Trial-Specific Feature Performance on Single-Channel Auditory Mismatch Negativity Detection.

Successful detection of uncommon events is vital in the survival of an organism. Specifically, the study of neuro-sensory detection lends itself widely to understanding the human brain. Mismatch Negativity (MMN) is an important Event-Related Potential (ERP) response to an oddball stimulus which is preceded by repeated homogeneous stimulation. MMN is associated with perceptual learning and medical diagnostics among other applications. Currently, MMN detection relies on visual inspection of ERPs by skilled clinicians which makes for a costly, slow and subjective tool. In this paper, we use MMN to quantify the discriminative abilities of healthy or diagnosed subjects. We introduce a novel algorithmic method to extract and select important trial-specific features for discriminating standard from deviant responses. We utilize machine learning and classification approaches to evaluate our novel model using single-subject trial data while minimizing the number of necessary selection features provided by statistical test parameters and Genetic Algorithm (GA). In this work, a large variety of methods with 27 subjects, hundreds of trials and electrode counts compete for the definitive discrimination of MMN events. Our model requires only one EEG channel, a single subject and as low as five deviant tones. The results show statistically significant detection improvement over the traditional methods while maximizing resource economy.

The epigenetic regulation of paraoxonase 1 (PON1) as an important enzyme in HDL function: The missing link between environmental and genetic regulation.

BACKGROUND: Paraoxonase 1 (PON1) is an important antiatherogenic and antioxidant enzyme in the circulation that has been associated with adverse health outcomes particularly cardiovascular disease (CVD) and other metabolic disorders. PON1 is a highly promiscuous enzyme and can hydrolyse a large variety of substrates, however, detailed structure/function studies have concluded that the natural substrates for PON1 are lipophilic lactones. The interindividual variability in PON1 activity has been mainly attributed to genetic determinants; however, it appears that the contribution of epigenetics has been ignored as a result of the lack of adequate research. CONTENT: Epigenetic processes, including the histone modifications in the PON1 gene, the methylation of CpG sites in the promoter region of the PON1 gene and the microRNA modulation of PON1 expression can be responsible for the under researched gap between the environmental and genetic regulation of PON1. Environmental factors, including diet, pollution and lifestyle-related factors widely differ between individuals and populations and can cause large differences in the distribution of PON1 and it is important to note that their effects may be exerted through the epigenetic processes. This review discusses and emphasizes the importance of the epigenetic regulation of PON1 as a less-studied subject to highlight future research landscapes. SUMMARY: Epigenetic regulation is known as an important contributor to the pathogenesis of human diseases, particularly multifactorial diseases such as CVD, which is life-threatening. Due to the importance of PON1 in the functionality of high-density lipoprotein (HDL) and its association with CVD, further explorations of its epigenetic regulation using advanced methods such as Methyl-Seq may lead to the identification of new epigenetic contributors that in turn may lead to targeted therapies.

Genotype and phenotype of salt-stimulated paraoxonase 1 (PON1) is associated with atherogenic indices in type 2 diabetes.

BACKGROUND: Paraoxonase 1 (PON1) and lipid abnormalities contribute to the development of cardiovascular disease, which is the principal cause of mortality in patients with type 2 diabetes (T2D). Data are not available on the potential association between salt-stimulated activity of PON1 (PON1-salt) and the atherogenic indices in T2D, therefore, we focused on these associations and evaluated whether the functional variants PON1-Q192R and PON1-L55M influence the associations. METHODS: Paraoxonase activity (PON1-para), arylesterase activity (PON1-aryl) and salt-stimulated activity (PON1-salt) were measured by spectrophotometric assays. The atherogenic index of plasma (AIP) was calculated from the log (TG/HDL-C). The genetic analyses were made by the restricted fragment length polymorphism after PCR amplification. RESULTS: We observed that PON1-salt was negatively correlated with total cholesterol (TC)/HDL-C (r = -0.441,p = 0.006), LDL-C/HDL-C (r = -0.415, p = 0.011), and AIP (r = -0.422, p = 0.009). Correlations between PON1-salt and all three atherogenic indices were significantly affected by PON1-L55M and PON1-Q192R. Linear regression showed that AIP (p = 0.002), LDL-C/HDL-C (p = 0.005), and TC/HDL-C (p = 0.002) were independently associated with PON1-salt. Based on Ridge regression, the standardized coefficients -0.358, -0.297, and - 0.044 were obtained for AIP, LDL-C/HDL-C, and TC/HDL-C, respectively, and this shows that AIP could have more negative effect on PON1-salt than the others. CONCLUSIONS: The decreased PON1-salt may be considered as a risk factor for atherosclerosis in T2D, therefore, understanding the associations between PON1-salt as an important although neglected property and atherogenic indices may be valuable in T2D. Accordingly, detection of PON1-salt status (phenotype and genotype) together with the atherogenic indices particularly AIP could be beneficial in identifying the increased atherogenicity in T2D.

The common variant Q192R at the paraoxonase 1 (PON1) gene and its activity are responsible for a portion of the altered antioxidant status in type 2 diabetes.

In this study, we investigated the effects of paraoxonase 1 (PON1) activities and the variant PON1-Q192R on the ferric reducing ability of plasma (FRAP) and total thiol. In addition, we examined the distribution of genotypes of this variant and the relationship of the genotypes with age in patients with type 2 diabetes (T2D). A total of 115 patients with T2D were enrolled in this study. Paraoxonase activity (PON-para) and arylesterase activity (PON-aryl) were determined using spectrophotometric assays. The distribution of the Q192R genotypes was determined by the double substrate method. The antioxidant status was evaluated by determining FRAP and total thiol. The frequencies of Q and R allozyme were 0.78 and 0.22, respectively. The multivariate analysis identified a significant association between the variables PON1-Q192R (Wilks' λ = 0.85, P = 0.002) and PON-aryl (Wilks' λ = 0.896, P = 0.017), with FRAP and total thiol. The significant difference observed for PON1-Q192R and PON-aryl is primarily due to the changes in FRAP levels (η(2 )= 0.127, P = 0.002 for PON1-Q192R; η(2 )= 0.083, P = 0.011 for PON-aryl). The interaction PON1-Q192R-PON-aryl increased the effect sizes from 8 to 19% for FRAP. Only in R-carrying genotypes, there were significant correlations between both PON-para/HDL (r = -0.574, P < 0.001) and PON-aryl/HDL (r = -0.577, P < 0.001) with age. Our data suggest that the variant PON1-Q192R and PON1 activity, particularly PON-aryl, influenced the antioxidant status in T2D. The interaction of this variant and PON1 activity increased the effect size on the antioxidant capacity. Moreover, the presence of the R allozyme may potentiate the effects of age on susceptibility to cardiovascular diseases in T2D.

The variant organic cation transporter 2 (OCT2)-T201M contribute to changes in insulin resistance in patients with type 2 diabetes treated with metformin.

AIMS: Insulin resistance is characterized by impaired biological response of peripheral tissues to the metabolic effects of insulin. Organic cation transporter 2 (OCT2) is responsible for 80% metformin clearance. Limited information is available on the potential relationship between genetic variants of OCT2 and insulin resistance. In this study, we examined the role of OCT2-T201M (602 C>T) variant in insulin resistance in patients with type 2 diabetes (T2D) who were treated with metformin. METHODS: Serum concentrations of insulin and C-peptide were assessed using ELISA. Homeostasis model assessment for insulin resistance (HOMA-IR) and HOMA for beta cell function (HOMA-BCF) were determined. PCR-based restriction fragment length polymorphism was used to genotype the OCT2-T201M variant. RESULTS: Patients with minor alleles had higher HbA1c concentrations (p=0.019), fasting glucose levels (p=0.023), HOMA-IR (p=0.03), and HOMA-BCF (p=0.26) than patients with common alleles. Multivariate analysis identified a significant association between the variables OCT2-T201M and gender, with HOMA-IR and HOMA-BCF (Wilks' λ=0.549, F=12.71, p<0.001 for OCT2-T201M and Wilks' λ=0.369, F=26.46, p<0.001 for gender. Changes in HOMA-BCF were inversely correlated with changes in fasting glucose levels (r=-0.412, p=0.008) and HbA1c (r=-0.257, p=0.114). CONCLUSIONS: Our findings suggest that the loss-of-function variant OCT2-T201M (rs145450955) contribute to changes in insulin resistance and beta cell activity in patients with T2D treated with metformin. Moreover, gender as an independent variable has a significant relationship with HOMA-BCF.