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Background: Human-induced pluripotent stem cells (hiPSCs) with normal or upregulated levels of CCND2 expression were differentiated into cardiomyocytes (CCND2 WT CMs or CCND2 OE CMs, respectively) and injected into infarcted pig hearts. Methods: Acute myocardial infarction (AMI) was induced via a 60-minute occlusion of the left-anterior descending coronary artery. Immediately after reperfusion, CCND2 WT CMs or CCND2 OE CMs (3×10 7 cells each), or an equivalent volume of the delivery vehicle was injected around the infarct border zone area. Results: The number of the engrafted CCND2 OE CMs exceeded that of the engrafted CCND2 WT CMs from 6 to 8-fold, rising from 1 week to 4 weeks post-implantation. In contrast to the treatment with the CCND2 WT CMs or the delivery vehicle, the administration of CCND2 OE CM was associated with significantly improved left-ventricular function, as revealed by magnetic resonance imaging (MRI). This correlated with the reduction of infarct size, fibrosis, ventricular hypertrophy, CM apoptosis, and the increase of vascular density and arterial density, as per the histological analysis of the treated hearts. Expression of the cell proliferation markers (e.g., Ki67, phosphorylated histone 3 [PH3] and Aurora Kinase B [Aurora B]) was also significantly upregulated in the recipient CMs from the CCND2 OE CM-treated than from the CCND2 WT CM-treated pigs. The cell proliferation rate and the hypoxia tolerance measured in cultured hiPSC-CMs were significantly greater after their treatment with exosomes isolated from the CCND2 OE CMs (CCND2 OE Exos) than from the CCND2 WT CMs (CCND2 WT Exos). As demonstrated by our study, CCND2 OE Exos can also promote the proliferation activity of postnatal rat and adult mouse cardiomyocytes. A bulk miRNA sequencing analysis of CCND2 OE Exos vs. CCND2 WT Exos identified 206 and 91 miRNAs that were significantly upand down-regulated, respectively. Gene ontology (GO) enrichment analysis identified significant differences in the expression profiles of miRNAs from various functional categories and pathways, including miRNAs implicated in cell-cycle checkpoints (G2/M and G1/S transitions), or the mechanism of cytokinesis. Conclusions: We have demonstrated that an enhanced potency of the CCND2 OE CMs promoted myocyte proliferation in both grafts and the recipient tissue in a large mammal acute myocardial infarction (AMI) model. These results suggest that the CCND2 OE CMs transplantation may be a potential therapeutic strategy for the repair of infarcted hearts.

The synthesis and biological activities of analogues of the peptide hormone angiotensin II (AT) for use in photoaffinity labeling and receptor isolation are described. In the modified sequence of AT, Sar-Arg-Val-Tyr-Val-His-Pro-Phe, the aromatic residues Tyr and Phe have been either singly or simultaneously replaced by L-4'-nitrophenylalanine, L-4'-amino-3',5'-diiodophenylalanine, L-4'-aminophenylalanine, L-4'-diazoniumphenylalanine, and L-4'-azidophenylalanine. The peptides were assembled by solid-phase synthesis and the functional groups in position 4 and/or 8 chemically modified. Radioactivity was introduced by catalytic tritiation of the iodinated peptides to form the photolabeling precursors containing L-4'-amino-3',5'-diiodophenylalanine. On rabbit aorta the AT analogues substituted in position 4 showed poor affinities (0--15%), in position 8 high relative affinities (16--118%), and in position 4 and 8 additive effects of simultaneous substitutions. It is also shown that the new Boc derivative of L-4'-amino-3',5'-diiodophenylalanine can be used in peptide synthesis without side-chain protection.

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BackgroundDrug repositioning is a cost-efficient and time-saving process to drug development compared to traditional techniques. A systematic method to drug repositioning is to identify candidate drug's gene expression profiles on target disease models and determine how similar these profiles are to approved drugs. Databases such as the CMAP have been developed recently to help with systematic drug repositioning.MethodsTo overcome the limitation of connectivity maps on data coverage, we constructed a comprehensive in silico drug-protein connectivity map called DMAP, which contains directed drug-to-protein effects and effect scores. The drug-to-protein effect scores are compiled from all database entries between the drug and protein have been previously observed and provide a confidence measure on the quality of such drug-to-protein effects.ResultsIn DMAP, we have compiled the direct effects between 24,121 PubChem Compound ID (CID), which were mapped from 289,571 chemical entities recognized from public literature, and 5,196 reviewed Uniprot proteins. DMAP compiles a total of 438,004 chemical-to-protein effect relationships. Compared to CMAP, DMAP shows an increase of 221 folds in the number of chemicals and 1.92 fold in the number of ATC codes. Furthermore, by overlapping DMAP chemicals with the approved drugs with known indications from the TTD database and literature, we obtained 982 drugs and 622 diseases; meanwhile, we only obtained 394 drugs with known indication from CMAP. To validate the feasibility of applying new DMAP for systematic drug repositioning, we compared the performance of DMAP and the well-known CMAP database on two popular computational techniques: drug-drug-similarity-based method with leave-one-out validation and Kolmogorov-Smirnov scoring based method. In drug-drug-similarity-based method, the drug repositioning prediction using DMAP achieved an Area-Under-Curve (AUC) score of 0.82, compared with that using CMAP, AUC = 0.64. For Kolmogorov-Smirnov scoring based method, with DMAP, we were able to retrieve several drug indications which could not be retrieved using CMAP. DMAP data can be queried using the existing C2MAP server or downloaded freely at: http://bio.informatics.iupui.edu/cmapsConclusionsReliable measurements of how drug affect disease-related proteins are critical to ongoing drug development in the genome medicine era. We demonstrated that DMAP can help drug development professionals assess drug-to-protein relationship data and improve chances of success for systematic drug repositioning efforts.

BackgroundHuman protein-protein interaction (PPI) data is essential to network and systems biology studies. PPI data can help biochemists hypothesize how proteins form complexes by binding to each other, how extracellular signals propagate through post-translational modification of de-activated signaling molecules, and how chemical reactions are coupled by enzymes involved in a complex biological process. Our capability to develop good public database resources for human PPI data has a direct impact on the quality of future research on genome biology and medicine.ResultsThe database of Human Annotated and Predicted Protein Interactions (HAPPI) version 2.0 is a major update to the original HAPPI 1.0 database. It contains 2,922,202 unique protein-protein interactions (PPI) linked by 23,060 human proteins, making it the most comprehensive database covering human PPI data today. These PPIs contain both physical/direct interactions and high-quality functional/indirect interactions. Compared with the HAPPI 1.0 database release, HAPPI database version 2.0 (HAPPI-2) represents a 485% of human PPI data coverage increase and a 73% protein coverage increase. The revamped HAPPI web portal provides users with a friendly search, curation, and data retrieval interface, allowing them to retrieve human PPIs and available annotation information on the interaction type, interaction quality, interacting partner drug targeting data, and disease information. The updated HAPPI-2 can be freely accessed by Academic users at http://discovery.informatics.uab.edu/HAPPI.ConclusionsWhile the underlying data for HAPPI-2 are integrated from a diverse data sources, the new HAPPI-2 release represents a good balance between data coverage and data quality of human PPIs, making it ideally suited for network biology.Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-017-3512-1) contains supplementary material, which is available to authorized users.

In this article, we described a new database framework to perform integrative “gene-set, network, and pathway analysis” (GNPA). In this framework, we integrated heterogeneous data on pathways, annotated list, and gene-sets (PAGs) into a PAG electronic repository (PAGER). PAGs in the PAGER database are organized into P-type, A-type and G-type PAGs with a three-letter-code standard naming convention. The PAGER database currently compiles 44 313 genes from 5 species including human, 38 663 PAGs, 324 830 gene–gene relationships and two types of 3 174 323 PAG–PAG regulatory relationships—co-membership based and regulatory relationship based. To help users assess each PAG’s biological relevance, we developed a cohesion measure called Cohesion Coefficient (CoCo), which is capable of disambiguating between biologically significant PAGs and random PAGs with an area-under-curve performance of 0.98. PAGER database was set up to help users to search and retrieve PAGs from its online web interface. PAGER enable advanced users to build PAG–PAG regulatory networks that provide complementary biological insights not found in gene set analysis or individual gene network analysis. We provide a case study using cancer functional genomics data sets to demonstrate how integrative GNPA help improve network biology data coverage and therefore biological interpretability. The PAGER database can be accessible openly at http://discovery.informatics.iupui.edu/PAGER/.Contact: jakechen@iupui.eduSupplementary information: Supplementary data are available at Bioinformatics online.

Background The key to fishery management is knowing the appropriate reproductive strategies of the targeted fish. For most gobiid species, the iteroparous pattern is dominant compared to semelparity. Albeit Butis koilomatodon plays an important role in the Mekong Delta’s food supply, its reproductive biological data have not been known. Hence, this study was conducted to provide new fundamental knowledge of reproductive traits of Butis koilomatodon in the Mekong Delta. Results A total of 1314 individuals (903 males and 411 females) were monthly collected by bottom gill nets from July 2019 to June 2020 at six sampling sites along estuarial and coastal regions, from Tra Vinh to Ca Mau provinces, southern of Vietnam. pH and salinity of these six sampling sites are 7.72–7.93 pH and 11.17–26.17‰, respectively. The pH varies with sites, but not seasons; whereas a reverse case is found in salinity. Different types of oocytes are found in histological specimens of ovaries prove that B. koilomatodon is a multi-spawner. The gonadosomatic index value, together with the monthly presence of mature ovaries reveal that this species spawns throughout the year. The length at first mature male Butis koilomatodon (5.1–8.6 cm) is higher than that of females (4.8–6.7 cm), except in Hoa Binh and Dong Hai. Batch fecundity (3085 to 32,087 eggs/female) increases with fish weight (1.48–12.30 g) and length (4.8–9.0 cm) due to high determination values (r2 > 0.6). Conclusion Knowledge of reproductive traits gained from this study was a reference source for future studies and helped manage this species’ resources.