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( Mitsutoshi Yamada ) 대한산부인과학회 2019 대한산부인과학회 학술대회 Vol.105 No.-
The high rate of early embryonic developmental arrest is common and presents a major obstacle to achieving better successful pregnancy outcome in assisted reproductive technology (ART) and also development of therapeutic cloning by somatic cell nuclear transfer (SCNT). After fertilization, the maternal genetic program governed by maternally derived RNAs and proteins is switched to the embryonic genetic program by de novo transcription; this switch is termed zygotic genome activation (ZGA). ZGA is essential for establishing pluripotency and genome stability. However, it is unclear how ZGA plays a role in development and preventing mitotic errors. Nuclear transfer embryonic stem cells (ntESCs) are assumed to be closer to embryonic stem cells (ESCs) than induced pluripotent stem cells (iPSCs). Initial attempts to produce human stem cells using SCNT failed, as only 16% (124 of 761) of ZGA transcripts were upregulated after genome exchange in SCNT human embryos. Histone deacetylase inhibitors (HDACi) supplementation during the first cell cycle induced zygotic transcription in SCNT embryos, which lead to isolate ntESCs giving rise to all three germ layers, including insulin-producing cells. Therefore, ZGA can be deemed indispensable for blastocyst development and stem cell derivation through SCNT. Mining gene-expression-profiling data identified a zygotic genome activation (ZGA) gene, we identified Zscan5b. Zscan5b-deficient ESCs showed random distribution of gaps in their chromosomes, elevated DNA-stress response and developed cancerous lesions. A co-immunoprecipitation analysis showed that ZSCAN5B bound to the linker protein histone H1. In addition, rescue analysis restored genome stability. Therefore, the Zscan5b gene can be classified as encoding a protein directly involved in DNA repair and protection of chromosomal architecture. Exploring reprogramming path based on ZGA can be useful for development not only of regenerative medicine but also of ART.
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Yoshiki Yasukoch,Jun Sakuma,Ichiro Takeuchi,Kimihiko Kato,Mitsutoshi Oguri,Tetsuo Fujimaki,Hideki Horibe,Yoshiji Yamada 생화학분자생물학회 2017 Experimental and molecular medicine Vol.49 No.-
Genome-wide association studies have identified various genetic variants associated with complex disorders. However, these studies have commonly been conducted in a cross-sectional manner. Therefore, we performed a longitudinal exome-wide association study (EWAS) in a Japanese cohort. We aimed to identify genetic variants that confer susceptibility to hypertension using ~ 244 000 single-nucleotide variants (SNVs) and physiological data from 6026 Japanese individuals who underwent annual health check-ups for several years. After quality control, the association of hypertension with SNVs was tested using a generalized estimating equation model. Finally, our longitudinal EWAS detected seven hypertension-related SNVs that passed strict criteria. Among these variants, six SNVs were densely located at 12q24.1, and an East Asian-specific motif (haplotype) ‘CAAAA’ comprising five derived alleles was identified. Statistical analyses showed that the prevalence of hypertension in individuals with the East Asian-specific haplotype was significantly lower than that in individuals with the common haplotype ‘TGGGT’. Furthermore, individuals with the East Asian haplotype may be less susceptible to the adverse effects of smoking on hypertension. The longitudinal EWAS for the recessive model showed that a novel SNV, rs11917356 of COL6A5, was significantly associated with systolic blood pressure, and the derived allele at the SNV may have spread throughout East Asia in recent evolutionary time.
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