Protein network-based Lasso regression model for the construction of disease-miRNA functional interactions

BackgroundThere is a growing body of evidence associating microRNAs (miRNAs) with human diseases. MiRNAs are new key players in the disease paradigm demonstrating roles in several human diseases. The functional association between miRNAs and diseases remains largely unclear and far from complete. With the advent of high-throughput functional genomics techniques that infer genes and biological pathways dysregulted in diseases, it is now possible to infer functional association between diseases and biological molecules by integrating disparate biological information.ResultsHere, we first used Lasso regression model to identify miRNAs associated with disease signature as a proof of concept. Then we proposed an integrated approach that uses disease-gene associations from microarray experiments and text mining, and miRNA-gene association from computational predictions and protein networks to build functional associations network between miRNAs and diseases. The findings of the proposed model were validated against gold standard datasets using ROC analysis and results were promising (AUC=0.81). Our protein network-based approach discovered 19 new functional associations between prostate cancer and miRNAs. The new 19 associations were validated using miRNA expression data and clinical profiles and showed to act as diagnostic and prognostic prostate biomarkers. The proposed integrated approach allowed us to reconstruct functional associations between miRNAs and human diseases and uncovered functional roles of newly discovered miRNAs.ConclusionsLasso regression was used to find associations between diseases and miRNAs using their gene signature. Defining miRNA gene signature by integrating the downstream effect of miRNAs demonstrated better performance than the miRNA signature alone. Integrating biological networks and multiple data to define miRNA and disease gene signature demonstrated high performance to uncover new functional associations between miRNAs and diseases.     

Influence of the protonation,deprotonation and transition metal ions on the fluorescence of 8-hydroxyquinoline: a computational study

8-Hydroxyquinoline (8HyQ) and its derivatives are the important constituents in a variety of pharmaceutical compounds. The effect of protonation and deprotonation of 8HyQ on its electronic structure and fluorescence was investigated using B3LYP/6-311G** level of theory. We also investigated the interaction of chemosensor, 8HyQ, with different transition metals (Zn²⁺, Fe²⁺, Ni²⁺ and Co²⁺) at the same level. Our results revealed that 8HyQ displays an unusual fluorescence intensity–proton transfer relationship with diminished emission in a protonated form but enhanced emission in a deprotonated form. The Zn²⁺, Fe²⁺, Ni²⁺ and Co²⁺ complexes of 8HyQ, which were investigated at the same level of theory, showed that the order of binding energies was 8HyQ-Ni²⁺>8HyQ-Zn²⁺>8HyQ-Co²⁺>8HyQ-Fe²⁺. Time-dependent density functional theory calculations indicated that Zn ion enhances the fluorescence of 8HyQ as a consequence of the inhibition of the proton transfer. The results are in good agreement between the predicted properties of transition metal complexes of 8HyQ and previously published experimental and theoretical results. A natural bond orbital analysis was performed to understand the nature of hydrogen-bonding interaction in 8HyQ and also to reveal the inter-relations between electronic structure and other properties.     

Local effects of forest fragmentation on diversity of aquatic insects in tropical forest streams: implications for biological conservation

The influence of forest fragmentation (habitat isolation) on biological and ecological diversity of aquatic insects was investigated in streams of fragmented forests in Hulu Gombak (6 streams) and Gunung Angsi (5 streams) and un-fragmented forest of Berembun (6 streams) in peninsular Malaysia. Several environmental parameters including canopy cover, DO, temperature and pH differed significantly among the three catchments (P < 0.05). We found that taxonomic richness in Berembun forest was significantly different from Gunung Angsi (P < 0.05), but not with Hulu Gombak forests (P > 0.05). Nestedness pattern that measures the effect of habitat isolation on taxonomic assemblages showed that aquatic insect’s community in un-fragmented forest (Berembun) was less nested (T = 54.4), indicating high diversity compared to highly nested (less diverse) in the two fragmented forests (Hulu Gombak, T = 30.45 and Gunung Angsi, T = 35.45). Taxa similarity in Berembun streams was negatively correlated with the geographical distance among streams (Mantel test, r = ? 0.462, P < 0.05). Such correlation was absent in both Gunung Angsi and Hulu Gombak streams. Forest fragmentation in Hulu Gombak and Gunung Angsi measured as the distance of the forests from the nearest forested area had negative effect on aquatic insects diversity (r ² = ? 0.149, P < 0.05), but not on their abundances (r ² = 0.003, P > 0.05). We concluded that local habitat conditions were the most important in shaping the aquatic insects community among streams of both unfragmented and fragmented forests.     

The insecticide DDT targets the OSCP and subunit D of the Apis mellifera ATP synthase

1,1-bis (p-chlorophenyl)-2, 2, 2-trichloroethane (DDT) has been used for control of malaria mosquitoes and other insect vectors of human diseases since 1945. Its use poses an environmental dilemma and efforts to replace it have been hampered by lack of information about its molecular target. This work identifies the 23 kDa band responsible for the DDT sensitivity in bees, as the OSCP and subunit "d" of the ATP synthase. The OSCP of the bee's ATP synthase contained 207 amino acids compared to 190 in bovine, which is insensitive to DDT, and the identities were only 47%. Subunit "d" of the bees had no counterpart in the bovine. Whether DDT is interacting only with OSCP, only with subunit "d", or with both subunits, remains to be assessed. Identification of the molecular target of DDT will lead the way to new target based insecticides aimed to protect plant, combat malaria and other insect transmitted diseases.     

Seedling and adult stage resistance to net form of net blotch (NFNB) in spring barley and stability of adult stage resistance to NFNB in Morocco

This study was conducted to identify stable resistance to net form of net blotch (NFNB) in spring barley in Moroccan environments. Seedling resistance to NFNB was evaluated by inoculating 336 barley genotypes with two NFNB isolates LDNH04Ptt-19 and TD-10 in the greenhouse. These genotypes were evaluated for adult plant resistance to NFNB under seven environments in Morocco in 2015 and 2016. The disease severity was estimated at GS 77–87 on barley leaves using a double-digit scale. To investigate stability of resistance, 149 barley genotypes were subjected to AMMI analysis. At the seedling stage, differential responses of barley genotypes to different NFNB isolates were identified, whereas genotypes had variable stability to NFNB resistance at the adult stages. Five genotypes, AM-68, AM-95, AM-250, AM-267 and AM-322, were resistant to both NFNB isolates at the seedling stage. There were significant (p < .001) effects of genotype (G) and G × E interaction on NFNB severity for barley genotypes at the adult stage. The principal components, IPCA1 and IPCA2, accounted for 48.4% and 18.7% variation for NFNB severity, respectively. The AMMI stability values (ASVs) ranged from 0.01 to 15.5, and fifty-nine barley genotypes had stable responses (ASV ≤ 0.05) across all seven environments. Specifically, two stable genotypes, AM-187 and AM-244, had lower mean NFNB severities across all environments, suggesting a quantitative resistance in these genotypes. Divergent environmental responses of NFNB severity were measured in Sidi El Ayedi 2015 and Sidi Allal Tazi 2016, suggesting that these environments may be suitable to capture resistance to diverse pathotypes. These stable genotypes are valuable resources for introgression of both qualitative resistance and quantitative resistance to NFNB in future.     

Metabolic profiling of human urine by CE-MS using a positively charged capillary coating and comparison with UPLC-MS

The potential of capillary electrophoresis time-of-flight mass spectrometry (CE-TOF-MS) using capillaries coated with a triple layer of polybrene-dextran sulfate-polybrene (PB-DS-PB) was evaluated for metabolic profiling of human urine. The method covers various metabolite classes and stable metabolic profiles of urine samples were obtained with favourable migration time repeatability (RSDs <1%). The PB-DS-PB CE-TOF-MS method was used for the analysis of human urine samples from 30 males and 30 females, which had been previously analyzed by reversed-phase UPLC-TOF-MS. Multivariate data analysis of the obtained data provided clear distinction between urine samples from males and females, emphasizing gender differences in metabolic signatures. Nearly all compounds responsible for male-female classification in CE-TOF-MS were different from the classifying compounds in UPLC-TOF-MS. Almost all compounds causing classification in the CE-TOF-MS study were highly polar and did not exhibit retention in the reversed-phase UPLC system. In addition, the CE-TOF-MS classifiers had an m/z value in the range of 50-150, whereas 95% of the classifying features found with UPLC-TOF-MS had an m/z value above 150. The CE-TOF-MS method therefore appears to be highly complementary to the UPLC-TOF-MS method providing classification based on different classes of metabolites.     

Reliability and validity of the Ethiopian version of the hospital anxiety and depression scale (HADS) in HIV infected patients

Background

The hospital anxiety and depression scale (HADS) is a widely used instrument for evaluating psychological distress from anxiety and depression. HADS has not yet been validated in Ethiopia. The aim of this study was to evaluate the reliability and validity of the Amharic (Ethiopian language) version of HADs among HIV infected patients.

Methods

The translated scale was administered to 302 HIV/AIDS patients on follow up for and taking anti-retroviral treatment. Consistency assessment was conducted using Cronbach''s alpha, test-retest reliability using intra-class correlation coefficients (ICC). Construct validity was examined using principal components analysis (PCA). Parallel analysis, Kaiser''s criterion and the scree test were used for factor extraction.

Results

The internal consistency was 0.78 for the anxiety, 0.76 for depression subscales and 0.87 for the full scale of HADS. The intra-class correlation coefficient (ICC) was 80%, 86%, and 84% for the anxiety and depression subscales, and total score respectively. PCA revealed a one dimensional scale.

Conclusion

This preliminary validation study of the Ethiopian version of the HADs indicates that it has promising acceptability, reliability and validity. The adopted scale has a single underlying dimension as indicated by Razavi''s model. The HADS can be used to examine psychological distress in HIV infected patients. Findings are discussed and recommendations made.     

Hepcidin levels and their determinants in different types of myelodysplastic syndromes

Iron overload may represent an additional clinical problem in patients with Myelodysplastic Syndromes (MDS), with recent data suggesting prognostic implications. Beyond red blood cells transfusions, dysregulation of hepcidin, the key iron hormone, may play a role, but studies until now have been hampered by technical problems. Using a recently validated assay, we measured serum hepcidin in 113 patients with different MDS subtypes. Mean hepcidin levels were consistently heterogeneous across different MDS subtypes, with the lowest levels in refractory anemia with ringed sideroblasts (RARS, 1.43 nM) and the highest in refractory anemia with excess blasts (RAEB, 11.3 nM) or in chronic myelomonocytic leukemia (CMML, 10.04 nM) (P = 0.003 by ANOVA). MDS subtypes remained significant predictors of hepcidin in multivariate analyses adjusted for ferritin and transfusion history. Consistently with current knowledge on hepcidin action/regulation, RARS patients had the highest levels of toxic non-transferrin-bound-iron, while RAEB and CMML patients had substantial elevation of C-Reactive Protein as compared to other MDS subtypes, and showed lost of homeostatic regulation by iron. Growth differentiation factor 15 did not appear as a primary hepcidin regulator in this series. If confirmed, these results may help to calibrate future treatments with chelating agents and/or hepcidin modulators in MDS patients.