Evidence that the novel receptor FGFRL1 signals indirectly via FGFR1

Fibroblast growth factor (FGF) receptor-like protein 1 (FGFRL1) is a recently discovered member of the FGF receptor (FGFR) family. Similar to the classical FGFRs, it contains three extracellular immunoglobulin-like domains and interacts with FGF ligands. However, in contrast to the classical receptors, it does not contain any intracellular tyrosine kinase domain and consequently cannot signal by transphosphorylation. In mouse kidneys, FgfrL1 is expressed primarily at embryonic stages E14-E15 in regions where nascent nephrons develop. In this study, we used whole-mount in situ hybridization to show the spatial pattern of five different Fgfrs in the developing mouse kidney. We compared the expression pattern of FgfrL1 with that of other Fgfrs. The expression pattern of FgfrL1 closely resembled that of Fgfr1, but clearly differed from that of Fgfr2‑Fgfr4. It is therefore conceivable that FgfrL1 signals indirectly via Fgfr1. The mechanisms by which FgfrL1 affects the activity of Fgfr1 remain to be elucidated.

Stereoselective synthesis and structure determination of a bicyclo[3.3.2]decapeptide

By analogy to the structural diversity of covalent bond networks between atoms within organic molecules, one can design topologically diverse peptides from mathematical graphs by assigning amino acids to graph nodes and peptide bonds to graph edges. The key is to use diamino acids or amino diacids as equivalents of trivalent graph nodes, which enables a variety of graph topologies beyond the standard linear and monocyclic graphs in natural peptides. Here the bicyclic decapeptide A1FGk2VFPE1AG2 (1b) was prepared and crystallized to assign its bridge stereochemistry. The bridge configuration appears as planned by the chirality of the branching amino acids. Bicyclization furthermore depends on the presence of matched chiralities in the branching amino acids. The stereoselective formation of the second bridge opens the way for the synthesis of a large family of bicyclic peptides as promising new scaffolds for drug design.

Expert opinion on toxicity profiling--report from a NORMAN expert group meeting.

This article describes the outcome and follow-up discussions of an expert group meeting (Amsterdam, October 9, 2009) on the applicability of toxicity profiling for diagnostic environmental risk assessment. A toxicity profile was defined as a toxicological "fingerprint" of a sample, ranging from a pure compound to a complex mixture, obtained by testing the sample or its extract for its activity toward a battery of biological endpoints. The expert group concluded that toxicity profiling is an effective first tier tool for screening the integrated hazard of complex environmental mixtures with known and unknown toxicologically active constituents. In addition, toxicity profiles can be used for prioritization of sampling locations, for identification of hot spots, and--in combination with effect-directed analysis (EDA) or toxicity identification and evaluation (TIE) approaches--for establishing cause-effect relationships by identifying emerging pollutants responsible for the observed toxic potency. Small volume in vitro bioassays are especially applicable for these purposes, as they are relatively cheap and fast with costs comparable to chemical analyses, and the results are toxicologically more relevant and more suitable for realistic risk assessment. For regulatory acceptance in the European Union, toxicity profiling terminology should keep as close as possible to the European Water Framework Directive (WFD) terminology, and validation, standardization, statistical analyses, and other quality aspects of toxicity profiling should be further elaborated.

Cone-beam computed tomography-guided stereotactic liver punctures: a phantom study

PURPOSE Images from computed tomography (CT), combined with navigation systems, improve the outcomes of local thermal therapies that are dependent on accurate probe placement. Although the usage of CT is desired, its availability for time-consuming radiological interventions is limited. Alternatively, three-dimensional images from C-arm cone-beam CT (CBCT) can be used. The goal of this study was to evaluate the accuracy of navigated CBCT-guided needle punctures, controlled with CT scans. METHODS Five series of five navigated punctures were performed on a nonrigid phantom using a liver specific navigation system and CBCT volumetric dataset for planning and navigation. To mimic targets, five titanium screws were fixed to the phantom. Target positioning accuracy (TPECBCT) was computed from control CT scans and divided into lateral and longitudinal components. Additionally, CBCT-CT guidance accuracy was deducted by performing CBCT-to-CT image coregistration and measuring TPECBCT-CT from fused datasets. Image coregistration was evaluated using fiducial registration error (FRECBCT-CT) and target registration error (TRECBCT-CT). RESULTS Positioning accuracies in lateral directions pertaining to CBCT (TPECBCT = 2.1 ± 1.0 mm) were found to be better to those achieved from previous study using CT (TPECT = 2.3 ± 1.3 mm). Image coregistration error was 0.3 ± 0.1 mm, resulting in an average TRE of 2.1 ± 0.7 mm (N = 5 targets) and average Euclidean TPECBCT-CT of 3.1 ± 1.3 mm. CONCLUSIONS Stereotactic needle punctures might be planned and performed on volumetric CBCT images and controlled with multidetector CT with positioning accuracy higher or similar to those performed using CT scanners.