ALBERT

Description: Motivation: Identifying microRNAs associated with diseases (disease miRNAs) is helpful for exploring the pathogenesis of diseases. Because miRNAs fulfill function via the regulation of their target genes and because the current number of experimentally validated targets is insufficient, some existing methods have inferred potential disease miRNAs based on the predicted targets. It is difficult for these methods to achieve excellent performance due to the high false-positive and false-negative rates for the target prediction results. Alternatively, several methods have constructed a network composed of miRNAs based on their associated diseases and have exploited the information within the network to predict the disease miRNAs. However, these methods have failed to take into account the prior information regarding the network nodes and the respective local topological structures of the different categories of nodes. Therefore, it is essential to develop a method that exploits the more useful information to predict reliable disease miRNA candidates. Results: miRNAs with similar functions are normally associated with similar diseases and vice versa. Therefore, the functional similarity between a pair of miRNAs is calculated based on their associated diseases to construct a miRNA network. We present a new prediction method based on random walk on the network. For the diseases with some known related miRNAs, the network nodes are divided into labeled nodes and unlabeled nodes, and the transition matrices are established for the two categories of nodes. Furthermore, different categories of nodes have different transition weights. In this way, the prior information of nodes can be completely exploited. Simultaneously, the various ranges of topologies around the different categories of nodes are integrated. In addition, how far the walker can go away from the labeled nodes is controlled by restarting the walking. This is helpful for relieving the negative effect of noisy data. For the diseases without any known related miRNAs, we extend the walking on a miRNA-disease bilayer network. During the prediction process, the similarity between diseases, the similarity between miRNAs, the known miRNA-disease associations and the topology information of the bilayer network are exploited. Moreover, the importance of information from different layers of network is considered. Our method achieves superior performance for 18 human diseases with AUC values ranging from 0.786 to 0.945. Moreover, case studies on breast neoplasms, lung neoplasms, prostatic neoplasms and 32 diseases further confirm the ability of our method to discover potential disease miRNAs. Availability and implementation: A web service for the prediction and analysis of disease miRNAs is available at http://bioinfolab.stx.hk/midp/ . Contact: guoyahong_hlju@163.com or lixia@hrbmu.edu.cn Supplementary information: Supplementary data are available at Bioinformatics online.

Description: Long-term exposure to environmental oxidative stressors, like the herbicide paraquat (PQ), has been linked to the development of Parkinson's disease (PD), the most frequent neurodegenerative movement disorder. Paraquat is thus frequently used in the fruit fly Drosophila melanogaster and other animal models to study PD and the degeneration of dopaminergic neurons (DNs) that characterizes this disease. Here, we show that a D 1 -like dopamine (DA) receptor, DAMB, actively contributes to the fast central nervous system (CNS) failure induced by PQ in the fly. First, we found that a long-term increase in neuronal DA synthesis reduced DAMB expression and protected against PQ neurotoxicity. Secondly, a striking age-related decrease in PQ resistance in young adult flies correlated with an augmentation of DAMB expression. This aging-associated increase in oxidative stress vulnerability was not observed in a DAMB -deficient mutant. Thirdly, targeted inactivation of this receptor in glutamatergic neurons (GNs) markedly enhanced the survival of Drosophila exposed to either PQ or neurotoxic levels of DA, whereas, conversely, DAMB overexpression in these cells made the flies more vulnerable to both compounds. Fourthly, a mutation in the Drosophila ryanodine receptor ( RyR ), which inhibits activity-induced increase in cytosolic Ca 2+ , also strongly enhanced PQ resistance. Finally, we found that DAMB overexpression in specific neuronal populations arrested development of the fly and that in vivo stimulation of either DNs or GNs increased PQ susceptibility. This suggests a model for DA receptor-mediated potentiation of PQ-induced neurotoxicity. Further studies of DAMB signaling in Drosophila could have implications for better understanding DA-related neurodegenerative disorders in humans.

Description: Silencing of fragile X mental retardation 1 ( FMR1 ) gene and loss of fragile X mental retardation protein (FMRP) cause fragile X syndrome (FXS), a genetic disorder characterized by intellectual disability and autistic behaviors. FMRP is an mRNA-binding protein regulating neuronal translation of target mRNAs. Abnormalities in actin-rich dendritic spines are major neuronal features in FXS, but the molecular mechanism and identity of FMRP targets mediating this phenotype remain largely unknown. Cytoplasmic FMR1-interacting protein 2 (Cyfip2) was identified as an interactor of FMRP, and its mRNA is a highly ranked FMRP target in mouse brain. Importantly, Cyfip2 is a component of WAVE regulatory complex, a key regulator of actin cytoskeleton, suggesting that Cyfip2 could be implicated in the dendritic spine phenotype of FXS. Here, we generated and characterized Cyfip2 -mutant ( Cyfip2 +/– ) mice. We found that Cyfip2 +/– mice exhibited behavioral phenotypes similar to Fmr1 -null ( Fmr1 –/y ) mice, an animal model of FXS. Synaptic plasticity and dendritic spines were normal in Cyfip2 +/– hippocampus. However, dendritic spines were altered in Cyfip2 +/– cortex, and the dendritic spine phenotype of Fmr1 –/y cortex was aggravated in Fmr1 –/y ; Cyfip2 +/– double-mutant mice. In addition to the spine changes at basal state, metabotropic glutamate receptor (mGluR)-induced dendritic spine regulation was impaired in both Fmr1 –/y and Cyfip2 +/– cortical neurons. Mechanistically, mGluR activation induced mRNA translation-dependent increase of Cyfip2 in wild-type cortical neurons, but not in Fmr1 –/y or Cyfip2 +/– neurons. These results suggest that misregulation of Cyfip2 function and its mGluR-induced expression contribute to the neurobehavioral phenotypes of FXS.

Description: Low levels of the survival motor neuron (SMN) protein cause spinal muscular atrophy, the leading genetic disorder for infant mortality. SMN is ubiquitously expressed in various cell types and localizes in both the cytoplasm and the nucleus, where it concentrates in two subnuclear structures termed Cajal body (CB) and gems. In addition, SMN can also be detected in the nucleolus of neurons. Mechanisms that control SMN sorting in the cell remain largely unknown. Here, we report that the ubiquitin (Ub) ligase Itch directly interacts with and monoubiquitinates SMN. Monoubiquitination of SMN has a mild effect on promoting proteasomal degradation of SMN. We generated two SMN mutants, SMN(K0), in which all lysines are mutated to arginines and thereby abolishing SMN ubiquitination, and Ub-SMN(K0), in which a single Ub moiety is fused at the N-terminus of SMN(K0) and thereby mimicking SMN monoubiquitination. Immunostaining assays showed that SMN(K0) mainly localizes in the nucleus, whereas Ub-SMN(K0) localizes in both the cytoplasm and the nucleolus in neuronal SH-SY5Y cells. Interestingly, canonical CB foci and coilin/small nuclear ribonucleoprotein (snRNP) co-localization are significantly impaired in SH-SY5Y cells stably expressing SMN(K0) or Ub-SMN(K0). Thus, our studies discover that Itch monoubiquitinates SMN and monoubiquitination of SMN plays an important role in regulating its cellular localization. Moreover, mislocalization of SMN disrupts CB integrity and likely impairs snRNP maturation.

Description: : Despite a growing interest in a correlation between copy number variations (CNVs) and flanking single nucleotide polymorphisms, few databases provide such information. In particular, most information on CNV available so far was obtained in Caucasian and Yoruba populations, and little is known about CNV in Asian populations. This article presents a database that provides CNV regions tagged by single nucleotide polymorphisms in about 4700 Koreans, which were detected under strict quality control, manually curated and experimentally validated. Availability: KGVDB is freely available for non-commercial use at http://biomi.cdc.go.kr/KGVDB . Contact: kbj6181@cdc.go.kr Supplementary information: Supplementary data are available at Bioinformatics online.

Description: The BDB database ( http://immunet.cn/bdb ) is an update of the MimoDB database, which was previously described in the 2012 Nucleic Acids Research Database issue. The rebranded name BDB is short for Biopanning Data Bank, which aims to be a portal for biopanning results of the combinatorial peptide library. Last updated in July 2015, BDB contains 2904 sets of biopanning data collected from 1322 peer-reviewed papers. It contains 25 786 peptide sequences, 1704 targets, 492 known templates, 447 peptide libraries and 310 crystal structures of target-template or target-peptide complexes. All data stored in BDB were revisited, and information on peptide affinity, measurement method and procedures was added for 2298 peptides from 411 sets of biopanning data from 246 published papers. In addition, a more professional and user-friendly web interface was implemented, a more detailed help system was designed, and a new on-the-fly data visualization tool and a series of tools for data analysis were integrated. With these new data and tools made available, we expect that the BDB database would become a major resource for scholars using phage display, with improved utility for biopanning and related scientific communities.