Aberrant DNA methylation is associated with the oncogenesis of a variety of human cancers, including endometrial cancer (eC), the seventh most common cancer among women. obesity is known to be a high-risk factor for EC; however, whether obesity influences DNA methylation in the presymptomatic uterus and if this influences EC development remain unclear. Here, we performed genome-wide DNA methylation analysis of isolated endometrial epithelial cells obtained from obese presymptomatic participants. Using the Illumina MethylationEPIC array (850 K), we identified 592 differentially methylated regions (DMRs), most of which undergo hypomethylated changes. these DMRs were enriched for pyrimidine metabolism, epstein-Barr virus infection, and B cell signaling pathways, indicating obesity-related dysregulation of certain metabolic processes in the presymptomatic uterus. Comparison of the DMRs with those in stage I EC revealed that 54 DMRs overlapped; additionally, B cell signaling and epstein-Barr virus infection pathways were shared between the presymptomatic uterus of obese women and stage I eC with greater hypomethylation in women with eC than in presymptomatic obese women. These findings indicated that obesity influences DNA methylation in presymptomatic endometrial epithelial cells, and persistent dysregulation of DNA methylation in obese women may result in eC development.Endometrial cancer (EC) is the seventh most common cancer among women, with 13,951 new cases and 2,243 deaths in Japan in 2014 1 . EC originates from endometrial epithelial cells, whereas endometriosis develops from endometrial stromal cells. The disease rate increases with age, peaking in the fifth-sixth decades of life. Based on differences in epidemiology and histopathology, there are two subtypes of EC: type I and type II. Type I endometrioid endometrial cancer accounts for approximately 80% of cases, occurs frequently in pre-and peri-menopausal women, is often well differentiated, and is correlated with obesity and overexposure to estrogen. Type II non-endometrioid endometrial cancer is more common in older, non-obese post-menopausal women and is poorly differentiated. Recent evidence revealed genetic alterations in the RTK/RAS/β-catenin and PI3K/ AKT/PTEN pathways in endometrial tumor tissue 2 ; however, it has also been reported that a significant subset (e.g. ~50%) 3 of EC does not contain genetic mutations in PTEN, TP53, or CTNNB1, suggesting an etiology other than common genetic mutations. One of the biological processes frequently contributing to oncogenesis is epigenetic modification: heritable changes in gene expression without mutation of the amino acid sequence. A well-known epigenetic event is DNA methylation. DNA methylation regulates gene expression and microRNA stability, contributes to the cellular phenotype, and plays important roles in various cellular processes, including development, genetic imprinting, immune response, and aging 4-6 .In DNA methylation, a methyl group (-CH 3 ) is covalently bound to the cytosine residues of C...

The network mechanisms underlying how inhibitory circuits regulate ON‐ and OFF‐responses (the b‐ and d‐waves) in the electroretinogram (ERG) remain unclear. The purpose of this study was to investigate the contribution of inhibitory circuits to the emergence of the b‐ and d‐waves in the full‐field ERG in the newt retina. To this end, we investigated the effects of several synaptic transmission blockers on the amplitudes of the b‐ and d‐waves in the ERG obtained from newt eyecup preparations. Our results demonstrated that (a) L‐APB blocked the b‐wave, indicating that the b‐wave arises from the activity of ON‐bipolar cells (BCs) expressing type six metabotropic glutamate receptors; (b) the combined administration of UBP310/GYKI 53655 blocked the d‐wave, indicating that the d‐wave arises from the activity of OFF‐BCs expressing kainate‐/AMPA‐receptors; (c) SR 95531 augmented both the b‐ and the d‐wave, indicating that GABAergic lateral inhibitory circuits inhibit both ON‐ and OFF‐BC pathways; (d) the administration of strychnine in the presence of SR 95531 attenuated the d‐wave, and this attenuation was prevented by blocking ON‐pathways with L‐APB, which indicated that the glycinergic inhibition of OFF‐BC pathway is downstream of the GABAergic inhibition of the ON‐system; and (e) the glycinergic inhibition from the ON‐ to the OFF‐system widens the response range of OFF‐BC pathways, specifically in the absence of GABAergic lateral inhibition. Based on these results, we proposed a circuitry mechanism for the regulation of the d‐wave and offered a tentative explanation of the circuitry mechanisms underlying ERG formation.

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Background and Aims First‐year students encounter substantial stress when they enter university. Their mental health often depends upon how well they cope with the stress of university life. Salivary components are well known to reflect the stress status of the students; however, the relationship between salivary components and coping styles remains unknown. Methods In this study, 54 healthy first‐year students voluntarily completed a questionnaire that addressed three different coping styles: problem‐focused, emotion‐focused, and escape‐focused. We simultaneously collected salivary samples from students in the classroom and measured concentrations of salivary cortisol and α‐amylase by enzyme‐linked immunosorbent assays over 4 months. Results We examined the relationship between coping style and salivary cortisol concentrations and found that the mean salivary cortisol concentrations were significantly lower in students who had a higher Likert‐type score for the problem‐focused coping style than in students who had a lower score. The difference in the mean cortisol concentrations between the two groups increased over time. However, we observed no apparent correlation between α‐amylase concentrations and Likert scores of the three coping styles. Conclusion These results suggest that salivary cortisol concentrations might reflect the stress‐coping status, particularly involving the problem‐focused coping style.

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