Twin study: genotype-dependent epigenetic factors affecting free thyroxine levels in the normal range.

Aim: To explore the clinical application of DNA methylation affecting thyroid function, we evaluated the association of DNA methylation with free thyroxine (FT4) and TSH measurements in monozygotic twins. Materials & methods: Discordant pairs for FT4 or TSH levels were examined for the relationship between the within-pair difference of each measurement and the DNA methylation levels using epigenome-wide association studies. The contribution of polymorphisms to the methylation sensitivity was also examined. Results: We found two CpG sites significantly associated with FT4 levels, and also some CpG sites showing significant differences in their methylation levels within FT4-discordant pairs depending on the polymorphism in EPHB2. Conclusion: The FT4 level may be associated with a combination of methylation and polymorphisms in the EPHB2 gene.

Factors affecting reasonable duration of continuous electrocardiographic monitoring to detect atrial fibrillation in acute ischemic stroke.

BACKGROUND: To examine the reasonable duration of continuous electrocardiographic monitoring (CEM) to detect AF at acute ischemic stroke. MATERIALS AND METHOD: 811 consecutive patients admitted to Tsuruga Municipal Hospital by acute ischemic stroke between April 2013 and December 2021 were enrolled in this study. Excluding 78 patients, 733 patients were analyzed by cluster analysis with SurvCART algorithm, followed by Kaplan-Meier analysis. RESULTS: The analysis provided step graphs for 8 subgroups. The duration of CEM to achieve the sensitivity of 0.8, 0.9, and 0.95 in each could be calculated. The duration of CEM to achieve the sensitivity of 0.8 are 18 days in female patients with heart failure (HF) (subgroup 1), 24 days in male patients with HF (subgroup 2), 22 days in patients without HF with arterial occlusion and pulse rate (PR) more than 91 (subgroup 3), 24 days in patients without HF with occlusion with PR less than 91 (subgroup 4), 18 days in patients without HF without occlusion with lacuna (subgroup 5), 26 days in patients without HF, occlusion, and lacuna, with arterial stenosis (subgroup 6), 15 days in patients without HF, occlusion, lacuna, and stenosis with BMI more than 21%(subgroup 7), and 44 days in patients without HF, occlusion, lacuna, stenosis and with BMI less than 21% (subgroup 8). CONCLUSIONS: Duration of CEM with the sensitivity of 0.8, 0.9, and 0.95 could be determined by presence of HF, female sex, arterial occlusion, PR more than 91/minute, presence of lacuna, presence of stenosis, and BMI more than 21%. (250).

Twin Study: Genetic and Epigenetic Factors Affecting Circulating Adiponectin Levels.

CONTEXT: Clarification of the association among phenotypes, genetic, and environmental factors with clinical laboratory traits can reveal the cause of diseases and assist in developing methods for the prediction and prevention of diseases. It is difficult to investigate the environmental effect on phenotypes using individual samples because their genetic and environmental factors differ, but we can easily investigate the influence of environmental factors using monozygotic (MZ) twins because they have the same genetic factors. OBJECTIVE: We aimed to examine the methylation level of CpG sites as an environmental factor affecting adiponectin levels on the basis of the same genetic background using MZ twins and to identify the epigenetic factors related to adiponectin levels and the genetic factors associated with sensitivity to acquired changes in adiponectin. METHODS: Using 2 groups built from each twin of 232 MZ twin pairs, we performed a replicated epigenome-wide association study to clarify the epigenetic factors affecting adiponectin levels adjusted by genetic risk score. Moreover, we divided twin pairs into concordant and discordant for adiponectin levels. We conducted a genome-wide association study to identify a genetic background specific for discordance. RESULTS: Methylation levels at 38 CpG sites were reproducibly associated with adjusted adiponectin levels, and some of these CpG sites were in genes related to adiponectin, including CDH13. Some genes related to adiponectin or insulin resistance were found to be genetic factors specific for discordance. CONCLUSION: We clarified specific epigenetic factors affecting adiponectin levels and genetic factors associated with sensitivity to acquired changes in adiponectin.

Ubiquitination of IgG1 cytoplasmic tail modulates B-cell signalling and activation.

Upon antigen stimulation, IgG+ B cells rapidly proliferate and differentiate into plasma cells, which has been attributed to the characteristics of membrane-bound IgG (mIgG), but the underlying molecular mechanisms remain elusive. We have found that a part of mouse mIgG1 is ubiquitinated through the two responsible lysine residues (K378 and K386) in its cytoplasmic tail and this ubiquitination is augmented upon antigen stimulation. The ubiquitination of mIgG1 involves its immunoglobulin tail tyrosine (ITT) motif, Syk/Src-family kinases and Cbl proteins. Analysis of a ubiquitination-defective mutant of mIgG1 revealed that ubiquitination of mIgG1 facilitates its ligand-induced endocytosis and intracellular trafficking from early endosome to late endosome, and also prohibits the recycling pathway, thus attenuating the surface expression level of mIgG1. Accordingly, ligation-induced activation of B-cell receptor (BCR) signalling molecules is attenuated by the mIgG1 ubiquitination, except MAP kinase p38 whose activation is up-regulated due to the ubiquitination-mediated prohibition of mIgG1 recycling. Adaptive transfer experiments demonstrated that ubiquitination of mIgG1 facilitates expansion of germinal centre B cells. These results indicate that mIgG1-mediated signalling and cell activation is regulated by ubiquitination of mIgG1, and such regulation may play a role in expansion of germinal centre B cells.

In Situ SR-XPS Observation of Ni-Assisted Low-Temperature Formation of Epitaxial Graphene on 3C-SiC/Si.

Low-temperature (~1073 K) formation of graphene was performed on Si substrates by using an ultrathin (2 nm) Ni layer deposited on a 3C-SiC thin film heteroepitaxially grown on a Si substrate. Angle-resolved, synchrotron-radiation X-ray photoemission spectroscopy (SR-XPS) results show that the stacking order is, from the surface to the bulk, Ni carbides(Ni3C/NiCx)/graphene/Ni/Ni silicides (Ni2Si/NiSi)/3C-SiC/Si. In situ SR-XPS during the graphitization annealing clarified that graphene is formed during the cooling stage. We conclude that Ni silicide and Ni carbide formation play an essential role in the formation of graphene.

Step-size analyses of the mitochondrial Hsp70 import motor reveal the Brownian ratchet in operation.

Newly synthesized mitochondrial precursor proteins have to become unfolded by the mitochondrial Hsp70 (mtHsp70) import motor to cross the mitochondrial membranes. To assess the mechanism of unfolding of precursor proteins by mtHsp70, we designed a system to measure step sizes of the mtHsp70 import motor, which are distances at which the motor system moves along polypeptide chains during a single turnover of ATP. We made a series of fusion proteins consisting of a mitochondrial presequence containing the first mtHsp70 binding site, a spacer sequence containing an Hsp70 avoidance segment followed by the second mtHsp70 binding site, and different folded mature domains. Analyses of the dependence of the import rates of those fusion proteins on the lengths of Hsp70 avoidance segments allowed us to estimate the step sizes, which differ for different mature domains and different lengths of the spacers. These results suggest that the mtHsp70 import motor functions at least as a molecular Brownian ratchet to unfold mitochondrial precursor proteins.

[Prevalence of intimate partner violence and related factors in a local city in Japan].

OBJECTIVES: This study sought to assess the prevalence of intimate partner violence in a local city of Fukui Prefecture, and whether the subjects' and their partners' demographic characteristics, alcohol use, and violence experienced in the families in which they were raised might be related risk factors. METHODS: We conducted a mail survey of 1,000 subjects aged 20-69 in the city randomly sampled from the population of 45,220 that were stratified by 10 years of age and sex and pulled 100 from each group. Data from two 248 respondents were eligible for analysis. The self-administered questionnaire included items on; 1) whether they were the victims of physical, sexual, social-economic and psychological violence from their intimate partners, and whether they perpetrated violence or not on their partners; 2) demographic characteristics of the subjects and their partners with information on gender, age, occupation, educational background, annual income, the cohabitants, and their alcohol use; 3) the subjects' experience of violence in the family in which they had grown up; exposure to violence between their parents, and being abused by them. RESULTS: Out of 248 subjects, men accounted for 41.5%. The prevalence rate of any violence experienced from intimate partners was 46.4%, and that of having perpetrated any violence on the partner was 43.1%. Women reported experiencing more "sexual violence" from their partners than did men. In addition, men admitted to more "physical, sexual, and psychological violence" on their partners than women. Those who had themselves been exposed to violence between parents or were victimized by their parents significantly had more experience of violence from their partners and perpetration than those who did not. CONCLUSION: The results suggest that questioning about the experience of violence in the family is useful for the early detection of intimate partner violence.