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Aims/introduction: Uric acid is synthesized by oxidation of hypoxanthine and xanthine using a catalyzing enzyme, xanthine oxidoreductase (XOR), which can be a source of reactive oxygen species. Plasma XOR activity is a metabolic biomarker associated with obesity, hyperuricemia, liver dysfunction and insulin resistance. However, it has recently been reported that XOR activity in fat tissue is low in humans, unlike in rodents, and that hypoxanthine is secreted from human fat tissue., Materials and Methods: The associations of obesity with hypoxanthine, xanthine and plasma XOR activity were investigated in 484 participants (men/women: 224/260) of the Tanno-Sobetsu Study., Results: Levels of hypoxanthine, xanthine and plasma XOR activity were significantly higher in men than in women. In 59 participants with hyperuricemia, 11 (men/women: 11/0) participants were being treated with an XOR inhibitor and had a significantly higher level of xanthine, but not hypoxanthine, than that in participants without treatment. In all of the participants, hypoxanthine concentration in smokers was significantly higher than that in non-smokers. Stepwise and multivariate regression analyses showed that body mass index, smoking habit and xanthine were independent predictors of hypoxanthine after adjustment of age, sex and use of antihyperuricemic drugs. Whereas, alanine transaminase, hypoxanthine and plasma XOR activity were independent predictors for xanthine, and alanine transaminase, triglycerides and xanthine were independent predictors for plasma XOR activity., Conclusions: The concentration of hypoxanthine, but not that of xanthine, is independently associated with obesity and smoking habit, indicating differential regulation of hypoxanthine and xanthine in a general population., (© 2020 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)

Background: Hyperthyroidism caused by activating mutations of the thyrotropin receptor gene (TSHR) is rare in the pediatric population., Methods: We found a Japanese family with hyperthyroidism without autoantibody. DNA sequence analysis of TSHR was undertaken in this family. The functional consequences for the Gs-adenylyl cyclase and Gq/11-phospholipase C signaling pathways and cell surface expression of receptors were determined in vitro using transiently transfected human embryonic kidney 293 cells., Results: We identified a heterozygous mutation (M453R) in exon 10 of TSHR. In this family, this mutation was found in all individuals who exhibited hyperthyroidism. The results showed that this mutation resulted in constitutive activation of the Gs-adenylyl cyclase system. However, this mutation also caused a reduction in the activation capacity of the Gq/11-phospholipase C pathway, compared with the wild type., Conclusion: We demonstrate that the M453R mutation is the cause of nonautoimmune hyperthyroidism.

Forty years have passed since our initial description of peculiar cases of adult-onset leukemia with abnormal cells having multi-convoluted nuclei and T cell properties, frequent in the southern regions of Japan in the early 1970s. Retrospectively, the study of adult T cell leukemia (ATL) and the related virus HTLV-I was a forerunner for all of human retrovirology, in which AIDS and the related retrovirus HIV were identified a few years later in the 1980s. Using the anti-TAC monoclonal antibody generated by the late Takashi Uchiyama during his stay in T. A. Waldmann's laboratory in NIH Bethesda, a cDNA encoding IL-2Rα chain was cloned by our group in Kyoto and by Waldmann's group in Bethesda. Abnormal IL-2Rα chain expression and the IL-2 dependency of ATL cell lines greatly contributed to the study of leukemogenesis of ATL. A new soluble factor named ADF/ATL-derived factor was also detected in ATL cell lines. After years of study, ADF proved to be a first human counterpart of thiol-related oxido-reductase thioredoxin/TRX, which opened the field of redox regulation of cell signaling involved in a variety of diseases. Close interaction among Drs. Kimishige Ishizaka, Kiyoshi Takastuki and T. A. Waldmanns before ATL and HTLV-I study was an essential base for our initiation of ATL research with Takashi Uchiyama and many other colleagues.

Context: Inactivating mutations in the TSH receptor gene (TSHR) cause TSH resistance. Most patients with TSH resistance have low to normal thyroidal radioiodine uptake (RAIU), which is consistent with the physiological knowledge that TSH stimulates iodine uptake. To date, only one TSHR mutation-carrying family with discrepantly high RAIU has been reported., Objective: We aimed to test whether TSHR mutation carriers with high RAIU are observed in a cohort of Japanese patients with congenital hypothyroidism (CH)., Subjects and Methods: Twenty-four Japanese CH patients with high RAIU were screened for TSHR mutations. The capacities of mutant TSHR to activate Gs- and Gq-coupled signaling pathways were evaluated in vitro., Results: Two patients were found to have biallelic TSHR mutations: p.[T145I]+[R450H] in one and p.[R450H]+[I661fs] in the other. The two subjects had permanent CH with slightly high RAIU (41.8 and 43.0%, reference 8-40) but did not have goiter. One had a slightly high perchlorate discharge rate (10%, reference <10). Expression experiments revealed that T145I-TSHR retained partial ability to transduce both Gs- and Gq-coupled pathways, whereas I661fs-TSHR could transduce neither of them. R450H-TSHR had partial ability to transduce Gs-coupled signaling but had abrogated ability to transduce Gq-coupled signaling, indicating that coupling to Gq was dominantly affected., Conclusions: We show that 8% of Japanese CH patients with high RAIU (two in 24) has inactivating TSHR mutations. Expression of this apparently discrepant phenotype, which we term nonclassic TSH resistance, is presumably associated with the characteristic signaling property of the mutant TSHR, namely the Gq-dominant coupling defect.

Methamphetamine (MAP) dependence is a highly heritable and aberrant dopaminergic signaling that has been implicated in the disease. Glial cell line-derived neurotrophic factor (GDNF), which plays an important role in the survival of dopaminergic neurons, may be involved in this disorder. In this study, we examined the association between GDNF and MAP dependence using a Japanese population-based sample. We selected eight single nucleotide polymorphisms (SNPs) in the GDNF locus for the association analysis. When patients with MAP dependence were divided into two subgroups consisting of multi-substance and MAP-only users, we detected a significant association between these two groups and the tagging SNP, rs2910704 (after Bonferroni's correction; allele P=0.034). Thus, GDNF is likely to be related to the severity of MAP use in the Japanese population., (Copyright © 2011 Elsevier Inc. All rights reserved.)

The tumor necrosis factor (TNF)-alpha pathway has a key role in regulating insulin resistance. TNF receptor 2 (TNFR2) is an emerging candidate gene for insulin resistance in essential hypertension. We examined the association of insulin resistance and enhanced TNF pathway with severe hypertension and the association of a microsatellite polymorphism of the TNFR2 gene with severe hypertension. Male severe essential hypertensive patients (HT) with the onset before 60 years of age and with genetic predispositions to hypertension were consecutively enrolled at our outpatient department (N=92). Normotensive men (NT) over 50 years of age were randomly registered from the participants in the annual health check program (N=78). Patients were selected as HT and NT who met stringent criteria for systolic/diastolic blood pressure (SBP/DBP) levels >or=180 and/or 110 mm Hg and <120/80 mm Hg, respectively. HT revealed significantly higher plasma insulin levels, C-reactive protein (CRP) and soluble fraction of TNFR2 concentrations (sTNFR2) than NT. A microsatellite polymorphism of the CA repeat in intron 4 of the TNFR2 gene was analyzed. The allele frequency of CA16 in HT differed significantly from that in NT (66/184 vs. 36/156, P=0.01 by chi(2) analysis). In HT, the CA16 carriers showed significantly higher SBP and plasma insulin levels and a higher tendency of sTNFR2 than did those without this allele. In NT, CA16 carriers revealed significantly higher sTNFR2 and CRP levels than did the CA16 non-carriers. These results suggest that the TNFR2 gene locus has a potential effect on developing severe hypertension through the augmented TNF pathway and insulin resistance.

Several lines of evidence, including genome-wide linkage scans and postmortem brain studies of patients with schizophrenia or bipolar disorder, have suggested that DARPP-32 (dopamine- and cAMP-regulated phosphoprotein, 32 kDa), a key regulatory molecule in the dopaminergic signaling pathway, is involved in these disorders. After evaluating the linkage disequilibrium pattern of the gene encoding DARPP-32 (PPP1R1B; located on 17q12), we conducted association analyses of this gene with schizophrenia and bipolar disorder. Single-marker and haplotypic analyses of four single nucleotide polymorphisms (SNPs; rs879606, rs12601930, rs907094, and rs3764352) in a sample set (subjects with schizophrenia=384, subjects with bipolar disorder=318, control subjects=384) showed that PPP1R1B polymorphisms were not significantly associated with schizophrenia, whereas, even after Bonferroni corrections, significant associations with bipolar disorder were observed for rs12601930 (corrected genotypic p=0.00059) and rs907094 (corrected allelic p=0.040). We, however, could not confirm these results in a second independent sample set (subjects with bipolar disorder=366, control subjects=370). We now believe that the significant association observed with the first sample set was a result of copy number aberrations in the region surrounding these SNPs. Our findings suggest that PPP1R1B SNPs are unlikely to be related to the development of schizophrenia and bipolar disorder in the Japanese population.

There is much uncertainty about cancer risks at the high radiation doses used in radiotherapy (RT). It has generally been assumed that cancer induction decreases rapidly at high doses due to cell killing. However, this is not seen in all RT groups, and a model recently developed by Sachs and Brenner [2005. Solid tumor risks after high doses of ionizing radiation. Proc. Natl Acad. Sci. USA 102, 13040-13045] proposed a mechanism for repopulation of cells after radiation exposure that explained why this might happen, at least for solid tumours. In this paper, this model is generalized to allow for heterogeneity in the dose received, and various alternate patterns of repopulation are also considered. The model is fitted to the Japanese atomic bomb survivor leukaemia incidence data, and data for various therapeutically irradiated groups. Two sets of parameters from these model fits are used to assess the sensitivity of model predictions. It is shown that in general allowing for heterogeneity in dose distribution and haematopoietic stem cell migration results in lower risks than the same average dose administered uniformly and without such migration, although this does not hold in the limiting case of complete stem cell repopulation between radiation dose fractions. We also investigate the difference made by assuming a compartmental repopulation signal, and a global repopulation signal. In general we show that in the absence of stochastic extinction, compartmental repopulation always predicts a larger number of mutated cells than global repopulation. However, in certain dose regimes stochastic extinction cannot be ignored, and in these cases the numbers of mutated cells predicted with global repopulation can exceed that for compartmental repopulation. In general, mutant cell numbers are highly overdispersed, with variance much greater than the mean.

We investigated the status of the components and target genes of the Wnt signaling pathway in Japanese anaplastic thyroid cancers (ATCs) in the present study. Nuclear and cytoplasmic positive staining of beta-catenin, which might indicate the existence of alterations in the Wnt signaling pathway, were found in 40.9% and 63.6% of the 22 ATC samples, respectively. The beta-catenin, adenomatous polyposis coli (APC) and Axin 1 gene mutations were observed in 4.5%, 9.0%, and 81.8% of the 22 ATC samples, respectively. Overexpression of cyclin D1 and c-myc, which are the target genes of the Wnt signaling pathway, was observed in 27.3% and 59.1% of the ATC samples, respectively. There was no significant correlation between nuclear or cytoplasmic positive staining of beta-catenin and nuclear positive staining of cyclin D1 or c-myc. Taken together, the results of beta-catenin immunohistochemistry suggest that alterations in the Wnt signaling pathway are associated with carcinogenesis of ATC, but the frequency of beta-catenin gene mutation in our series is lower than that previously reported. Furthermore, cyclin D1 and c-myc frequently accumulated in ATC, independently of dysfunction in the Wnt signaling pathway.

One Japanese pedigree of familial essential thrombocythemia (FET) inherited in an autosomal-dominant manner is presented. A unique point mutation, serine 505 to asparagine 505 (Ser505Asn), was identified in the transmembrane domain of the c-MPL gene in all of the 8 members with thrombocythemia, but in none of the other 8 unaffected members in this FET family. The Ba/F3 cells expressing the mutant Asn505 acquired interleukin 3 (IL-3)-independent survival capacity, whereas those expressing wild-type Ser505 did not. The autonomous phosphorylation of Mek1/2 and Stat5b was observed in the mutant Ba/F3 cells in the absence of IL-3. The former was also found in platelets derived from the affected individual in the absence of thrombopoietin. These results show that the Asn505 is an activating mutation with respect to the intracellular signaling and survival of the cells. This is the first report of FET deriving from a dominant-positive activating mutation of the c-MPL gene.

We have previously shown that the systemic injection of sodium tungstate, a general protein-tyrosine phosphatase (PTPase) inhibitor, efficiently produces characteristic color-pattern modifications on the wings of the Painted Lady butterfly, Vanessa cardui. By using this method in the present study, we analyzed modification patterns of six species of Japanese butterflies. Whereas in Vanessa indica the black spots on the forewings reduced in size in response to the treatment, in Lycaena phlaeas the morphologically similar black spots enlarged in size. However, the metallic blue spots on the forewings of V. indica did enlarge in size, showing different behavior even within a single wing surface. The response patterns of Ypthima argus differed markedly from those of other species in that ectopic color-pattern elements were created. Colias erate showed minor modifications that coincidentally resembled the natural color-pattern of a closely related species, Colias palaeno. Through a comprehensive literature search, we confirmed the existence of naturally occurring aberrant color patterns with close similarities to the experimentally induced phenocopies in each of the modified species. Our results point out the possibility that a hypothetical transduction pathway with a PTPase for the scale-cell differentiation globally coordinates the wing-wide color-pattern development in butterflies.

Fully grown immature oocytes acquire the ability to be fertilized with sperm after meiotic maturation, which is finally accomplished by the formation and activation of the maturation-promoting factor (MPF). MPF is the complex of Cdc2 and cyclin B, and its function in promoting metaphase is common among species. The Mos/mitogen-activated protein kinase (MAPK) pathway is also commonly activated during vertebrate oocyte maturation, but its function seems to be different among species. We investigated the function of the Mos/MAPK pathway during oocyte maturation of the frog Rana japonica. Although MAPK was activated in accordance with MPF activation during oocyte maturation, MPF activation and germinal vesicle breakdown (GVBD) was not initiated when the Mos/MAPK pathway was activated in immature oocytes by the injection of c-mos mRNA. Inhibition of Mos synthesis by c-mos antisense RNA and inactivation of MAPK by CL100 phosphatase did not prevent progesterone-induced MPF activation and GVBD. However, continuous MAPK activation and MAPK inhibition through oocyte maturation accelerated and delayed MPF activation, respectively. Furthermore, Mos induced a low level of cyclin B protein synthesis in immature oocytes without the aid of MAPK. These results suggest that the general function of the Mos/MAPK pathway, which is not essential for MPF activation and GVBD in Rana oocytes, is to enhance cyclin B translation by Mos itself and to stabilize cyclin B protein by MAPK during oocyte maturation.

A very-low-calorie conventional Japanese diet of 370 kcal/day has been shown to be useful for weight reduction and its long-term maintenance. Sources of the diet were mainly from chicken fillet, egg white, fish white-meat, mushroom, seaweed and low- or non-calorie fiber-rich vegetable, and contained 4.4g fat, 38.1g protein, 45.2g carbohydrate and essential minerals and vitamins. However, metabolic and neural implications of a commercial very-low-calorie liquid formula diet have rarely been investigated from the view point of food intake and appetite regulation. Animal studies have demonstrated the rationale for efficacy of the very-low calorie conventional Japanese diet as follows: (1) Increased hypothalamic histamine suppressed food intake through H1-receptors in the ventromedial hypothalamus (VMH) and paraventricular nucleus, the satiety centers. (2) Low energy intake enhanced satiety and decreased food intake through histaminergic activation of VMH neurons. (3) Mastication activated afferent signal transmission from proprioceptors in the oral cavity to the mesencephalic trigeminal nucleus(Me5). Histaminergic systems in the hypothalamus were activated by mastication and low energy supply, which was accompanied by satiation through the action of histamine in the VMH. Usefulness of the very-low-calorie conventional Japanese diet derives from utilization of conventional Japanese food stuffs as a fiber rich, low energy food source, and from enhancement of satiation by increased mastication required of the diet. The properties of the diet seemed to effect a closed positive feedback loop between histaminergic activation in hypothalamic satiety centers and behavioral changes to enhance satiation and cause feeding suppression.