigen processing (TAP) translocates antigenic peptides from the cytosol into the endoplasmic reticular lumen for subsequent loading onto major histocompatibility complex (MHC) class I molecules. These peptide-MHC complexes are inspected at the cell surface by cytotoxic T-lymphocytes. Assembly of the functional peptide transport and loading complex depends on intra- and intermolecular packing of transmembrane helices (TMs). Here, we have examined the membrane topology of human TAP1 within an assembled and functional transport complex by cysteine-scanning mutagenesis. The accessibility of single cysteine residues facing the cytosol or endoplasmic reticular lumen was probed by a minimally invasive approach using membrane-impermeable, thiol-specific fluorophores in semipermeabilized "living" cells. TAP1 contains ten transmembrane segments, which place the N and C termini in the cytosol. The transmembrane domain consists of a translocation core of six TMs, a building block conserved among most ATP-binding cassette transporters, and a unique additional N-terminal domain of four TMs, essential for tapasin binding and assembly of the peptide-loading complex. This study provides a first map of the structural organization of the TAP machinery within the macromolecular MHCI peptide-loading complex.