Identify RNA-Associated Subcellular Localizations Based on Multi-Label Learning Using Chou’s 5-Steps Rule

Background: Biological functions of biomolecules rely on the cellular compartments where they are located in cells. Importantly, RNAs are assigned in specific locations of a cell, enabling the cell to implement diverse biochemical processes in the way of concurrency. However, lots of existing RNA subcellular localization classifiers only solve the problem of single-label classification. It is of great practical significance to expand RNA subcellular localization into multi-label classification problem. Results: In this study, we extract multi-label classification datasets about RNA-associated subcellular localizations on various types of RNAs, and then construct subcellular localization datasets on four RNA categories. In order to study Homo sapiens, we further establish human RNA subcellular localization datasets. Furthermore, we utilize different nucleotide property composition models to extract effective features to adequately represent the important information of nucleotide sequences. In the most critical part, we achieve a major challenge that is to fuse the multivariate information through multiple kernel learning based on Hilbert-Schmidt independence criterion. The optimal combined kernel can be put into an integration support vector machine model for identifying multi-label RNA subcellular localizations. Our method obtained excellent results of 0.703, 0.757, 0.787, and 0.800, respectively on four RNA data sets on average precision. Conclusion: To be specific, our novel method performs outstanding rather than other prediction tools on novel benchmark datasets. Moreover, we establish user-friendly web server with the implementation of our method

A Double-Blinded Placebo-Controlled Evaluation of Adipose-Derived Mesenchymal Stem Cells in Treatment of Canine Atopic Dermatitis

Mesenchymal stem cells (MSCs) have emerged as a new therapy for various immune-mediated inflammatory diseases. In this study we perform the first double-blinded, placebo-controlled evaluation of the efficacy of adipose-derived allogenic canine MSCs for the treatment of canine atopic dermatitis (cAD). Enrolled canine patients were randomly divided into placebo (PBS saline), low-dose (5 × 105 cells/kg), and high-dose (5 × 106 cells/kg) treatment groups. Each patient received three subcutaneous MSCs treatments or PBS saline at four-week intervals with injections at five sites. Patients were monitored by physical exams, pruritus visual analog scales (PVAS) signed by the primary caretaker, canine atopic dermatitis extent and severity index-4 (CADESI-4) scores by two veterinarians, and complete blood count and serum chemistry analysis along with laboratory analysis for potential biomarkers. Patients were kept off any immune-modulating drugs during the study period, and oral antibiotics and topicals were used for managing pruritus and secondary infections. The PVAS scores and the serum miR-483 levels were significantly lower in the high dose group compared to the placebo group at day90 post first-treatment. The CADESI-4 scores of the high dose group also showed downward trends. No severe adverse effects were observed in any patient in this study. The high dose MSC treatment is efficacious in alleviating the clinical signs of cAD until 30 days after the last subcutaneous administration of MSCs, and miRNA-483 may be a reliable prognostic biomarker for cAD. The MSCs efficacy and potential biomarkers should be further explored by a larger scale clinical trial

Dorsomorphin, a Selective Small Molecule Inhibitor of BMP Signaling, Promotes Cardiomyogenesis in Embryonic Stem Cells

Background: Pluripotent embryonic stem (ES) cells, which have the capacity to give rise to all tissue types in the body, show great promise as a versatile source of cells for regenerative therapy. However, the basic mechanisms of lineage specification of pluripotent stem cells are largely unknown, and generating sufficient quantities of desired cell types remains a formidable challenge. Small molecules, particularly those that modulate key developmental pathways like the bone morphogenetic protein (BMP) signaling cascade, hold promise as tools to study in vitro lineage specification and to direct differentiation of stem cells toward particular cell types. Methodology/Principal Findings: We describe the use of dorsomorphin, a selective small molecule inhibitor of BMP signaling, to induce myocardial differentiation in mouse ES cells. Cardiac induction is very robust, increasing the yield of spontaneously beating cardiomyocytes by at least 20 fold. Dorsomorphin, unlike the endogenous BMP antagonist Noggin, robustly induces cardiomyogenesis when treatment is limited to the initial 24-hours of ES cell differentiation. Quantitative-PCR analyses of differentiating ES cells indicate that pharmacological inhibition of BMP signaling during the early critical stage promotes the development of the cardiomyocyte lineage, but reduces the differentiation of endothelial, smooth muscle, and hematopoietic cells. Conclusions/Significance: Administration of a selective small molecule BMP inhibitor during the initial stages of ES cell differentiation substantially promotes the differentiation of primitive pluripotent cells toward the cardiomyocytic lineage, apparently at the expense of other mesodermal lineages. Small molecule modulators of developmental pathways like dorsomorphin could become versatile pharmacological tools for stem cell research and regenerative medicine

Distinct signalling pathways regulate sprouting angiogenesis from the dorsal aorta and the axial vein

Angiogenesis, the formation of new blood vessels from preexisting vessels, is critical to most physiological processes and many pathological conditions. During zebrafish development, angiogenesis expands the axial vessels into a complex vascular network that is necessary for efficient oxygen delivery. Although the dorsal aorta (DA) and the axial vein (AV) are spatially juxtaposed, the initial angiogenic sprouts from these vessels extend in opposite directions, suggesting that distinct cues may regulate angiogenesis of the axial vessels. In this report, we found that angiogenic sprouts from the DA are dependent on Vegf-A signaling, and do not respond to Bmp signals. In contrast, sprouts from the AV are regulated by Bmp signaling independent of Vegf-A signals, suggesting that Bmp is a vein-specific angiogenic cue during early vascular development. Our results support a paradigm, whereby different signals regulate distinct programs of sprouting angiogenesis from the AV and DA, and suggest that signaling heterogeneity contributes to the complexity of vascular networks