MicroRNAs are noncoding RNAs which downregulate a large number of target mRNAs and modulate cell activity. Despite continued progress, bioinformatics prediction of microRNA targets remains a challenge since available software still suffer from a lack of accuracy and sensitivity. Moreover, these tools show fairly inconsistent results from one another. Thus, in an attempt to circumvent these difficulties, we aggregated all human results of four important prediction algorithms (miRanda, PITA, SVmicrO, and TargetScan) showing additional characteristics in order to rerank them into a single list. Instead of deciding which prediction tool to use, our method clearly helps biologists getting the best microRNA target predictions from all aggregated databases. The resulting database is freely available through a webtool called miRabel¹ which can take either a list of miRNAs, genes, or signaling pathways as search inputs. Receiver operating characteristic curves and precision-recall curves analysis carried out using experimentally validated data and very large data sets show that miRabel significantly improves the prediction of miRNA targets compared to the four algorithms used separately. Moreover, using the same analytical methods, miRabel shows significantly better predictions than other popular algorithms such as MBSTAR, miRWalk, ExprTarget and miRMap. Interestingly, an F-score analysis revealed that miRabel also significantly improves the relevance of the top results. The aggregation of results from different databases is therefore a powerful and generalizable approach to many other species to improve miRNA target predictions. Thus, miRabel is an efficient tool to guide biologists in their search for miRNA targets and integrate them into a biological context.

The sequence of human urotensin II (UII) has been recently established as H-Glu-Thr-Pro-Asp-Cys-Phe-Trp-Lys-Tyr-Cys-Val-OH, and it has been reported that UII is the most potent mammalian vasoconstrictor peptide identified so far. A series of UII analogues was synthesized, and the contractile activity of each compound was studied in vitro using de-endothelialised rat aortic rings. Replacement of each amino acid by an l-alanine or by a d-isomer showed that the N- and C-terminal residues flanking the cyclic region of the amidated peptide were relatively tolerant to substitution. Conversely, replacement of any residue of the cyclic region significantly reduced the contractile activity of the molecule. The octapeptide UII(4–11) was 4 times more potent than UII, indicating that the C-terminal region of the molecule possesses full biological activity. Alanine or d-isomer substitutions in UII(4–11) or in UII(4–11)-NH2, respectively, showed a good correlation with the results obtained for UII-NH2. Disulfide bridge disruption or replacement of the cysteine residues by their d-enantiomers markedly reduced the vasoconstrictor effect of UII and its analogues. In contrast, acetylation of the N-terminal residue of UII and UII-NH2 enhanced the potency of the peptide. Finally, monoiodination of the Tyr6 residue in UII(4–11) increased by 5 fold the potency of the peptide in the aortic ring bioassay. This structure–activity relationship study should provide useful information for the rational design of selective and potent UII receptor agonists and antagonists.

Urotensin II (UII) is an evolutionarily conserved neuropeptide initially isolated from teleost fish on the basis of its smooth muscle-contracting activity. Subsequent studies have demonstrated the occurrence of several UII-related peptides (URPs), such that the UII family is now known to include four paralogue genes called UII, URP, URP1 and URP2. These genes probably arose through the two rounds of whole genome duplication that occurred during early vertebrate evolution. URP has been identified both in tetrapods and teleosts. In contrast, URP1 and URP2 have only been observed in ray-finned and cartilaginous fishes, suggesting that both genes were lost in the tetrapod lineage. In the present study, the distribution of urp1 mRNA compared to urp2 mRNA is reported in the central nervous system of zebrafish. In the spinal cord, urp1 and urp2 mRNAs were mainly colocalized in the same cells. These cells were also shown to be GABAergic and express the gene encoding the polycystic kidney disease 2-like 1 (pkd2l1) channel, indicating that they likely correspond to cerebrospinal fluid-contacting neurons. In the hindbrain, urp1-expressing cells were found in the intermediate reticular formation and the glossopharyngeal-vagal motor nerve nuclei. We also showed that synthetic URP1 and URP2 were able to induce intracellular calcium mobilization in human UII receptor (hUT)-transfected CHO cells with similar potencies (pEC50=7.99 and 7.52, respectively) albeit at slightly lower potencies than human UII and mammalian URP (pEC50=9.44 and 8.61, respectively). The functional redundancy of URP1 and URP2 as well as the colocalization of their mRNAs in the spinal cord suggest the robustness of this peptidic system and its physiological importance in zebrafish.