Ancient Jomon genome sequence analysis sheds light on migration patterns of early East Asian populations

Anatomically modern humans reached East Asia more than 40,000 years ago. However, key questions still remain unanswered with regard to the route(s) and the number of wave(s) in the dispersal into East Eurasia. Ancient genomes at the edge of the region may elucidate a more detailed picture of the peopling of East Eurasia. Here, we analyze the whole-genome sequence of a 2,500-year-old individual (IK002) from the main-island of Japan that is characterized with a typical Jomon culture. The phylogenetic analyses support multiple waves of migration, with IK002 forming a basal lineage to the East and Northeast Asian genomes examined, likely representing some of the earliest-wave migrants who went north from Southeast Asia to East Asia. Furthermore, IK002 shows strong genetic affinity with the indigenous Taiwan aborigines, which may support a coastal route of the Jomon-ancestry migration. This study highlights the power of ancient genomics to provide new insights into the complex history of human migration into East Eurasia

An Analysis of Carbonized Rice Grains Excavated from the Iwasaki Site in Fukuoka Pref.

東京大学考古学研究室は、福岡県八女市岩崎から出土した炭化米を所蔵している。この炭化米は、大正12 年に中山平次郎が採集して本研究室に寄贈したものである。本稿ではこの炭化米の植物形態学的研究と放射性炭素年代測定、炭素・窒素同位体比分析をおこなった。その結果、これらはほとんどが短粒の小型米という弥生後期以前の形態である可能性が示唆され、年代測定の結果と整合性を示し、中山の見通しの正しさが検証された。また、水稲である可能性が示唆された。The archaeology laboratory of the University of Tokyo possesses carbonized rice grains excavated from Iwasaki, Yame-shi, Fukuoka pref. This carbonized rice was collected by Heijirou Nakayama in 1923 and subsequently donated to the laboratory. In the following paper, a plant-ecological examination of these materials, together with a carbon-14 dating will be conducted in addition to a comparative analysis of carbon and nitrogen isotopes. The results of this paper indicate the possibility that almost all of the carbonized rice grains belong to a type of small, short-grain rice dating from before the late Yayoi period. The consistency of these findings in relation to the results of the carbon-14 dating is used to examine the validity of Nakayama\u27s predictions. Moreover, the possibility that these carbonized rice grains may have been a variation of wet rice is also suggested

Population pharmacokinetic analysis of letrozole in Japanese postmenopausal women

Purpose: Letrozole is an orally active aromatase inhibitor for treatment of breast cancer. The objectives of this study were to examine pharmacokinetic profile of letrozole in Japanese subjects and identify factors which influence variability in PK of letrozole using population pharmacokinetic (PPK) analysis. Methods: Twenty-five healthy postmenopausal Japanese women were enrolled in the study and received 2.5 mg letrozole once daily for 14 or 28 days. A PPK model was developed using NONMEM software. Age, body weight (WT), AST, ALT, total bilirubin, serum creatinine (CRE), and genotype of CYP2A6 were studied as covariates. Estrone, estrone sulfate, and estradiol in plasma were measured as pharmacodynamic markers. Results: CYP2A6 genotype, CRE and AST were significant covariates for apparent systemic clearance (CL/F), and WT was a significant covariate for apparent distribution volume (Vd/F). Population mean estimates of CL/F and Vd/F in subjects without CYP2A6 mutation were 1.03 × (CRE/0.70)-1.27 × (AST/17.5)-0.793 L/hr and 94.2 × (WT/51.1)1.12 L, respectively. CL/F in subjects possessing 1 and 2 CYP2A6 mutation alleles were 84.3% and 44.8% of the value in the subjects without mutation, respectively. Estrogen levels fell to below detection limits in most subjects after letrozole administration. Three mild and transient adverse events (upper respiratory tract inflammation, arthralgia, and vomiting) were reported in the study. Conclusions: CYP2A6 genotype largely influences CL/F of letrozole. Genetic polymorphism of CYP2A6 and body weight will be causes of ethnic difference in PK. However, dose adjustment is not necessary, due to the wide therapeutic range

Ancient Jomon genome sequence analysis sheds light on migration patterns of early East Asian populations.

Anatomically modern humans reached East Asia more than 40,000 years ago. However, key questions still remain unanswered with regard to the route(s) and the number of wave(s) in the dispersal into East Eurasia. Ancient genomes at the edge of the region may elucidate a more detailed picture of the peopling of East Eurasia. Here, we analyze the whole-genome sequence of a 2,500-year-old individual (IK002) from the main-island of Japan that is  characterized with a typical Jomon culture. The phylogenetic analyses support multiple waves of migration, with IK002 forming a basal lineage to the East and Northeast Asian genomes examined, likely representing some of the earliest-wave migrants who went north from Southeast Asia to East Asia. Furthermore, IK002 shows strong genetic affinity with the indigenous Taiwan aborigines, which may support a coastal route of the Jomon-ancestry migration. This study highlights the power of ancient genomics to provide new insights into the complex history of human migration into East Eurasia

Generation of Novel Chimeric Mice with Humanized Livers by Using Hemizygous cDNA-uPA/SCID Mice.

We have used homozygous albumin enhancer/promoter-driven urokinase-type plasminogen activator/severe combined immunodeficient (uPA/SCID) mice as hosts for chimeric mice with humanized livers. However, uPA/SCID mice show four disadvantages: the human hepatocytes (h-heps) replacement index in mouse liver is decreased due to deletion of uPA transgene by homologous recombination, kidney disorders are likely to develop, body size is small, and hemizygotes cannot be used as hosts as more frequent homologous recombination than homozygotes. To solve these disadvantages, we have established a novel host strain that has a transgene containing albumin promoter/enhancer and urokinase-type plasminogen activator cDNA and has a SCID background (cDNA-uPA/SCID). We applied the embryonic stem cell technique to simultaneously generate a number of transgenic lines, and found the line with the most appropriate levels of uPA expression-not detrimental but with a sufficiently damaged liver. We transplanted h-heps into homozygous and hemizygous cDNA-uPA/SCID mice via the spleen, and monitored their human albumin (h-alb) levels and body weight. Blood h-alb levels and body weight gradually increased in the hemizygous cDNA-uPA/SCID mice and were maintained until they were approximately 30 weeks old. By contrast, blood h-alb levels and body weight in uPA/SCID chimeric mice decreased from 16 weeks of age onwards. A similar decrease in body weight was observed in the homozygous cDNA-uPA/SCID genotype, but h-alb levels were maintained until they were approximately 30 weeks old. Microarray analyses revealed identical h-heps gene expression profiles in homozygous and hemizygous cDNA-uPA/SCID mice were identical to that observed in the uPA/SCID mice. Furthermore, like uPA/SCID chimeric mice, homozygous and hemizygous cDNA-uPA/SCID chimeric mice were successfully infected with hepatitis B virus and C virus. These results indicate that hemizygous cDNA-uPA/SCID mice may be novel and useful hosts for producing chimeric mice for use in future long-term studies, including hepatitis virus infection analysis or drug toxicity studies

Histopathological findings in chimeric mouse livers and kidneys.

<p>H&E staining of left lateral lobes of (A) uPA/SCID chimeric mice, (B) #1C2 homozygous and (C) #1C2 hemizygous chimeric mice, and magnifications of the rectangular parts (D) on the left side of A and (E) on the right side of A, (F) in B, and (G) in C are shown. h-heps with a clear cytoplasm and lipid droplets occupied most areas of the liver sections (A-G). Arrows show (D) degenerating m-heps and (E) hyperplastic m-hep nodules in uPA/SCID chimeric mice. M-heps with eosinophilic cytoplasm of various sizes are shown by arrows in (F) #1C2 homozygous and (G) hemizygous chimeric mice. (H) The left lateral lobe of a #1C2 hemizygous chimeric mouse was immunostained with anti-hCK8/18 antibodies. H-heps were brown-colored, and (I) an area of rectangle was magnified. m, m-heps, h, h-heps. Kidney sections in (J, M) uPA/SCID, (K, N) #1C2 homozygote and (L, O) hemizygous chimeric mice were stained with H&E. Enlarged glomeruli and glomerulosclerosis were observed in uPA/SCID mice (J, M). No pathological findings were observed in (K, N) #1C2 homozygote and (L, O) hemizygous chimeric mouse kidneys. (M), (N) and (O) were high magnification of (J), (K) and (L), respectively. Bar, 100 μm in D-G, I and J-O. Bar, 1 mm in A-C and H.</p