RAS GTPases mediate a wide variety of cellular functions, including cell proliferation, survival, and differentiation. Recent studies have revealed that germline mutations and mosaicism for classical RAS mutations, including those in HRAS, KRAS, and NRAS, cause a wide spectrum of genetic disorders. These include Noonan syndrome and related disorders (RAS/mitogen-activated protein kinase [RAS/MAPK] pathway syndromes, or RASopathies), nevus sebaceous, and Schimmelpenning syndrome. In the present study, we identified a total of nine missense, nonsynonymous mutations in RIT1, encoding a member of the RAS subfamily, in 17 of 180 individuals (9%) with Noonan syndrome or a related condition but with no detectable mutations in known Noonan-related genes. Clinical manifestations in the RIT1-mutation-positive individuals are consistent with those of Noonan syndrome, which is characterized by distinctive facial features, short stature, and congenital heart defects. Seventy percent of mutation-positive individuals presented with hypertrophic cardiomyopathy; this frequency is high relative to the overall 20% incidence in individuals with Noonan syndrome. Luciferase assays in NIH 3T3 cells showed that five RIT1 alterations identified in children with Noonan syndrome enhanced ELK1 transactivation. The introduction of mRNAs of mutant RIT1 into 1-cell-stage zebrafish embryos was found to result in a significant increase of embryos with craniofacial abnormalities, incomplete looping, a hypoplastic chamber in the heart, and an elongated yolk sac. These results demonstrate that gain-of-function mutations in RIT1 cause Noonan syndrome and show a similar biological effect to mutations in other RASopathy-related genes.

The total prevalence of variation in the origin of the LVA was 6.0 % and of the RVA, 3.8 %. The total prevalence of variation in entry level into the TF was 7.0 % for the LVA and 6.2 % for the RVA. Recognition and reporting of these variations is important in interpreting CT angiography to prevent complications during surgery of the aortic arch or lower neck.

Molecular dynamics simulations have been performed to give an estimate on the solid-liquid interfacial properties of bcc iron, namely the kinetic coefficients and solid-liquid interfacial energy. The kinetic coefficients for different orientations were estimated from the propagation velocity of planar solid-liquid interfaces. The anisotropy of kinetic coefficients, m, was confirmed to be m (100) Ͼm (110) , which is similar to the literatures using other interatomic potentials. Moreover, growing and shrinking behavior of the freestanding spherical crystal and semi-spherical crystal on the substrate in the undercooled liquid was examined. There is a critical temperature dividing shrink or growth of both the freestanding spherical crystal and semi-spherical crystal on the substrate. The solid-liquid interfacial energy was then estimated from Gibbs-Thomson relation in the critical temperature as a function of the inverse of crystal radius.

We analyzed genome-wide single-nucleotide polymorphism data of 11,069 Japanese individuals recruited from all 47 prefectures of Japan to clarify their genetic structure. The principal component analysis at the prefectural level enabled us to study the relationship between geographical location and genetic differentiation. The results revealed that the mainland Japanese were not genetically homogeneous, and the genetic structure could be explained mainly by the degree of Jomon ancestry and the geographical location. One of the interesting findings was that individuals in the Shikoku region (i.e., Tokushima Prefecture, Kagawa Prefecture, Ehime Prefecture, and Kochi Prefecture) were genetically close to Han Chinese. Therefore, the genetic components of immigrants from continental East Asia in the Yayoi period may have been well maintained in Shikoku. The present results will be useful for understanding the peopling of Japan, and also provide suggestions for recruiting subjects in genetic association studies. Japanese who do not live in Okinawa Prefecture as mainland Japanese. There are three major models about the demographic history of the Japanese population (i.e., transformation, replacement, and hybridization models). Of these, the "dual-structure model," one of the hybridization models, is the most widely accepted. According to the dual-structure model, the present Japanese population was formed by admixture between indigenous Jomon people and immigrants from continental East Asia [1]. Previous studies on cranial morphology suggested that the Ainu and Ryukyuans were closer to Jomon people than the mainland Japanese were and, among the mainland Japanese, people in the Tohoku region were morphologically closer to Ainu [1, 2]. Genetic studies also corroborate the relatedness between Jomon people and the Ainu and Ryukyuans; the Ainu and Ryukyuans were likely to retain more Jomon ancestry in their genomes than the mainland Japanese were [3, 4]. Although several genetic studies have shown genetic differentiation between the mainland Japanese and Okinawa people [5-9], the genetic difference among prefectures in the mainland Japanese is not well understood. Yamaguchi-Kabata et al. [8], based on the genome-wide single-nucleotide polymorphism (SNP) data of 7003 Japanese patients treated at hospitals in seven geographic regions, found that Japanese are genetically differentiated.