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Progress in research on endocannabinoid signaling has greatly advanced our understanding of how it controls neural circuit excitability in health and disease. In general, endocannabinoid signaling at excitatory synapses suppresses seizures by inhibiting glutamate release. In contrast, endocannabinoid signaling promotes seizures by inhibiting GABA release at inhibitory synapses. The physiological distribution of endocannabinoid signaling molecules becomes disrupted with the development of epileptic focus in patients with mesial temporal lobe epilepsy and in animal models of experimentally induced epilepsy. Augmentation of endocannabinoid signaling can promote the development of epileptic focus at initial stages. However, at later stages, increased endocannabinoid signaling delays it and suppresses spontaneous seizures. Thus, the regulation of endocannabinoid signaling at specific synapses that cause hyperexcitability during particular stages of disease development may be effective for treating epilepsy and epileptogenesis. [ABSTRACT FROM AUTHOR]

Japan Pharmacogenomics Data Science Consortium (JPDSC) has assembled a database for conducting pharmacogenomics (PGx) studies in Japanese subjects. The database contains the genotypes of 2.5 million single-nucleotide polymorphisms (SNPs) and 5 human leukocyte antigen loci from 2994 Japanese healthy volunteers, as well as 121 kinds of clinical information, including self-reports, physiological data, hematological data and biochemical data. In this article, the reliability of our data was evaluated by principal component analysis (PCA) and association analysis for hematological and biochemical traits by using genome-wide SNP data. PCA of the SNPs showed that all the samples were collected from the Japanese population and that the samples were separated into two major clusters by birthplace, Okinawa and other than Okinawa, as had been previously reported. Among 87 SNPs that have been reported to be associated with 18 hematological and biochemical traits in genome-wide association studies (GWAS), the associations of 56 SNPs were replicated using our data base. Statistical power simulations showed that the sample size of the JPDSC control database is large enough to detect genetic markers having a relatively strong association even when the case sample size is small. The JPDSC database will be useful as control data for conducting PGx studies to explore genetic markers to improve the safety and efficacy of drugs either during clinical development or in post-marketing. [ABSTRACT FROM AUTHOR]

DNA from plasmid pUC18 was irradiated with low-LET (13 keV/μm) or high-LET (60 keV/μm) carbon ions or X-rays (4 keV/μm) in solutions containing several concentrations of Tris (0.66-200 mM) to determine the yield of abasic (AP) sites and the effect of scavenging capacity. The yield of AP sites, detected as single-strand breaks (SSB) after digestion with E. coli endonuclease IV (Nfo), was compared with that of SSB and base lesions. At higher concentrations of Tris, the yields of single or clustered AP sites were significantly lower than those of single or clustered base lesions. The relative yields of single AP sites and AP clusters were less than 10 and 7 %, respectively, of the total damage produced at a scavenger capacity mimicking that in cells. The dependence of the yield of AP sites on scavenging capacity was similar to that of prompt strand breaks. The ratios of the yield of isolated AP sites to that of SSB induced by carbon ion or X-ray irradiation were relatively constant at 0.45 ± 0.15 over the tested range of scavenger capacity, although the ratio of SSB to double-strand breaks (DSB) showed the characteristic dependence on both scavenging capacity and radiation quality. These results indicate that the reaction of water radiolysis products, presumably OH radicals, with the sugar-phosphate moieties in the DNA backbone induces both AP sites and SSB with similar efficiency. Direct ionization of DNA is notably more involved in the production of DSB and base lesion clusters than in the production of AP site clusters. [ABSTRACT FROM AUTHOR]

It is demonstrated through two case studies that a careful evaluation of the likelihood polynomial results in a more accurate localization of disease locus. The evaluation of the likelihood function as a polynomial enables more flexible exploration of the disease locus. Visualization by a contour plot of the function on a unit square of paternal and maternal recombination fractions along with a superimposed ellipsoid of the Fisher information matrix helps us to find a more accurate localization of the disease locus. [ABSTRACT FROM AUTHOR]

We developed a software program, NDesign, for the design of a study intended for detecting rare variants from next-generation sequencing (NGS) data. In this study design, the optimal depth of coverage and the average depth of coverage are first evaluated, and then the ability of the designed experiment to obtain a desired power is determined. NDesign has been developed to calculate both these depths, as well as to evaluate the power of the designed experiment. It has a simple implementation in the JavaScript language, and is expected to enable researchers to design optimal NGS studies. [ABSTRACT FROM AUTHOR]