Prioritization of SNPs for genome-wide association studies using an interaction model of genetic variation,gene expression,and trait variation

The identification of true causal loci to unravel the statistical evidence of genotype-phenotype correlations and the biological relevance of selected single-nucleotide polymorphisms (SNPs) is a challenging issue in genome-wide association studies (GWAS). Here, we introduced a novel method for the prioritization of SNPs based on p-values from GWAS. The method uses functional evidence from populations, including phenotype-associated gene expressions. Based on the concept of genetic interactions, such as perturbation of gene expression by genetic variation, phenotype and gene expression related SNPs were prioritized by adjusting the p-values of SNPs. We applied our method to GWAS data related to drug-induced cytotoxicity. Then, we prioritized loci that potentially play a role in druginduced cytotoxicity. By generating an interaction model, our approach allowed us not only to identify causal loci, but also to find intermediate nodes that regulate the flow of information among causal loci, perturbed gene expression, and resulting phenotypic variation.     

Early Gestational Weight Gain Rate and Adverse Pregnancy Outcomes in Korean Women

During pregnancy, many women gain excessive weight, which is related to adverse maternal and neonatal outcomes. In this study, we evaluated whether rate of gestational weight gain (RGWG) in early, mid, and late pregnancy is strongly associated with adverse pregnancy outcomes. A retrospective chart review of 2,789 pregnant Korean women was performed. Weights were recorded at the first clinic visit, during the screening test for fetal anomaly, and during the 50g oral glucose challenge test and delivery, to represent early, mid, and late pregnancy, respectively. A multivariate logistic regression analysis was performed to examine the relationship between RGWG and adverse pregnancy outcomes. At early pregnancy, the RGWG was significantly associated with high risk of developing gestational diabetes mellitus (GDM), pregnancy-induced hypertension (PIH), large for gestational age (LGA) infants, macrosomia, and primary cesarean section (P-CS). The RGWG of mid pregnancy was not significantly associated with any adverse pregnancy outcomes. The RGWG at late pregnancy was significantly associated with a lower risk of developing GDM, preterm birth and P-CS, but with a higher risk of developing LGA infants and macrosomia. When the subjects were divided into three groups (Underweight, Normal, and Obese), based on pre-pregnancy body mass index (BMI), the relationship between early RGWG and adverse pregnancy outcomes was significantly different across the three BMI groups. At early pregnancy, RGWG was not significantly associated to adverse pregnancy outcomes for subjects in the Underweight group. In the Normal group, however, early RGWG was significantly associated with GDM, PIH, LGA infants, macrosomia, P-CS, and small for gestational weight (SGA) infants, whereas early RGWG was significantly associated with only a high risk of PIH in the Obese group. The results of our study suggest that early RGWG is significantly associated with various adverse pregnancy outcomes and that proper preemptive management of early weight gain, particularly in pregnant women with a normal or obese pre-pregnancy BMI, is necessary to reduce the risk of developing adverse pregnancy outcomes.     

Vacuolar membrane structures and their roles in plant–pathogen interactions

Plant Molecular Biology - Short review focussing on the role and targeting of vacuolar substructure in plant immunity and pathogenesis. Plants lack specialized immune cells, therefore each plant...     

(-)-3,5-Dicaffeoyl-muco-quinic acid isolated from Aster scaber contributes to the differentiation of PC12 cells: through tyrosine kinase cascade signaling

Aster scaber T. (Asteraceae) has been used in traditional Korean and Chinese medicine to treat bruises, snakebites, headaches, and dizziness. (-)-3,5-Dicaffeoyl-muco-quinic acid (DQ) isolated from A. scaber induced neurite outgrowth in PC12 cells. It has been reported that the activation of the extracellular signal regulated kinase 1/2 (Erk 1/2) and phosphoinositide 3 (PI3) kinase plays a crucial role in the NGF-induced differentiation of PC12 cells. This study showed that the effect of DQ on neurite outgrowth is mediated via the Erk 1/2 and PI3 kinase-dependent pathways like NGF. Furthermore, DQ stimulated the phosphorylation of Trk A. Overall, DQ elicited the differentiation of PC12 cells through Trk A phosphorylation followed by Erk 1/2 and PI3 kinase activation.     

Evaluation of Antimicrobial Properties of Lichen Substances against Plant Pathogens

Plant pathogens pose major threats on agriculture and horticulture, causing significant economic loss worldwide. Due to the continuous and excessive use of synthetic pesticides, emergence of pesticide resistant pathogens has become more frequent. Thus, there is a growing needs for environmentally-friendly and selective antimicrobial agents with a novel mode of action, which may be used in combination with conventional pesticides to delay development of pesticide resistance. In this study, we evaluated the potentials of lichen substances as novel biopesticides against eight bacterial and twelve fungal plant pathogens that have historically caused significant phytopathological problems in South Korea. Eight lichen substances of diverse chemical origins were extracted from axenic culture or dried specimen, and further purified for comparative analysis of their antimicrobial properties. Usnic acid and vulpinic acid exhibited strong antibacterial activities against Clavibacter michiganensis subsp. michiganensis. In addition, usnic acid and vulpinic acid were highly effective in the growth inhibition of fungal pathogens, such as Diaporthe eres, D. actinidiae, and Sclerotinia sclerotiorum. Intriguingly, the growth of Rhizoctonia solani was specifically inhibited by lecanoric acid, indicating that lichen substances exhibit some degrees of selectivity to plant pathogens. These results suggested that lichen substance can be used as a selective biopesticide for controlling plant disease of agricultural and horticultural significance, minimizing possible emergence of pesticide resistant pathogens in fields.     

The extended interactions and Gla domain of blood coagulation factor Xa

The serine protease factor Xa (FXa) is inhibited by ecotin with picomolar affinity. The structure of the tetrameric complex of ecotin variant M84R (M84R) with FXa has been determined to 2.8 A. Substrate directed induced fit of the binding interactions at the S2 and S4 pockets modulates the discrimination of the protease. Specifically, the Tyr at position 99 of FXa changes its conformation with respect to incoming ligand, changing the size of the S2 and S4 pockets. The role of residue 192 in substrate and inhibitor recognition is also examined. Gln 192 from FXa forms a hydrogen bond with the P2 carbonyl group of ecotin. This confirms previous biochemical and structural analyses on thrombin and activated protein C, which suggested that residue 192 may play a more general role in mediating the interactions between coagulation proteases and their inhibitors. The structure of ecotin M84R-FXa (M84R-FXa) also reveals the structure of the Gla domain in the presence of Mg(2+). The first 11 residues of the domain assume a novel conformation and likely represent an intermediate folding state of the domain.     

Hepatitis C virus (HCV) genotyping by annealing reverse transcription-PCR products with genotype-specific capture probes

The genotype of the hepatitis C virus (HCV) strain infecting a given patient is an important predictive factor for the clinical outcome of chronic liver disease and its response to anti-viral therapeutic agents. We herein sought to develop a new easy, sensitive and accurate HCV genotyping method using annealing genotype-specific capture probes (AGSCP) in an automation-friendly 96-well plate format. The validation of our new AGSCP was performed using the Standard HCV Genotype Panel. We then used both our AGSCP and the commercially available INNO-LiPA assay to analyze the HCV genotypes from 111 Korean patients. Discordant results were analyzed by direct sequencing. AGSCP successfully genotyped the standard panel. The genotypes of 111 patient samples were also obtained successfully by AGSCP and INNO-LiPA. We observed a high concordance rate (93 matched samples, 83.8%) between the two assays. Sequencing analysis of the 18 discordant results revealed that the AGSCP had correctly identified 12 samples, whereas the INNO-LiPA had correctly identified only 6. These results collectively indicate that AGSCP assay is a convenient and sensitive method for large-scale genotyping, and it may be a promising tool for the determination of HCV and other genotypes in clinical settings.