記述言語：英語   掲載種別：研究論文（学術雑誌）  

Evolution of novel traits is a challenging subject in biological research. Several snake lineages developed elaborate venom systems to deliver complex protein mixtures for prey capture. To understand mechanisms involved in snake venom evolution, we decoded here the ~1.4-Gb genome of a habu, Protobothrops flavoviridis. We identified 60 snake venom protein genes (SV) and 224 nonvenom paralogs (NV), belonging to 18 gene families. Molecular phylogeny reveals early divergence of SV and NV genes, suggesting that one of the four copies generated through two rounds of whole genome duplication was modified for use as a toxin. Among them, both SV and NV genes in four major components were extensively duplicated after their diversification, but accelerated evolution is evident exclusively in the SV genes. Both venom-related SV and NV genes are significantly enriched in microchromosomes. The present study thus provides a genetic background for evolution of snake venom composition.

リポジトリ公開URL： https://hdl.handle.net/2324/7326351

記述言語：英語   掲載種別：研究論文（学術雑誌）  

In reptiles, the mode of reproduction is typically sexual. However, facultative parthenogenesis occurs in some Squamata, such as Komodo dragon (Varanus komodoensis) and Burmese python (Python bivittatus). Here, we report facultative parthenogenesis in the green anaconda (Eunectes murinus). We found two fully developed female neonates and 17 undeveloped eggs in the oviduct of a female anaconda isolated from other individuals for eight years and two months at Ueno Zoo, Japan. To clarify the zygosity of the neonates, we analyzed 18 microsatellite markers of which 16 were informative. We observed only maternal alleles and no paternal alleles for all 16 markers. To examine the possibility of the long-term sperm storage, we estimated allele frequencies in a putative parental stock by genotyping five unrelated founders. If all founders, including the mother, are originated from a single Mendelian population, then the probability that the neonates were produced by sexual reproduction with an unrelated male via long-term sperm storage was infinitesimally small (2.31E-32 per clutch). We also examined samples from two additional offspring that the mother delivered eight years before her death. We consistently observed paternal alleles in these elder offspring, indicating that the mother had switched from sexual reproduction to asexual reproduction during the eight years of isolation. This is the first case of parthenogenesis in Eunectes to be validated by DNA analysis, and suggests that facultative parthenogenesis is widespread in the Boidae.

リポジトリ公開URL： https://hdl.handle.net/2324/7326343

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Dominant intermediate CharcoteMarieeTooth disease F (CMTDIF) is an autosomal dominant hereditary form of CharcoteMarieeTooth disease (CMT) caused by variations in the guanine nucleotide-binding protein, subunit beta-4 gene (GNB4). We examined two Japanese familial cases with CMT. Case 1 was a 49-year-old male whose chief complaint was slowly progressive gait disturbance and limb dysesthesia that appeared at the age of 47. On neurological examination, he showed hyporeflexia or areflexia, distal limb muscle weakness, and distal sensory impairment with lower dominancy. Nerve conduction studies demonstrated demyelinating sensorimotor neuropathy with reduced action potentials in the lower limbs. Case 2 was an 80-year-old man, Case 1's father, who reported difficulty in riding a bicycle at the age of 76. On neurological examination, he showed areflexia in the upper and lower limbs. Distal sensory
impairment in the lower limbs was also observed. Nerve conduction studies revealed mainly axonal involvement. Exome sequencing identified a novel heterozygous nonsynonymous variant (NM_021629.3:c.659T > C [p.Gln220Arg]) in GNB4 exon 8, which is known to be responsible for CMT. Sanger sequencing confirmed that both patients are heterozygous for the variation, which causes an amino acid substitution, Gln220Arg, in the highly conserved region of the WD40 domain of GNB4. The frequency of this variant in the Exome Aggregation Consortium Database was 0.000008247, and we confirmed its absence in 502 Japanese control subjects. We conclude that this novel GNB4 variant is causative for CMTDIF in these patients, who represent the first record of the disease in the Japanese
population.

リポジトリ公開URL： https://hdl.handle.net/2324/7326342

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Spastic paraplegia (SPG) type 28 is an autosomal recessive SPG caused by mutations in the DDHD1 gene. We examined a Japanese 54-years-old male patient with autosomal recessive SPG. His parents were consanguineous. He needed a wheelchair for transfer due to spastic paraplegia. There was a history of operations for bilateral hallux valgus, thoracic ossification of the yellow ligament, bilateral carpal tunnel syndrome, bilateral ankle contracture, and lumbar spinal canal stenosis. He noticed gait disturbance at age 14. He used a cane for walking in his 40s. On neurological examination, he showed hyperreflexia, spasticity, and weakness in the lower extremities and bilateral Babinski reflexes. Urinary dysfunctions and impaired vibration sense in the lower limbs were observed. By exome sequencing analysis using Agilent SureSelect and Illumina MiSeq, we identified 17,248 homozygous nucleotide variants in the patient. Through the examination of 48 candidate genes known to be responsible for autosomal recessive SPG, we identified a novel homozygous 4-bp deletion, c.914_917delGTAA, p.Ser305Ilefs*2 in exon2 of the DDHD1 gene encoding phosphatidic acid-preferring phospholipase A1 (PA-PLA1). The mutation is expected to cause a frameshift generating a premature stop codon 3-bp downstream from the deletion. In consequence, the DDHD domain that is known to be critical for PLA1 activity is completely depleted in the mutated DDHD1 protein, predicted to be a functionally null mutation of the DDHD1 gene. By Sanger sequencing, we confirmed that both parents are heterozygous for the mutation. This variation was not detected in 474 Japanese control subjects as well as the data of the 1,000G Project. We conclude that the novel mutation in DDHD1 is the causative variant for the SPG28 patient that is the first record of the disease in Japanese population.

DOI： 10.1016/j.ejmg.2016.05.010

リポジトリ公開URL： https://hdl.handle.net/2324/7326311

記述言語：英語   掲載種別：研究論文（学術雑誌）  

There are four Habu species currently recognized in Japan: Protobothrops flavoviridis from the Amami Islands and the Okinawa Islands, P. tokarensis from the Tokara Islands, P. elegans from the Yaeyama Islands and Ovophis okinabvensis from the Amami Islands and the Okinawa Islands. To clarify their taxonomic positions, we determined the complete mitochondria genome sequence (approx. 17 kb) from two specimens from two different islands each for P. flavoviridis, P. tokarensis and P. elegans as well as one specimen of O. okinavensis and reconstructed the molecular phylogeny of Protobothrops using the published sequences of related species. The maximum likelihood tree showed four major species groups within Protbothrops: Group I consisting of P. cornutus, P. dabieshanensis, P. jerdonii and P. xiangchengensis; Group II consisting of P. flavoviridis and P. tokarensis; Group III consisting of P. maolensis, P. mucrosquamatus and P. elegans; Group IV consisting of P. himalayanus and P. kaubacki. Since we observed an unexpected divergence and the paraphyly of the two samples of P. flavoviridis collected from different islands, Amami-Oshima and Okinawajima within the Group II, we expanded the analysis by increasing the number of P. flavoviridis and P. tokarensis collected from 10 islands: Amami-Oshima (5 specimens), Kakeromajima (4) and Tokunoshima (4) from the Amami Islands, Okinawajima (4), Iheyajima (4), Iejima (4), Tokashikijima (4) and Kumejima (4) from the Okinawa Islands, Kodakarajima (P. tokarensis) (4) and Takarajima (P. tokarensis) (4) from the Tokara Islands. The maximum likelihood tree of the 44 samples replicated the significant divergence of P. flavoviridis between the Amami Clade including Amami-Oshima, Kakeromajima and Tokunoshima and the Okinawa Clade including Okinawajima, Iheyajima, Iejima, Tokashikijima and Kumejima. The Amami Clade also include all specimens from the Tokara Islands currently known as an independent species, P. tokarensis, suggesting the paraphyly of the taxon, P. flavoviridis. In contrast, we observed a distinct lineage of the two specimens from the Yaeyama Islands, supporting the validity of the taxon, P. elegans as an independent species. By MCMC method, we estimated the divergence time between the Amami Clade and the Okinawa Clade to be 6.51 MYA, suggesting that the vicariance of the two clades preceded the geological separation of the Amami Islands and the Okinawa Islands (~1.5 MYA). As expected from the limited mobility of terrestrial reptiles including snakes, we observed high genetic divergence in Habu mtDNA among Japanese subtropical island populations.

DOI： 10.1016/j.ympev.2016.04.027

リポジトリ公開URL： https://hdl.handle.net/2324/7326289

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Persistent elevation of serum creatine kinase (CK) without any symptoms has been called idiopathic hyper CKemia
(IHCK).We examined a four-generation Japanese pedigree of familial IHCK. Themultipoint linkage analysis
of the pedigree showed seven clear peaks of logarithm of odds (LOD) scores (>1.4). By the exome sequencing
followed bymultiple filtering processes,we identified one novel heterozygous nonsynonymous single nucleotide
variant (SNV), c.7034GNC, p.S2345T in the ryanodine receptor 1 gene, RYR1 cosegregated with IHCK in the pedigree.
Mutation Taster predicted this substitution as “disease causing” (p = 0.999). The PolyPhen-2 and PANTHER
subPSEC scores for the substitution are 0.911 (possibly damaging) and−3.56 (probably damaging), respectively.
We confirmed the absence of the SNV in 511 healthy Japanese individuals excluding the possibility of a normal
variant with a very low frequency. Immunohistochemistry andWestern blotting of biopsy samples consistently
showed the expression level of RYR1 reduced in the patient. In real-time RT-PCR, the mRNA expression level of
RYR1 was also significantly reduced in the patient (p = 0.009). These results suggest that the novel
nonsynonymous SNV contribute to the vulnerability of the RYR1 protein through the dominant negative effect.
We conclude that the SNV in the RYR1 gene is one of the responsible genes of IHCK.

DOI： 10.1016/j.jns.2015.06.035

リポジトリ公開URL： https://hdl.handle.net/2324/7326288

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Background: In the male germline, neonatal prospermatogonia give rise to spermatogonia, which include stem cell
population (undifferentiated spermatogonia) that supports continuous spermatogenesis in adults. Although the levels of
DNA methyltransferases change dynamically in the neonatal and early postnatal male germ cells, detailed genome-wide
DNA methylation profiles of these cells during the stem cell formation and differentiation have not been reported.
Results: To understand the regulation of spermatogonial stem cell formation and differentiation, we examined the DNA
methylation and gene expression dynamics of male mouse germ cells at the critical stages: neonatal prospermatogonia,
and early postntal (day 7) undifferentiated and differentiating spermatogonia. We found large partially methylated
domains similar to those found in cancer cells and placenta in all these germ cells, and high levels of non-CG
methylation and 5-hydroxymethylcytosines in neonatal prospermatogonia. Although the global CG methylation levels
were stable in early postnatal male germ cells, and despite the reported scarcity of differential methylation in the adult
spermatogonial stem cells, we identified many regions showing stage-specific differential methylation in and around
genes important for stem cell function and spermatogenesis. These regions contained binding sites for specific
transcription factors including the SOX family members.
Conclusions: Our findings show a distinctive and dynamic regulation of DNA methylation during spermatogonial stem
cell formation and differentiation in the neonatal and early postnatal testes. Furthermore, we revealed a unique
accumulation and distribution of non-CG methylation and 5hmC marks in neonatal prospermatogonia. These findings
contrast with the reported scarcity of differential methylation in adult spermatogonial stem cell differentiation and
represent a unique phase of male germ cell development.

DOI： 10.1186/s12864-015-1833-5

リポジトリ公開URL： https://hdl.handle.net/2324/7326287

記述言語：英語   掲載種別：研究論文（学術雑誌）  

OBJECTIVES:　To search for schizophrenia susceptibility loci, we carried out a case-control study using 28601 microsatellite markers distributed across the entire genome.
MATERIALS AND METHODS: To control the highly multiple testing, we designed three sequential steps of screening using three independent sets of pooled samples, followed by the confirmatory step using an independent sample set (>2200 case-control pairs).
RESULTS: The first screening using pooled samples of 157 case-control pairs showed 2966 markers to be significantly associated with the disorder (P<0.05). After the second and the third screening steps using pooled samples of 150 pairs each, 374 markers remained significantly associated with the disorder. We individually genotyped all screening samples using a total of 1536 tag single nucleotide polymorphisms (SNPs) located in the vicinity of ∼200 kb from the 59 positive microsatellite markers. Of the 167 SNPs that replicated the significance, we selected 31 SNPs on the basis of the levels of P values for the confirmatory association test using an independent-sample set. The best association signal was observed in rs13404754, located in the upstream region of SLC23A3. We genotyped six additional SNPs in the vicinity of rs13404754. Significant associations were observed in rs13404754, rs6436122, and rs1043160 in the cumulative samples (2617 cases and 2698 controls) (P=0.005, 0.035, and 0.011, respectively). These SNPs are located in the linkage disequilibrium block of 20 kb in size containing SLC23A3, CNPPD1, and FAM134A genes.
CONCLUSION: Genome-wide association study using microsatellite markers suggested SLC23A3, CNPPD1, and FAM134A genes as candidates for schizophrenia susceptibility in the Japanese population.

リポジトリ公開URL： https://hdl.handle.net/2324/7326134

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Background: The glutamate receptors (GluRs) play a vital role in the mediation of excitatory synaptic transmission in the central nervous system. To clarify the evolutionary dynamics and mechanisms of the GluR genes in the lineage leading to humans, we determined the complete sequences of the coding regions and splice sites of 26 chimpanzee GluR genes.
Results: We found that all of the reading frames and splice sites of these genes reported in humans were completely conserved in chimpanzees, suggesting that there were no gross structural changes in humans after their divergence from the human-chimpanzee common ancestor. We observed low KA/KS ratios in both humans and chimpanzees, and we found no evidence of accelerated evolution. We identified 30 human-specific "fixed" amino acid substitutions in the GluR genes by analyzing 80 human samples of seven different populations worldwide. Grantham's distance analysis showed that GRIN2C and GRIN3A are the most and the second most diverged GluR genes between humans and chimpanzees. However, most of the substitutions are non-radical and are not clustered in any particular region. Protein motif analysis assigned 11 out of these 30 substitutions to functional regions. Two out of these 11 substitutions, D71G in GRIN3A and R727H in GRIN3B, caused differences in the functional assignments of these genes between humans and other apes.
Conclusion: We conclude that the GluR genes did not undergo drastic changes such as accelerated evolution in the human lineage after the divergence of chimpanzees. However, there remains a possibility that two human-specific "fixed" amino acid substitutions, D71G in GRIN3A and R727H in GRIN3B, are related to human-specific brain function.

その他リンク： http://www.biomedcentral.com/1471-2148/9/224

リポジトリ公開URL： https://hdl.handle.net/2324/7326101

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Based on the hypothesis that a glutamatergic dysfunction is involved in the pathophysiology of schizophrenia, we have been conducting systematic studies on the association between glutamate receptor genes and schizophrenia. Here we report association studies of schizophrenia with polymorphisms in group III metabotropic glutamate receptor genes, GRM4 and GRM7. We selected 8 and 43 common SNPs distributed in the entire gene regions of GRM4 (> 111 kb) and GRM7 (> 900 kb), respectively. We scanned significant associations with schizophrenia using 100 case-control pairs of Japanese. We identified two neighboring SNPs (rs12491620 and rs1450099) in GRM7 showing highly significant haplotype association with schizophrenia surviving the FDR correction. We then performed additional typing of the two SNPs using the expanded sample set (404 cases and 420 controls) and confirmed the significant association with the disease. We conclude that at least one susceptibility locus for schizophrenia is located within or nearby GRM7, whereas GRM4 is unlikely to be a major susceptibility gene for schizophrenia in the Japanese population.

リポジトリ公開URL： https://hdl.handle.net/2324/7326099

記述言語：英語   掲載種別：研究論文（学術雑誌）  

On the basis of the glutamatergic dysfunction hypothesis of schizophrenia, we have been conducting a systematic study of the association of glutamate receptor genes with schizophrenia. Here we report association studies of schizophrenia with polymorphisms in three kainate receptor genes: GRIK3, GRIK4 and GRIK5. We selected 16, 24 and 5 common single nucleotide polymorphisms (SNPs) distributed in the entire gene regions of GRIK3 (N240 kb), GRIK4 (N430 kb) and GRIK5 (N90 kb), respectively. We tested associations of the polymorphisms with schizophrenia using 100 Japanese case–control pairs (the Kyushu set). We observed no significant bsingle markerQ associations with the disease in any of the 45 SNPs tested except for one (rs3767092) in GRIK3 showing a nominal level of significance. The significant association, however, disappeared after the application of the Bonferroni correction. We also observed significant haplotype associations in seven SNP pairs in GRIK3 and in four SNP pairs in GRIK4. None, however, remained significant after Bonferroni correction. We also failed to replicate the nominally significant haplotype associations in a second sample set, the Aichi set (106 cases and 100 controls). We conclude that SNPs in the gene regions of GRIK3, GRIK4 or GRIK5 do not play a major role in schizophrenia pathogenesis in the Japanese population.

リポジトリ公開URL： https://hdl.handle.net/2324/7326035

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Objectives: The glutamatergic dysfunction is one of the main hypotheses for the pathophysiology of schizophrenia. N-methyl-D-aspartate receptors are of major interest because phencyclidine, a non-competitive antagonist of N-methyl-D-aspartate receptors, produces a schizophrenia-like psychosis. Therefore, the genes encoding N-methyl-D-aspartate receptor subunits are strong candidates for schizophrenia susceptibility genes. We focused on the N-methyl-D-aspartate receptor subunit NR2D gene in the case-control study of schizophrenia.

Methods: We screened for polymorphisms in exons, exon-intron boundaries and the 5' upstream region of GRIN2D by direct sequencing in 32 Japanese patients. Out of the total 13 single-nucleotide polymorphisms identified, we genotyped 200-201 Japanese patients and 219-221 controls for nine common single-nucleotide polymorphisms (minor allele frequency over 0.05).

Results: None of the nine single-nucleotide polymorphisms showed significant differences in genotype and allele frequencies between cases and controls. We observed significant associations of pairwise haplotypes in three combinations of four single-nucleotide polymorphisms, INT10SNP-EX13SNP2, EX13SNP2-EX13SNP3 and EX6SNP-EX13SNP2, with the disease even after the Bonferroni correction (P=1.094 x 10(-6), Pcorrected=2.297 x 10(-5), P=2.825 x 10(-6), Pcorrected=5.933 x 10(-5) and P=2.02 x 10(-4), Pcorrected=4.242 x 10(-3), respectively). The same results were also obtained using the false discovery rate (BL) method at the threshold P value, 2.908 x 10(-3).

Conclusions: We conclude that the GRIN2D locus is a possible genomic region contributing to schizophrenia susceptibility in the Japanese population.

DOI： 10.1097/00041444-200509000-00014

リポジトリ公開URL： https://hdl.handle.net/2324/7325996

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Background: The glutamatergic dysfunction hypothesis of schizophrenia suggests that genes involved in glutametergic transmission are candidates for schizophrenic susceptibility genes. We have been performing systematic association studies of schizophrenia with the glutamate receptor and transporter genes. In this study we report an association study of the excitatory amino acid transporter 2 gene, SLC1A2 with schizophrenia.
Methods: We genotyped 100 Japanese schizophrenics and 100 controls recruited from the Kyushu area for 11 single nucleotide polymorphism (SNP) markers distributed in the SLC1A2 region using the direct sequencing and pyrosequencing methods, and examined allele, genotype and haplotype association with schizophrenia.The positive finding observed in the Kyushu samples was re-examined using 100 Japanese schizophrenics and 100 controls recruited from the Aichi area.
Results: We found significant differences in genotype and allele frequencies of SNP2 between cases and controls (P = 0.013 and 0.008, respectively). After Bonferroni corrections, the two significant differences disappeared. We tested haplotype associations for all possible combinations of SNP pairs. SNP2 showed significant haplotype associations with the disease (P = 9.4 × 10-5, P = 0.0052 with Bonferroni correction, at the lowest) in 8 combinations. Moreover, the significant haplotype association of SNP2-SNP7 was replicated in the cumulative analysis of our two sample sets.
Conclusion: We concluded that at least one susceptibility locus for schizophrenia is probably located within or nearby SLC1A2 in the Japanese population.

DOI： 10.1186/1471-244X-4-21

リポジトリ公開URL： https://hdl.handle.net/2324/7325989

記述言語：英語   掲載種別：研究論文（学術雑誌）  

The glutamatergic dysfunction has been im- plicated in pathophysiology of schizophre- nia. The Group III metabotropic glutamate receptor 4 (mGluR4), 6, 7, and 8 are thought to modulate glutamatergic transmission in the brain by inhibiting glutamate release at the synapse. We tested association of schi- zophrenia with GRM8 using 22 single nucleo- tide polymorphisms (SNPs) with the average intervals of 40.3 kb in the GRM8 region in 100 case-control pairs for the SNPs. Although we observed significant associations of schizo- phrenia with two SNPs, SNP18 (rs2237748, allele: P1⁄40.0279; genotype: P1⁄40.0124) and SNP19 (rs2299472, allele: P 1⁄4 0.0302; geno- type: P1⁄40.0127), none of two SNPs showed significant association with disease after Bonferroni correction. Both SNP18 and SNP19 were included in a large region (>330 kb) in which SNPs are in linkage dis- equilibrium (LD) at the 30 region of GRM8. We also tested haplotype association of schizo- phrenia with constructed haplotypes of the SNPs in LD. Significant associations were detected for the combinations of SNP5-SNP6 (x2 1⁄4 18.12, df 1⁄4 3, P 1⁄4 0.0004, P corr 1⁄4 0.0924 with Bonferroni correction), SNP4-SNP5-

DOI： 10.1002/ajmg.b.20108

リポジトリ公開URL： https://hdl.handle.net/2324/7325980

記述言語：英語   掲載種別：研究論文（学術雑誌）  

To determine if there are common genes that contribute to the susceptibility for schizophrenia, first-stage genome-wide scan was carried out by genotyping 417 short-tandem repeat (STR) markers in 338 individuals from 130 families with 148 affected sib-pairs identified at 16 sites nationwide in Japan. Data was from the Japanese Schizophrenia Sib-pair Linkage Group (JSSLG), which is a multi-site collaborative study group established to create a national resource for genetic studies of schizophrenia in Japan. All subjects were Japanese, and the probands and their siblings had schizophrenia. Multipoint non-parametric linkage analysis and exclusion mapping were performed with GENEHUNTER software. Simulation studies suggested that in the absence of linkage we could expect one multipoint maximum LOD score (MLS) of 1.9 per genome scan. An MLS of 3.7 would be expected only once in every 20 genome scans and thus corresponds to a genome-wide significance of 0.05. No loci in the initial screen fulfilled the criteria for significant or suggestive evidence for linkage. Ten chromosomes (1, 2, 3, 4, 5, 8, 9, 14, 17, and 20) had at least one region with a nominal P value < 0.05. Susceptibility genes with lambdas of 3 and 2 were excluded from 98 and 70% of the genome, respectively. Our results suggest that common genes that contribute significantly to susceptibility for schizophrenia are unlikely to exist in the Japanese population.

DOI： 10.1002/ajmg.b.20022

リポジトリ公開URL： https://hdl.handle.net/2324/7331663

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Objectives: Glutamatergic dysfunction is one of the major hypotheses of schizophrenia pathophysiology. We have been conducting systematic studies on the association between glutamate receptors and schizophrenia. We focused on the metabotropic glutamate receptor type 3 gene (GRM3) as a candidate for schizophrenia susceptibility.

Methods: We genotyped Japanese schizophrenics (n=100) and controls (n=100) for six single nucleotide polymorphisms (SNPs) located in the GRM3 region at intervals of approximately 50 kb. Statistical differences in genotype, allele and haplotype frequencies between cases and controls were evaluated by the chi2 test and Fisher's exact probability test at a significance level of 0.05. Haplotype frequencies were estimated by the EM algorithm.

Results: A case-control association study identified a significant difference in allele frequency distribution of a SNP, rs1468412, between schizophrenics and controls (P=0.011). We also observed significant differences in haplotype frequencies estimated from SNP frequencies between schizophrenics and controls. The haplotype constructed from three SNPs, including rs1468412, showed a significant association with schizophrenia (P=8.30 x 10-4).

Conclusions: Our data indicate that at least one susceptibility locus for schizophrenia is situated within or very close to the GRM3 region in the Japanese patients.

DOI： 10.1097/01.ypg.0000056682.82896.b0

リポジトリ公開URL： https://hdl.handle.net/2324/7325979

記述言語：英語   掲載種別：研究論文（学術雑誌）  

The glutamatergic dysfunction hypothesis suggests that genes involved in the glutamate neurotransmitter system are candidates for schizophrenia-susceptibility genes. We have been conducting systematic studies of the association between glutamate receptors and schizophrenia. We report on a positive association of some haplotypes of the AMPA receptor subunit GluR4 gene (GRIA4) with schizophrenia. We genotyped 100 Japanese schizophrenics and 100 controls for six single nucleotide polymorphism (SNP) markers distributed at intervals of about 50 kb in the GRIA4 region, and estimated the degree of linkage disequilibrium (LD) between the SNPs. We constructed haplotypes of the SNPs in LD using the EM algorithm to test their association with schizophrenia. Significant associations were detected for the combination of SNP4-5 (chi(2) = 12.54, df = 3, P = 0.0057, P = 0.029 with Bonferroni correction) and for the combination of SNP3-4-5 (chi(2) = 18.9, df = 7, P = 0.0085, P = 0.043 with Bonferroni correction). These results suggest that at least one susceptibility locus for schizophrenia is located within or very close to the GRIA4 region in Japanese.

DOI： 10.1002/ajmg.b.10041

リポジトリ公開URL： https://hdl.handle.net/2324/7325942

記述言語：英語   掲載種別：研究論文（学術雑誌）  

The glutamatergic dysfunction hypothesis of schizophrenia suggests genes involved in glutamatergic transmission as candidates for schizophrenia-susceptibility genes. The GluR6 kainate receptor gene GRIK2 is located on chromosome 6q16.3-q21, a schizophrenia susceptibility region, as suggested by multiple linkage studies. We examined 15 SNPs evenly distributed in the entire GRIK2 region (>700 kb) in Japanese patients with schizophrenia (n=100) and controls (n=100). Neither genotype nor allele frequency showed a significant association with the disorder. We constructed 2-SNP haplotypes from the 15 SNPs. Although we observed three long linkage disequilibrium blocks (>150 kb) within the GRIK2 region, none of the pairwise haplotypes showed a significant association with the disorder. Therefore, we conclude that GRIK2 does not play a major role in the pathogenesis of schizophrenia in the Japanese population.

DOI： 10.1016/S0165-1781(02)00231-7

リポジトリ公開URL： https://hdl.handle.net/2324/7325941

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Dysfunction of the gene for the NR1 subunit of the N-methyl-D-aspartate (NMDA) receptor (GRIN1) has been implicated in the pathogenesis of schizophrenia. In support of this hypothesis are behavioral abnormalities reminiscent of schizophrenia in mice with an attenuated expression of the NR1 subunit receptor and the reduced level of NR1 mRNA in postmortem brains of patients with schizophrenia. We screened single nucleotide polymorphisms (SNPs) in the upstream region between +51 and -941 from the translation initiation codon of GRIN1 and identified 17 SNPs, 10 of which were located within the region containing the Sp1 motif and the GSG motifs. As genotyping of 191-196 Japanese patients with schizophrenia and 202-216 controls revealed no significant association between schizophrenia and the SNPs in the upstream region of GRIN1, these SNPs apparently do not play a critical role in the pathogenesis of schizophrenia in the Japanese population.

DOI： 10.1016/S0920-9964(02)00161-5

リポジトリ公開URL： https://hdl.handle.net/2324/7325940

記述言語：英語   掲載種別：研究論文（学術雑誌）  

The glutamatergic dysfunction hypothesis suggests genes involved in glutamatergic transmission as candidates for schizophrenia susceptibility genes. We screened single nucleotide polymorphisms (SNPs) in the entire coding sequence of the GluR5 kainate receptor gene, GRIK1, by polymerase chain reaction-single strand conformation polymorphism and direct sequencing. We identified six SNPs including three known ones, 522A/C (174T, synonymous), 1173C/T (391D, synonymous), and 2705C/T (902L/S), as well as three novel ones, 995C/T (332A/V), 2400C/T (800L, synonymous), and 2585A/G (862R/Q). We genotyped Japanese samples of schizophrenia (n = 193-203) and healthy controls (n = 199-215) for three SNPs those were commonly observed in our samples, 522A/C, 1173C/T, and 2705C/T. We observed no significant associations of the SNPs and their haplotypes with schizophrenia. Therefore, we conclude that GRIK1 does not play a major role in schizophrenia pathogenesis in the Japanese population.

DOI： 10.1097/00041444-200109000-00005

リポジトリ公開URL： https://hdl.handle.net/2324/7325705

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Human ataxin-2 contains a polyglutamine repeat that is expanded in patients with spinocerebellar ataxia type 2 (SCA2). Ataxin-2 is highly conserved in evolution with orthologs in mouse, Caenorhabditis elegans, and Drosophila melanogaster. It interacts at its C-terminus with ataxin-2 binding protein 1, A2BP1. This study presents a highly conserved mouse ortholog of A2BP1, designated A2bp1. The amino acid sequence of the human and mouse protein is 97.6% identical. This remarkable degree of conservation supports the fact that these proteins have an important basic function in development and differentiation. Sequence analysis reveals the existence of RNA binding motifs. The A2bp1 transcript was found in various regions of the CNS including cerebellum, cerebral cortex, brain stem, and thalamus/hypothalamus. The A2bp1 protein was detected by immunocytochemistry in the CNS and connective tissue of the mouse embryo starting at stage E11, as well as in the heart at all stages. Mouse embryos showed varying expression of A2bp1 at all stages. Previous studies in other model systems had implicated the orthologs of ataxin-2 and A2BP1 in development. This study suggests a role for A2bp1 in embryogenesis as well as in the adult nervous system, possibly mediated by a function in RNA distribution or processing.

リポジトリ公開URL： https://hdl.handle.net/2324/7325704

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Spinocerebellar ataxia type 2 (SCA2) is caused by expansion of a polyglutamine tract in ataxin-2, a protein of unknown function. Using the yeast two- hybrid system, we identified a novel protein, A2BP1 (ataxin-2 binding protein 1) which binds to the C- terminus of ataxin-2. Northern blot analysis showed that A2BP1 was predominantly expressed in muscle and brain. By immunocfluorescent staining, A2BP1 and ataxin-2 were both localized to the trans-Golgi network. Immunocytochemistry showed that A2BP1 was expressed in the cytoplasm of Purkinje cells and dentate neurons in a pattern similar to that seen for ataxin-2 labeling. Western blot analysis of subcel- lular fractions indicated enrichment of A2BP1 in the same fractions as ataxin-2. Sequence analysis of the A2BP1 cDNA revealed an RNP motif that is highly conserved among RNA-binding proteins. A2BP1 had striking homology with a human cDNA clone, P83A20, of unknown function and at least two copies of A2BP1 homologs are found in the Caenorhabditis elegans genome database. A2BP1 and related proteins appear to form a novel gene family sharing RNA-binding motifs.

リポジトリ公開URL： https://hdl.handle.net/2324/7325619

記述言語：英語   掲載種別：研究論文（学術雑誌）  

We show that RNA can serve as a primer in PCR. Use of rTth DNA polymerase is essential because it has strong reverse transcriptase activity. RNA primers can be obtained by in vitro transcription and are less costly than DNA primers, which are chemically synthesized. RNA-primed PCR also opens the possibility that a specific amplification reaction can be achieved in the absence of knowledge of the target nucleotide sequence.

DOI： 10.1101/gr.5.4.400

リポジトリ公開URL： https://hdl.handle.net/2324/7178542

記述言語：英語   掲載種別：研究論文（学術雑誌）  

From the analysisof restriction maps of the Amy region in eight sibling species belonging to the
Drosophilamelanogaster species subgroup, we herein show that the patterns of duplication of the Amy gene are almost the same in all species. Thisindicates that duplication occurred before speciation within this species subgroup. From the nucleotide sequence data, we show a strong within-species similarity between the duplicated loci in the Amy coding region. This is in contrast to a strong similarity in the 5’ and 3‘ flanking regions within each locus (proximal or distal) throughout the species subgroup. This means that concerted evolution occurred only in the Amy coding region and that differentiated evolution between the duplication occurred in the flanking regions. Moreover, when comparing the species, we also found a significant excess of nonsynonymous substitutions.In particular, all the fixed substitutions specific to D.erecta were found to be nonsynonymous. We thus conclude that adaptive protein evolution occurred in the lineage of D. erecta that is a “specialist” species for host plants and probably also occurs in the process of speciation in general.

リポジトリ公開URL： https://hdl.handle.net/2324/7178541

記述言語：英語   出版者・発行元：Journal of Human Genetics  

Hereditary spinocerebellar ataxia (SCA) is a group of clinically and genetically heterogeneous inherited disorders characterized by slowly progressive cerebellar ataxia. We ascertained a Japanese pedigree with autosomal dominant SCA comprising four family members, including two patients. We identified a GGCCTG repeat expansion of intron 1 in the NOP56 gene by Southern blotting, resulting in a molecular diagnosis of SCA36. RNA sequencing using peripheral blood revealed that the expression of genes involved in ribosomal organization and translation was decreased in patients carrying the GGCCTG repeat expansion. Genes involved in pathways associated with ribosomal organization and translation were enriched and differentially expressed in the patients. We propose a novel hypothesis that the GGCCTG repeat expansion contributes to the pathogenesis of SCA36 by causing a global disruption of translation resulting from ribosomal dysfunction.

DOI： 10.1038/s10038-024-01260-7

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記述言語：英語   出版者・発行元：Scientific Reports  

Although previous studies have reported that pre-mRNA splicing factors (SFs) are involved in the repair of DNA double-strand breaks (DSBs) via homologous recombination (HR), their exact role in promoting HR remains poorly understood. Here, we showed that SART1, an SF upregulated in several types of cancer, promotes DSB end resection, an essential first step of HR. The resection-promoting function of SART1 requires phosphorylation at threonine 430 and 695 by ATM/ATR. SART1 is recruited to DSB sites in a manner dependent on transcription and its RS domain. SART1 is epistatic with BRCA1, a major HR factor, in the promotion of resection, especially transcription-associated resection in the G2 phase. SART1 and BRCA1 accumulate at DSB sites in an interdependent manner, and epistatically counteract the resection blockade posed by 53BP1 and RIF1. Furthermore, chromosome analysis demonstrated that SART1 and BRCA1 epistatically suppressed genomic alterations caused by DSB misrepair in the G2 phase. Collectively, these results indicate that SART1 and BRCA1 cooperatively facilitate resection of DSBs arising in transcriptionally active genomic regions in the G2 phase, thereby promoting faithful repair by HR, and suppressing genome instability.

DOI： 10.1038/s41598-024-68926-2

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記述言語：英語   出版者・発行元：(一社)日本腎臓学会  

記述言語：英語   出版者・発行元：Human Genome Variation  

Autosomal dominant episodic ataxia type 2 (EA2) is caused by variants in CACNA1A. We examined a 20-year-old male with EA symptoms from a Japanese family with hereditary EA. Cerebellar atrophy was not evident, but single photon emission computed tomography showed cerebellar hypoperfusion. We identified a novel nonsynonymous variant in CACNA1A, NM_001127222.2:c.1805T>G (p.Leu602Arg), which is predicted to be functionally deleterious; therefore, this variant is likely responsible for EA2 in this pedigree.

DOI： 10.1038/s41439-023-00261-w

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Autosomal dominant episodic ataxia type 2 (EA2) is caused by variants in CACNA1A. We examined a 20-year-old male with EA symptoms from a Japanese family with hereditary EA. Cerebellar atrophy was not evident, but single photon emission computed tomography showed cerebellar hypoperfusion. We identified a novel nonsynonymous variant in CACNA1A, NM_001127222.2:c.1805T>G (p.Leu602Arg), which is predicted to be functionally deleterious; therefore, this variant is likely
responsible for EA2 in this pedigree.

DOI： doi: 10.1038/s41439-023-00261-w.

その他リンク： https://www.frontiersin.org/articles/10.3389/fgene.2023.1155998/full

記述言語：英語   出版者・発行元：Nature Publishing Group  

反復発作性運動失調症(EA)2型患者のCACNA1A遺伝子から、新規の非同義変異が認められたため報告する。症例は20歳の日本人男性で、小児期から短時間で消失する運動失調を認め、典型的なEA2表現型を呈していた。また、母親と母方の祖父も20歳時まで同様の運動失調症状が認められ、16歳の弟と9歳の妹も同様の運動失調症状を呈していた。なお、画像所見では脳MRIでは明らかな小脳萎縮が確認できなかったが、脳SPECTにより小脳と脳幹および外側後頭葉で血流量の低下が観察された。エクソームシーケンシングにより、患者のCACNA1A遺伝子から新規のヘテロ接合性非同義変異c.1805T>G;p.Leu602Argが同定され、Sangerシーケンシングにより確認された。なお、本変異は機能的に有害と予測され、ACMG/AMP/CAPガイドラインによりlikely pathogenicに分類された。本例から、患者がEA症状を主訴とする際に脳MRIで小脳萎縮が認められなくても、脳SPECTで小脳の血流量低下を精査することが推奨された。

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Background The intestinal microbiome is involved in the pathogenesis of chronic kidney disease (CKD). Despite its impor- tance, the microbiome of the small intestinal mucosa has been little studied due to sampling difficulties, and previous studies have mainly focused on fecal sources for microbiome studies. We aimed to characterize the small intestinal microbiome of CKD patients by studying the microbiome collected from duodenal and fecal samples of CKD patients and healthy controls. Methods Overall, 28 stage 5 CKD patients and 21 healthy participants were enrolled. Mucosal samples were collected from the deep duodenum during esophagogastroduodenoscopy and fecal samples were also collected. The 16S ribosomal RNA gene sequencing using Qiime2 was used to investigate and compare the microbial structure and metagenomic function of the duodenal and fecal microbiomes.
Results The duodenal flora of CKD patients had decreased alpha diversity compared with the control group. On the basis of taxonomic composition, Veillonella and Prevotella were significantly reduced in the duodenal flora of CKD patients. The tyrosine and tryptophan metabolic pathways were enhanced in the urea toxin-related metabolic pathways based on the Kyoto Encyclopedia of Genes and Genomes database.
Conclusion The small intestinal microbiome in CKD patients is significantly altered, indicating that increased intestinal permeability and production of uremic toxin may occur in the upper small intestine of CKD patients.

DOI： 10.1007/s10157-023-02434-x

その他リンク： https://doi.org/10.1007/s10157-023-02434-x (2023).

記述言語：英語   出版者・発行元：Frontiers in Genetics  

Frontotemporal dementia and/or amyotrophic lateral sclerosis 6, also known as amyotrophic lateral sclerosis 14, is an autosomal dominant, progressive neurodegenerative disorder caused by various mutations in the valosin-containing protein gene. In this report, we examined a 51-year-old female Japanese patient with frontotemporal dementia and amyotrophic lateral sclerosis. The patient began noticing gait disturbances at the age of 45 years. Neurological examination at the age of 46 years met the Awaji criteria for clinically probable amyotrophic lateral sclerosis. At the age of 49 years, she tended to have poor mood and an aversion to activity. Her symptoms gradually worsened. She required a wheelchair for transport and had difficulty communicating with others because of poor comprehension. She then began to frequently exhibit irritability. Eventually, she was admitted to the psychiatric hospital because uncontrollable violent behavior throughout the day. Longitudinal brain magnetic resonance imaging revealed progressive brain atrophy with temporal dominance, non-progressive cerebellar atrophy, and some non-specific white matter intensities. Brain single photon emission computed tomography showed hypoperfusion in the bilateral temporal lobes and cerebellar hemispheres. Clinical exome sequencing revealed the presence of a heterozygous nonsynonymous variant (NM_007126.5, c.265C>T; p.Arg89Trp) in the valosin-containing protein gene, which was absent in the 1000 Genomes Project, the Exome Aggregation Consortium Database, and the Genome Aggregation Database, and was predicted to be “damaging” by PolyPhen-2 and “deleterious” using SIFT with a Combined Annotation Dependent Depletion score of 35. We also confirmed the absence of this variant in 505 Japanese control subjects. Therefore, we concluded that the variant in the valosin-containing protein gene was responsible for the symptoms of this patient.

DOI： 10.3389/fgene.2023.1155998

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Frontotemporal dementia and/or amyotrophic lateral sclerosis 6, also known as amyotrophic lateral sclerosis 14, is an autosomal dominant, progressive neurodegenerative disorder caused by various mutations in the valosin- containing protein gene. In this report, we examined a 51-year-old female Japanese patient with frontotemporal dementia and amyotrophic lateral sclerosis. The patient began noticing gait disturbances at the age of 45 years. Neurological examination at the age of 46 years met the Awaji criteria for clinically probable amyotrophic lateral sclerosis. At the age of 49 years, she tended to have poor mood and an aversion to activity. Her symptoms gradually worsened. She required a wheelchair for transport and had difficulty communicating with others because of poor comprehension. She then began to frequently exhibit irritability. Eventually, she was admitted to the psychiatric hospital because uncontrollable violent behavior throughout the day. Longitudinal brain magnetic resonance imaging revealed progressive brain atrophy with temporal dominance, non- progressive cerebellar atrophy, and some non-specific white matter intensities. Brain single photon emission computed tomography showed hypoperfusion in the bilateral temporal lobes and cerebellar hemispheres. Clinical exome sequencing revealed the presence of a heterozygous nonsynonymous variant (NM_007126.5, c.265C>T; p.Arg89Trp) in the valosin-containing protein gene, which was absent in the 1000 Genomes Project, the Exome Aggregation Consortium Database, and the Genome Aggregation Database, and was predicted to be “damaging” by PolyPhen-2 and “deleterious” using SIFT with a Combined Annotation Dependent Depletion score of 35. We also confirmed the absence of this variant in 505 Japanese control subjects. Therefore, we concluded that the variant in the valosin-containing protein gene was responsible for the symptoms of this patient.

その他リンク： https://www.frontiersin.org/articles/10.3389/fgene.2023.1155998/full

リポジトリ公開URL： https://hdl.handle.net/2324/7326352

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Hereditary spastic paraplegia is a genetic neurological disorder characterized by spasticity of the lower limbs, and spastic paraplegia type 28 is one of its subtypes. Spastic paraplegia type 28 is a hereditary neurogenerative disorder with an autosomal recessive inheritance caused by loss of function of DDHD1. DDHD1 encodes phospholipase A1, which catalyzes phospholipids to lysophospholipids such as phosphatidic acids and phosphatidylinositols to lysophosphatidic acids and lysophoshatidylinositols. Quantitative changes in these phospholipids can be key to the pathogenesis of SPG28, even at subclinical levels. By lipidome analysis using plasma from mice, we globally examined phospholipids to identify molecules showing significant quantitative changes in Ddhd1 knockout mice. We then examined reproducibility of the quantitative changes in human sera including SPG28 patients. We identified nine kinds of phosphatidylinositols that show significant increases in Ddhd1 knockout mice. Of these, four kinds of phosphatidylinositols replicated the highest level in the SPG28 patient serum. All four kinds of phosphatidylinositols contained oleic acid. This observation suggests that the amount of oleic acid-containing PI was affected by loss of function of DDHD1. Our results also propose the possibility of using oleic acid-containing PI as a blood biomarker for SPG28.

その他リンク： https://www.mdpi.com/2227-9059/11/4/1092

リポジトリ公開URL： https://hdl.handle.net/2324/7329596

記述言語：英語   出版者・発行元：Biomedicines  

Hereditary spastic paraplegia is a genetic neurological disorder characterized by spasticity of the lower limbs, and spastic paraplegia type 28 is one of its subtypes. Spastic paraplegia type 28 is a hereditary neurogenerative disorder with an autosomal recessive inheritance caused by loss of function of DDHD1. DDHD1 encodes phospholipase A1, which catalyzes phospholipids to lysophospholipids such as phosphatidic acids and phosphatidylinositols to lysophosphatidic acids and lysophoshatidylinositols. Quantitative changes in these phospholipids can be key to the pathogenesis of SPG28, even at subclinical levels. By lipidome analysis using plasma from mice, we globally examined phospholipids to identify molecules showing significant quantitative changes in Ddhd1 knockout mice. We then examined reproducibility of the quantitative changes in human sera including SPG28 patients. We identified nine kinds of phosphatidylinositols that show significant increases in Ddhd1 knockout mice. Of these, four kinds of phosphatidylinositols replicated the highest level in the SPG28 patient serum. All four kinds of phosphatidylinositols contained oleic acid. This observation suggests that the amount of oleic acid-containing PI was affected by loss of function of DDHD1. Our results also propose the possibility of using oleic acid-containing PI as a blood biomarker for SPG28.

DOI： 10.3390/biomedicines11041092

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記述言語：英語   出版者・発行元：Multidisciplinary Digital Publishing Institute (MDPI)  

Background: Cardiopulmonary disorders are the most common cause of central cyanosis, and methemoglobinemia is often overlooked in the differential diagnosis of patients with central cyanosis. In most cases, methemoglobinemia is acquired and hereditary congenital methemoglobinemia is rare. Only a few case reports of congenital methemoglobinemia can be found in PubMed. To date, only four cases of congenital methemoglobinemia diagnosed after the age of 50 years have been reported. / Case Presentation: A 79-year-old Japanese woman presented at our hospital with the chief complaints of dyspnea and cyanosis. She exhibited cyanosis of the lips and extremities, and her SpO2 was 80%, with oxygen administration at 5 L/min. Blood gas analysis revealed a PaO2 of 325.4 mmHg and methemoglobin level of 36.9%. The SpO2 and PaO2 values were dissociated, and methemoglobin levels were markedly elevated. Genetic analysis revealed a nonsynonymous variant in the gene encoding nicotinamide adenine dinucleotide cytochrome (NADH) B5 reductase 3 (CYB5R3), and the patient was diagnosed with congenital methemoglobinemia. Conclusions: It is important to consider methemoglobinemia in the differential diagnosis of patients with central cyanosis. At 79 years of age, our patient represents the oldest patient with this diagnosis. This report indicates that it is crucial to consider the possibility of methemoglobinemia regardless of the patient’s age.

CiNii Research

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Background: Cardiopulmonary disorders are the most common cause of central cyanosis, and methemoglobinemia is often overlooked in the differential diagnosis of patients with central cyanosis. In most cases, methemoglobinemia is acquired and hereditary congenital methemoglobinemia is rare. Only a few case reports of congenital methemoglobinemia can be found in PubMed. To date, only four cases of congenital methemoglobinemia diagnosed after the age of 50 years have been reported. Case Presentation: A 79-year-old Japanese woman presented at our hospital with the chief complaints of dyspnea and cyanosis. She exhibited cyanosis of the lips and extremities, and her SpO2 was 80%, with oxygen administration at 5 L/min. Blood gas analysis revealed a PaO2 of 325.4 mmHg and methemoglobin level of 36.9%. The SpO2 and PaO2 values were dissociated, and methemoglobin levels were markedly elevated. Genetic analysis revealed a nonsynonymous variant in the gene encoding nicotinamide adenine dinucleotide cytochrome (NADH) B5 reductase 3 (CYB5R3), and the patient was diagnosed with congenital methemoglobinemia. Conclusions: It is important to consider methemoglobinemia in the differential diagnosis of patients with central cyanosis. At 79 years of age, our patient represents the oldest patient with this diagnosis. This report indicates that it is crucial to consider the possibility of methemoglobinemia regardless of the patient’s age.

その他リンク： https://www.mdpi.com/1648-9144/59/3/615

リポジトリ公開URL： https://hdl.handle.net/2324/7173585

記述言語：英語   出版者・発行元：Medicina (Lithuania)  

Background: Cardiopulmonary disorders are the most common cause of central cyanosis, and methemoglobinemia is often overlooked in the differential diagnosis of patients with central cyanosis. In most cases, methemoglobinemia is acquired and hereditary congenital methemoglobinemia is rare. Only a few case reports of congenital methemoglobinemia can be found in PubMed. To date, only four cases of congenital methemoglobinemia diagnosed after the age of 50 years have been reported. Case Presentation: A 79-year-old Japanese woman presented at our hospital with the chief complaints of dyspnea and cyanosis. She exhibited cyanosis of the lips and extremities, and her SpO2 was 80%, with oxygen administration at 5 L/min. Blood gas analysis revealed a PaO2 of 325.4 mmHg and methemoglobin level of 36.9%. The SpO2 and PaO2 values were dissociated, and methemoglobin levels were markedly elevated. Genetic analysis revealed a nonsynonymous variant in the gene encoding nicotinamide adenine dinucleotide cytochrome (NADH) B5 reductase 3 (CYB5R3), and the patient was diagnosed with congenital methemoglobinemia. Conclusions: It is important to consider methemoglobinemia in the differential diagnosis of patients with central cyanosis. At 79 years of age, our patient represents the oldest patient with this diagnosis. This report indicates that it is crucial to consider the possibility of methemoglobinemia regardless of the patient’s age.

DOI： 10.3390/medicina59030615

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記述言語：英語   出版者・発行元：Human Genome Variation  

Dystonia (DYT) is a heterogeneous neurological disorder, and there are many types of DYT depending on the responsible genes. DYT11 is an autosomal dominant DYT caused by functional variants in the SGCE gene. We examined a Japanese patient with myoclonic dystonia. By using exome analysis, we identified a rare variant in the SGCE gene, NM_003919.3: c.304C > T [Arg102*], in this patient. Therefore, this patient has been molecularly diagnosed with DYT11. By Sanger sequencing, we confirmed that this variant was paternally inherited in this patient. By allele-specific PCR, we confirmed that the maternally inherited normal allele of SGCE was silenced, and only the paternally inherited variant allele was expressed in this patient. Despite the pathogenicity, identical variants have been recurrently reported in eight independent families from different ethnicities, suggesting recurrent mutations at this mutational hotspot in SGCE.

DOI： 10.1038/s41439-022-00207-8

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Dystonia (DYT) is a heterogeneous neurological disorder, and there are many types of DYT depending on the responsible genes. DYT11 is an autosomal dominant DYT caused by functional variants in the SGCE gene. We examined a Japanese patient with myoclonic dystonia. By using exome analysis, we identified a rare variant in the SGCE gene, NM_003919.3: c.304C > T [Arg102*], in this patient. Therefore, this patient has been molecularly diagnosed with DYT11. By Sanger sequencing, we confirmed that this variant was paternally inherited in this patient. By allele-specific PCR, we confirmed that the maternally inherited normal allele of SGCE was silenced, and only the paternally inherited variant allele was expressed in this patient. Despite the pathogenicity, identical variants have been recurrently reported in eight independent families from different ethnicities, suggesting recurrent mutations at
this mutational hotspot in SGCE.

その他リンク： https://www.nature.com/articles/s41439-022-00207-8

リポジトリ公開URL： https://hdl.handle.net/2324/7329591

記述言語：英語   出版者・発行元：Nature Publishing Group  

SGCE遺伝子に病的変異が検出された、ミオクローヌス性ジストニア症候群の日本人症例を報告した。症例は19歳女性で、不随意運動の家族歴は有さなかったが、8歳時に右手けいれんを発症し、右手で物を把持することが困難になった。また、症状は精神的ストレスにより悪化し、徐々に左手にも症状が及んだため、クロナゼパム投与が施行された。投薬後、症状は劇的に改善され、ミオクローヌス性ジストニア症候群と診断された。また、エクソームシーケンシングを行ったところ、SGCE遺伝子に稀な変異c.304C>T[Arg102*]が同定されたため、遺伝性ジストニアDYT11と確定診断された。遺伝子解析結果から、さらに、患者と両親のSangerシーケンシングを行ったところ、これらの変異が父性遺伝であることが確認され、アレル特異的PCR法により、母性遺伝によるSGCE遺伝子の正常アレルがサイレンシングされ、父性遺伝した変異型アレルのみ発現したことが明らかにされた。なお、これらの病的変異は、民族が異なる血縁関係のない8家系にも報告されていることから、本変異はホットスポット変異による反復突然変異と考えられた。

記述言語：英語   出版者・発行元：Digestion  

Introduction: An association has been found between human-gut microbiota and various diseases (e.g., metabolic disease) by analyzing fecal or colonic microbiota. Despite the importance of the small intestinal microbiota, sampling difficulties prevent its full analysis. We investigated the composition and metagenomic functions of microbiota along the small intestine and compared them with the microbiota from feces and from other gastrointestinal (GI) sites. Methods: Mucosal samples from the six GI sites (stomach, duodenum, distal jejunum, proximal ileum, terminal ileum, and rectum) were collected under balloon-assisted enteroscopy. Fecal samples were collected from all participants. The microbial structures and metagenomic functions of the small intestinal mucosal microbiota were compared with those from feces and other GI sites using 16S ribosomal RNA gene sequencing. Results: We analyzed 133 samples from 29 participants. Microbial beta diversity analysis showed that the jejunum and ileum differed significantly from the lower GI tract and the feces (p < 0.001). Jejunal and duodenal microbiotas formed similar clusters. Wide clusters spanning the upper and lower GI tracts were observed with the ileal microbiota, which differed significantly from the jejunal microbiota (p < 0.001). Veillonella and Streptococcus were abundant in the jejunum but less so in the lower GI tract and feces. The metagenomic functions associated with nutrient metabolism differed significantly between the small intestine and the feces. Conclusions: The fact that the compositional structures of small intestinal microbiota differed from those of fecal and other GI microbiotas reveals that analyzing the small intestinal microbiota is necessary for association studies on metabolic diseases and gut microbiota.

DOI： 10.1159/000524023

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記述言語：英語   出版者・発行元：Toxins  

Genes encoding snake venom toxins have been studied extensively. However, genes involved in the modification and functioning of venom proteins are little known. Protobothrops is a genus of pit vipers, which are venomous and inhabit the Nansei (Southwest) islands of Japan, Tai-wan China, Vietnam, Thailand, Myanmar, Nepal, Bhutan, and India. Our previous study decoded the genome of Protobothrops flavoviridis, a species endemic to the Nansei Islands, Japan, and revealed unique evolutionary processes of some venom genes. In this study, we analyzed genes that are highly expressed in venom glands to survey genes for candidate enzymes or chaperone proteins involved in toxin folding and modification. We found that, in addition to genes that encode venom proteins and ribosomal proteins, genes that encode protein disulfide isomerase (PDI) family members (orthologs of human P4HB and PDIA3), Selenoprotein M (SELENOM), and Calreticulin (CALR) are highly expressed in venom glands. Since these enzymes or chaperones are involved in protein modification and potentially possess protein folding functions, we propose that P4HB, SELENOM, CALR, and PDIA3 encode candidate enzymes or chaperones to confer toxic functions upon the venom transcriptome.

DOI： 10.3390/toxins14050300

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Introduction: An association has been found between human-gut microbiota and various diseases (e.g., metabolic disease) by analyzing fecal or colonic microbiota. Despite the importance of the small intestinal microbiota, sampling difficulties prevent its full analysis. We investigated the composition and metagenomic functions of microbiota along the small intestine and compared them with the microbiota from feces and from other gastrointestinal (GI) sites. Methods: Mucosal samples from the six GI sites (stomach, duodenum, distal jejunum, proximal ileum, terminal ileum, and rectum) were collected under balloon-assisted enteroscopy. Fecal samples were collected from all participants. The microbial structures and metagenomic functions of the small intestinal mucosal microbiota were compared with those from feces and other GI sites using 16S ribosomal RNA gene sequencing. Results: We analyzed 133 samples from 29 participants. Microbial beta diversity analysis showed that the jejunum and ileum differed significantly from the lower GI tract and the feces (p < 0.001). Jejunal and duodenal microbiotas formed similar clusters. Wide clusters spanning the upper and lower GI tracts were observed with the ileal microbiota, which differed significantly from the jejunal microbiota (p < 0.001). Veillonella and Streptococcus were abundant in the jejunum but less so in the lower GI tract and feces. The metagenomic functions associated with nutrient metabolism differed significantly between the small intestine and the feces. Conclusions: The fact that the compositional structures of small intestinal microbiota differed from those of fecal and other GI microbiotas reveals that analyzing the small intestinal microbiota is necessary for association studies on metabolic diseases and gut microbiota.

リポジトリ公開URL： https://hdl.handle.net/2324/7329584

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Background/Aims: Recent studies suggested a favorable effect of indigo naturalis (IN) in inducing remission for refractory ul- cerative colitis (UC), however, the maintenance effect of IN for patients with UC remains unknown. Therefore, we conducted a prospective uncontrolled open-label study to analyze the efficacy and safety of IN for patients with UC. Methods: Patients with moderate to severe active UC (clinical activity index [CAI] ≥ 8) took 2 g/day of IN for 52 weeks. CAI at weeks 0, 4, 8, and 52 and Mayo endoscopic subscore (MES) and Geboes score (GS) at weeks 0, 4, and 52 were assessed. Clinical remission (CAI ≤ 4), mucosal healing (MES ≤ 1), and histological healing (GS ≤ 1) rates at each assessment were evaluated. Overall adverse events (AEs) during study period were also evaluated. The impact of IN on mucosal microbial composition was assessed using 16S ribosomal RNA gene sequences. Results: Thirty-three patients were enrolled. The rates of clinical remission at weeks 4, 8, and 52 were 67%, 76%, and 73%, respectively. The rates of mucosal healing at weeks 4 and 52 were 48% and 70%, respectively. AEs occurred in 17 patients (51.5%) during follow-up. Four patients (12.1%) showed severe AEs, among whom 3 manifested acute colitis. No significant alteration in the mucosal microbial composition was observed with IN treatment. Conclusions: One-year treatment of moderate to severe UC with IN was effective. IN might be a promising therapeutic option for maintaining remis- sion in UC, although the relatively high rate of AEs should be considered. (Intest Res 2022;20:260-268)

リポジトリ公開URL： https://hdl.handle.net/2324/7161613

記述言語：英語   出版者・発行元：Intestinal Research  

Background/Aims: Recent studies suggested a favorable effect of indigo naturalis (IN) in inducing remission for refractory ulcerative colitis (UC), however, the maintenance effect of IN for patients with UC remains unknown. Therefore, we conducted a prospective uncontrolled open-label study to analyze the efficacy and safety of IN for patients with UC. Methods: Patients with moderate to severe active UC (clinical activity index [CAI] ≥ 8) took 2 g/day of IN for 52 weeks. CAI at weeks 0, 4, 8, and 52 and Mayo endoscopic subscore (MES) and Geboes score (GS) at weeks 0, 4, and 52 were assessed. Clinical remission (CAI ≤ 4), mucosal healing (MES ≤ 1), and histological healing (GS ≤ 1) rates at each assessment were evaluated. Overall adverse events (AEs) during study period were also evaluated. The impact of IN on mucosal microbial composition was assessed using 16S ribosomal RNA gene sequences. Results: Thirty-three patients were enrolled. The rates of clinical remission at weeks 4, 8, and 52 were 67%, 76%, and 73%, respectively. The rates of mucosal healing at weeks 4 and 52 were 48% and 70%, respectively. AEs occurred in 17 patients (51.5%) during follow-up. Four patients (12.1%) showed severe AEs, among whom 3 manifested acute colitis. No significant alteration in the mucosal microbial composition was observed with IN treatment. Conclusions: One-year treatment of moderate to severe UC with IN was effective. IN might be a promising therapeutic option for maintaining remission in UC, although the relatively high rate of AEs should be considered. (Intest Res 2022;20:260-268

DOI： 10.5217/ir.2021.00124

Web of Science

Scopus

PubMed

記述言語：日本語   掲載種別：研究論文（大学，研究機関等紀要）  

リポジトリ公開URL： https://hdl.handle.net/2324/7329783

記述言語：英語   出版者・発行元：Nature Publishing Group  

広島県に居住する日本人親子からDAG1遺伝子の新規変異が検出され、無症候性(特発性)高クレアチンキナーゼ血症(ASCK)が認められたため報告した。家族構成は両親と14歳と10歳の男児2人と発端者の11歳女児1人の5人家族で、父親ときょうだい3人から血清中CK高値が認められたが、明確な神経学的異常はみられなかった。次に、発端者である長女と次男の弟について、全エクソームシークエンシングとSangerシークエンシングを行ったところ、DAG1遺伝子のエクソン3領域に、新規の1bp欠失変異c.930delC:p.R311Gfs*70が共通して同定された。これらの変異により、コドン477領域で未成熟な翻訳終止が生じ、必須となるDAG1ドメインが完全に欠如したタンパク質産生が惹起されたと推測された。なお、本例で認められたDAG1遺伝子の新規の1塩基欠失変異は、ASCKの顕性遺伝(優性遺伝)による病原性変異と推測された。

記述言語：英語  

DOI： 10.1038/s41439-022-00182-0

Web of Science

PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Asymptomatic hyper-CK-emia (ASCK) is characterized by persistent elevation of creatine kinase (CK) in serum without any neurological symptoms. We ascertained a two-generation family of ASCK patients without clear neurological abnormalities except for the high levels of serum CK (810.5 ± 522.4 U/L). We identified a novel 1-bp deletion variant in the DAG1 gene shared by the patients in the family (NM_001177639: exon 3: c.930delC:p.R311Gfs*70). The variant causes premature termination of translation at codon 477, resulting in a protein product completely devoid of the essential DAG1 domain. Since ASCK has been associated with DAG1 in only one case carrying compound heterozygous missense variants, our new finding of a novel 1-bp deletion revealed the previously unknown dominant effect of DAG1 on ASCK.

リポジトリ公開URL： https://hdl.handle.net/2324/7329583

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Objective. Adenoid cystic carcinoma (AdCC) is a rare, indolent salivary gland tumor that is reported to be driven by fusion genes. However, MYB/MYBL1-NFIB fusions have been detected in only <60% of all AdCC cases and the oncogenic driver mutations in approximately 40% of AdCC remain unknown. Our aim was to identify novel gene fusions in AdCC.
Study Design. We investigated 20 AdCC cases using a targeted RNA-sequencing panel to identify gene fusions and performed qRT-PCR to assess MYB, MYBL1, and NFIB expression levels.
Results. A total of 36 fusion transcripts in 15 cases were detected and validated by Sanger sequencing. The MYB-NFIB and MYBL1-NFIB fusion genes were detected in nine and three cases, respectively, in a mutually exclusive manner. Furthermore, novel gene fusions, namely NFIB-EPB41L2, MAP7-NFIB, NFIB-MCMDC2, MYBL1-C8orf34, C8orf34-NFIB, and NFIB-CASC20, were identified. Among them, NFIB-EPB41L2 and NFIB-MCMDC2 are thought to activate MYB and MYBL1 expression, respectively, through the insertion of a genomic segment in proximity to MYB and MYBL1 genes, respectively.

リポジトリ公開URL： https://hdl.handle.net/2324/7329580

記述言語：英語   掲載種別：研究論文（学術雑誌）  

To investigate the mucosal microbiota in the stomach of patients with Helicobacter pylori-negative mucosa-associated lymphoid tissue (MALT) lymphoma by means of metagenomic analysis.
Although some gastric MALT lymphomas are associated with the presence of H. pylori, other gastric MALT lymphomas occur independently of H. pylori infection. The pathogenesis of H. pylori-negative MALT lymphoma remains unclear.
Mucosal biopsy specimens were collected from the gastric body from 33 MALT lymphoma patients with gastric lesions, including both H. pylori-infection naïve patients and posteradication patients, as well as 27 control participants without H. pylori infection or cancer. Subsequently, the samples were subjected to 16S rRNA gene sequencing. Quantitative insights into microbial ecology, linear discriminant analysis effect size, and phylogenetic investigation of communities by reconstruction of unobserved states softwares were used to analyze the participants’ microbiota.
H. pylori-negative MALT lymphoma patients had significantly lower alpha diversity (P = .04), compared with control participants. Significant differences were evident in the microbial composition (P = .04), as determined by comparison of beta diversity between the 2 groups. Taxonomic composition analysis indicated that the genera Burkholderia and Sphingomonas were significantly more abundant in MALT lymphoma patients, while the genera Prevotella and Veillonella were less abundant. Functional microbiota prediction showed that the predicted gene pathways “replication and repair,” “translation,” and “nucleotide metabolism” were downregulated in MALT lymphoma patients.
H. pylori-negative MALT lymphoma patients exhibited altered gastric mucosal microbial compositions, suggesting that altered microbiota might be involved in the pathogenesis of H. pylori-negative MALT lymphoma.

リポジトリ公開URL： https://hdl.handle.net/2324/7329577

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Spastic paraplegia (SPG) type 4 is an autosomal dominant SPG caused by functional variants in the SPAST gene. We examined a Japanese family with three autosomal dominant SPG patients. These patients presented with typical symptoms of SPG, such as spasticity of the lower limbs. We identified a rare nonsynonymous variant, NM_014946.4: c.1252G>A [p.Glu418Lys], in all three family members. This variant has previously been reported in a Russian SPG family as a “likely pathogenic” variant. Ascertainment of additional patients carrying this variant in an unrelated Japanese SPG family further supports its pathogenicity. Molecular diagnosis of SPG4 in this family with hereditary spastic paraplegia is confirmed.

リポジトリ公開URL： https://hdl.handle.net/2324/7329574

記述言語：英語   掲載種別：研究論文（学術雑誌）  

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.

リポジトリ公開URL： https://hdl.handle.net/2324/7329620

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Because the pathogenesis of gastrointestinal follicular lymphoma (GI-FL) remains unclear, no standardized treatment strategy has been established. Of the gastrointes- tinal lymphomas, gastric mucosa-associated lymphoid tissue lymphomas are strongly associated with Helicobacter pylori; hence, the microbiota may be involved in GI-FL pathogenesis. However, the association between GI-FL and the microbiota remains uninvestigated. Therefore, we compared the mucosal microbiotas of GI-FL patients with those of controls to identify microbiota changes in GI-FL patients. Mucosal biopsy sam- ples were obtained from the second portion of the duodenum from 20 GI-FL patients with duodenal lesions and 20 controls. Subsequent 16S rRNA gene sequencing was per- formed on these samples. QIIME pipeline and LEfSe software were used to analyze the microbiota. The GI-FL patients had significantly lower alpha diversity (P = .049) than did the controls, with significant differences in the microbial composition (P = .023) evalu- ated by the beta diversity metrics between the two groups. Comparing the taxonomic compositions indicated that the genera Sporomusa, Rothia, and Prevotella and the family Gemellaceae were significantly less abundant in the GI-FL patients than in the controls. GI-FL patients presented altered duodenal mucosal microbial compositions, suggesting that the microbiota might be involved in the GI-FL pathogenesis.

リポジトリ公開URL： https://hdl.handle.net/2324/7329565

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Small serum proteins (SSPs) are low-molecular-weight proteins in snake serum with affinities for various venom proteins. Five SSPs, PfSSP-1 through PfSSP-5, have been reported in Protobothrops flavoviridis (“habu”, Pf) serum so far. Recently, we reported that the five genes encoding these PfSSPs are arranged in tandem on a single chromosome. However, the physiological functions and evolutionary origins of the five SSPs remain poorly understood. In a detailed analysis of the habu draft genome, we found a gene encoding a novel SSP, SSP-6. Structural analysis of the genes encoding SSPs and their genomic arrangement revealed the following: (1) SSP-6 forms a third SSP subgroup; (2) SSP-5 and SSP-6 were present in all snake genomes before the divergence of non- venomous and venomous snakes, while SSP-4 was acquired only by venomous snakes; (3) the composition of paralogous SSP genes in snake genomes seems to reflect snake habitat differences; and (4) the evolutionary emergence of SSP genes is probably related to the physiological functions of SSPs, with an initial snake repertoire of SSP-6 and SSP-5. SSP-4 and its derivative, SSP-3, as well as SSP-1 and SSP-2, appear to be venom-related and were acquired later.

リポジトリ公開URL： https://hdl.handle.net/2324/7329564

記述言語：日本語   掲載種別：研究論文（大学，研究機関等紀要）  

リポジトリ公開URL： https://hdl.handle.net/2324/7329785

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Snakebite envenoming is a serious and neglected tropical disease that kills ~100,000 people annually. High-quality, genome- enabled comprehensive characterization of toxin genes will facilitate development of effective humanized recombinant anti- venom. We report a de novo near-chromosomal genome assembly of Naja naja, the Indian cobra, a highly venomous, medically important snake. Our assembly has a scaffold N50 of 223.35 Mb, with 19 scaffolds containing 95% of the genome. Of the 23,248 predicted protein-coding genes, 12,346 venom-gland-expressed genes constitute the ‘venom-ome’ and this included 139 genes from 33 toxin families. Among the 139 toxin genes were 19 ‘venom-ome-specific toxins’ (VSTs) that showed venom- gland-specific expression, and these probably encode the minimal core venom effector proteins. Synthetic venom reconstituted through recombinant VST expression will aid in the rapid development of safe and effective synthetic antivenom. Additionally, our genome could serve as a reference for snake genomes, support evolutionary studies and enable venom-driven drug discovery.

リポジトリ公開URL： https://hdl.handle.net/2324/7329619

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Spinocerebellar ataxia 27 (SCA27) is an autosomal dominant SCA caused by variants in the fibroblast growth factor 14 (FGF14) gene. We examined a Japanese SCA patient whose deceased father also suffered from SCA. The patient was a 63-year-old male. He graduated from junior high school but received no further education. The predominant complaint was slowly progressive dysarthria and gait disturbance, which appeared at age 47. He showed pathological saccadic dysmetria, saccadic intrusions into smooth pursuit eye movements, dysarthria, and limb and truncal ataxia. His gait was wide-based but he did not require a walking stick. Limb muscle strength was intact. Deep tendon reflexes were normal or slightly reduced. Pathological reflexes were absent. He demonstrated mildly impaired vibration sense in the lower limbs. There was no urinary dysfunction. Brain MRI showed cerebellar atrophy without brainstem involvement. We first confirmed the absence of repeat expansion in genes known to be responsible for SCAs 1–3, 6–8, 10, 12, 17, 36 and dentatorubral-pallidoluysian atrophy. By exome analysis, we identified a novel heterozygous variant (NM_004115, c.529A>T; Lys177X) in exon 4 of the FGF14 gene. This variant is expected to generate a truncated FGF14 protein lacking the heparin binding sites, those are likely to modify the activity of FGF14. We confirmed the absence of the variant in 502 healthy Japanese individuals by Sanger sequencing. There is no record of the variant in public databases. We conclude that the novel variation in FGF14 is causative for SCA27 in this patient.

リポジトリ公開URL： https://hdl.handle.net/2324/7326909

記述言語：英語   掲載種別：研究論文（学術雑誌）  

リポジトリ公開URL： https://hdl.handle.net/2324/7326916

記述言語：英語   掲載種別：研究論文（大学，研究機関等紀要）  

Thyroid-related hormones (TRHs) are involved the regulation of endocrine function and metabolic processes of the thyroid gland, and hyperthyroidism is known to cause tremors, weight loss, and excessive sweating. As a part of examining the relationship between TRHs and the metabolism of amino acid in the plasma, we analyzed the correlation between TRHs and plasma levels of amino acids using samples from seven healthy volunteers. We measured three types of TRHs: thyroid-stimulating hormone (TSH), free triiodothyronine (FT3), and free thyroxine (FT4) in addition to 39 different amino acids including the 20 proteinogenic amino acids in the plasma collected from the healthy volunteers. We observed significant correlations between levels of taurine and FT4 (p = 0.018), valine and FT4 (p = 0.043), hydroxyproline and TSH (p = 0.049), and citrulline and TSH (p = 0.011). We also observed a correlation between the levels of hydroxyproline and citruline (p = 0.0079). These results suggest that the interaction between hydroxyproline and citrulline may be involved in plasma amino acid metabolism of TRHs.

リポジトリ公開URL： https://hdl.handle.net/2324/7326350

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Spinocerebellar ataxia 27 (SCA27) is an autosomal dominant SCA caused by variants in the fibroblast growth factor 14 (FGF14) gene. We examined a Japanese SCA patient whose deceased father also suffered from SCA. The patient was a 63-year-old male. He graduated from junior high school but received no further education. The predominant complaint was slowly progressive dysarthria and gait disturbance, which appeared at age 47. He showed pathological saccadic dysmetria, saccadic intrusions into smooth pursuit eye movements, dysarthria, and limb and truncal ataxia. His gait was wide-based but he did not require a walking stick. Limb muscle strength was intact. Deep tendon reflexes were normal or slightly reduced. Pathological reflexes were absent. He demonstrated mildly impaired vibration sense in the lower limbs. There was no urinary dysfunction. Brain MRI showed cerebellar atrophy without brainstem involvement. We first confirmed the absence of repeat expansion in genes known to be responsible for SCAs 1–3, 6–8, 10, 12, 17, 36 and dentatorubral-pallidoluysian atrophy. By exome analysis, we identified a novel heterozygous variant (NM_004115, c.529A>T; Lys177X) in exon 4 of the FGF14 gene. This variant is expected to generate a truncated FGF14 protein lacking the heparin binding sites, those are likely to modify the activity of FGF14. We confirmed the absence of the variant in 502 healthy Japanese individuals by Sanger sequencing. There is no record of the variant in public databases. We conclude that the novel variation in FGF14 is causative for SCA27 in this patient.

リポジトリ公開URL： https://hdl.handle.net/2324/7326907

記述言語：英語   掲載種別：研究論文（学術雑誌）  

The human occupation history of Southeast Asia (SEA) remains heavily debated. Current evidence suggests that SEA was occupied by Hòabìnhian hunter-gatherers until ~4000 years ago, when farming economies developed and expanded, restricting foraging groups to remote habitats. Some argue that agricultural development was indigenous; others favor the “two-layer” hypothesis that posits a southward expansion of farmers giving rise to present-day Southeast Asian genetic diversity. By sequencing 26 ancient human genomes (25 from SEA,1 Japanese Jōmon), we show that neither interpretation fits the complexity of Southeast Asian history: Both Hòabìnhian hunter-gatherers and East Asian farmers contributed to current Southeast Asian diversity, with further migrations affecting island SEA and Vietnam. Our results help resolve one of the long-standing controversies in Southeast Asian prehistory.

リポジトリ公開URL： https://hdl.handle.net/2324/7329610

記述言語：英語   掲載種別：研究論文（学術雑誌）  

To analyze a specific genome region using next-generation sequencing technologies, the enrichment of DNA libraries with targeted capture methods has been standardized. For enrichment of mitochondrial genome, a previous study developed an original targeted capture method that use baits constructed from long-range polymerase chain reaction (PCR) amplicons, common laboratory reagents, and equipment. In this study, a new targeted capture method is presented, that of bacterial artificial chromosome (BAC) double capture (BDC), modifying the previous method, but using BAC libraries as baits for sequencing a relatively large gene. We applied the BDC approach for the 214 kb autosomal region, ring finger protein 213, which is the susceptibility gene of moyamoya disease (MMD). To evaluate the reliability of BDC, cost and data quality were compared with those of a commercial kit. While the ratio of duplicate reads was higher, the cost was less than that of the commercial kit. The data quality was sufficiently the same as that of the kit. Thus, BDC can be an easy, low-cost, and useful method for analyzing individual genome regions with substantial length.

リポジトリ公開URL： https://hdl.handle.net/2324/7326349

記述言語：英語   掲載種別：研究論文（学術雑誌）  

The Japanese rat snake (Elaphe climacophora) is a common species in Japan and is widely distributed across the Japanese islands. An albino mutant of the Japanese rat snake (“pet trade” albino) has been bred and traded by hobbyists for around two decades because of its remarkable light-yellowish coloration with red eyes, attributable to a lack of melanin. Another albino Japanese rat snake mutant found in a natural population of the Japanese rat snake at high frequency in Iwakuni City, Yamaguchi Prefecture is known as “Iwakuni no Shirohebi”. It has been conserved by the government as a natural monument. The Iwakuni albino also lacks melanin, having light-yellowish body coloration and red eyes. Albino mutants of several organisms have been studied, and mutation of the tyrosinase gene (TYR) is responsible for this phenotype. By determining the sequence of the TYR coding region of the pet trade albino, we identified a nonsense mutation in the second exon. Furthermore, RT-PCR revealed that TYR transcripts were not detected in this snake. These findings suggest that mutation of TYR is responsible for the albino phenotype of the pet trade line of the Japanese rat snake. However, the Iwakuni albino did not share this TYR mutation; thus, these two albino lines differ in their origins.

リポジトリ公開URL： https://hdl.handle.net/2324/7326906

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Background and Aim: The gut microbiota is suggested to play an important role in the pathogenesis of ulcerative colitis (UC). However, interindividual and spatial variations hamper the identification of UC-related changes. We thus investigated paired mucosa-associated microbiota obtained from both inflamed and non-inflamed sites of UC patients and corresponding sites of non-inflammatory bowel disease (IBD) controls.
Methods: Mucosal biopsies of both inflamed and non-inflamed sites were obtained from 14 patients with active UC of the left-sided or proctitis type. Paired mucosal biopsies of the corresponding sites were obtained from 14 non-IBD controls. The microbial community structure was investigated using 16S ribosomal RNA gene sequences, followed by data analysis using QIIME and LEfSe softwares.
Results: Microbial alpha diversity in both inflamed and non-inflamed sites was significantly lower in UC patients compared with non-IBD controls. There were more microbes of the genus Cloacibacterium and the Tissierellaceae family, and there were less microbes of the genus Neisseria at the inflamed site when compared with the non-inflamed site in UC patients. Decreased abundance of the genera Prevotella, Eubacterium, Neisseria, Leptotrichia, Bilophila, Desulfovibrio, and Butyricimonas was evident at the inflamed site of UC patients compared with the corresponding site of non-IBD controls. Among these taxa, the genera Prevotella and Butyricimonas were also less abundant at the noninflamed site of UC patients compared with the corresponding site in non-IBD controls.
Conclusions: Mucosal microbial dysbiosis occurs at both inflamed and non-inflamed sites in UC patients. The taxa showing altered abundance in UC patients might mediate colonic inflammation.

リポジトリ公開URL： https://hdl.handle.net/2324/7326348

記述言語：日本語   掲載種別：研究論文（大学，研究機関等紀要）  

電位依存性カルシウムチャネルα1Aサブユニット遺伝子であるCACNA1A遺伝子上にあるDNAの三塩基配列CAGリピートの異常伸長が脊髄小脳失調症６型(Spinocerebellar ataxia type 6: SCA6)の発症に関わることが知られている。SCA6の原因遺伝子であるCACNA1A遺伝子上ではCAGリピート数が健常者では4から19, 罹患者では21から33となる。また、SCA6は家族歴のある常染色体優性遺伝性の罹患者が多く、日本では優性遺伝性の脊髄小脳失調症の約30％を占めている。本研究では孤発性(非遺伝性)のSCA6の罹患者および両親の末梢血検体を使用し、遺伝学的解析によるCAGリピート異常から家族歴の遺伝性を検証した。結果としてSCA6の罹患者はCAGリピートの異常伸長(変異アレルでリピート数23)が認められた。さらに遺伝学的解析により両親とも健常であるが、おそらく父親由来の正常アレルから罹患者の変異アレルに表現促進現象が起こったのではないかと示唆された。これらのことから孤発性の症例でも遺伝学的解析により原因の究明ができる可能性が考えられる。

リポジトリ公開URL： https://hdl.handle.net/2324/7329784

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Case: Methylene blue is useful for the treatment of methemoglobinemia. However, even after the patient’s methemoglobin (metHb)
rate has improved, careful observation is important because they could have undiagnosed congenital methemoglobinemia. In this
case, a 67-year-old man underwent gastrointestinal endoscopy with the use of lidocaine for local anesthesia. During the examination,
he complained of dyspnea and had low SpO2 despite normal PaO2 and SaO2. He was transferred to our department as a suspected
case of acquired methemoglobinemia.
Outcome: The patient’s metHb level was 26.2%. We administered methylene blue i.v. and his metHb level subsequently decreased
to 1.6%. However, his metHb level gradually increased to 18.2%, and we suspected that he had congenital methemoglobinemia. We
administered riboflavin and ascorbic acid orally, and his metHb level decreased to 6.4%. We also obtained genomic DNA from the
patient and identified a novel variant of CYB5R3.
Conclusion: We report a novel variant of congenital methemoglobinemia that deteriorated after methylene blue treatment.

リポジトリ公開URL： https://hdl.handle.net/2324/7326344

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Krüppel-Like Factor 14 (KLF14) gene, which appears to be a master regulator of gene expression in the adipose tissue and have previously been associated with BMI and Type 2 diabetes (T2D) by large genome-wide association studies. In order to find predictive biomarkers for the development of T2D, it is necessary to take epigenomic changes affected by environmental factors into account. This study focuses on ageing and obesity, which are T2D risk factors, and examines epigenetic changes and inflammatory changes. We investigated DNA methylation changes in the Klf14 promoter region in different organs of mice for comparing aging and weight. We found that methylation levels of these sites were increased with aging and weight in the spleen, the adipose tissue, the kidney, the lung, the colon and the whole blood cells. In addition, in the spleen, the adipose tissue and the whole blood, these epigenetic changes were also significantly associated with inflammatory levels. Moreover, not only Klf14, but also expression levels of some downstream genes were decreased with methylation in the spleen, the adipose tissue and the whole blood cells. Taken together, our results suggest that methylation changes of Klf14 in those tissues may be associated with changes in gene expression and inflammation on the adipose tissue of obesity and T2D. In addition, the methylation changes in the whole blood cells may serve as a predictive epigenetic biomarker for the development of T2D.

リポジトリ公開URL： https://hdl.handle.net/2324/7326347

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Background: Epidemiological studies of DNA methylation profiles may uncover the molecular mechanisms through
which genetic and environmental factors contribute to the risk of multifactorial diseases. There are two types of
commonly used DNA bioresources, peripheral blood cells (PBCs) and EBV-transformed lymphoblastoid cell lines (LCLs),
which are available for genetic epidemiological studies. Therefore, to extend our knowledge of the difference in DNA
methylation status between LCLs and PBCs is important in human population studies that use these DNA sources to
elucidate the epigenetic risks for multifactorial diseases. We analyzed the methylation status of the autosomes for 192
and 92 DNA samples that were obtained from PBCs and LCLs, respectively, using a human methylation 450 K array.
After excluding SNP-associated methylation sites and low-call sites, 400,240 sites were subjected to analysis using a
generalized linear model with cell type, sex, and age as the independent variables.
Results: We found that the large proportion of sites showed lower methylation levels in LCLs compared with PBCs,
which is consistent with previous reports. We also found that significantly different methylation sites tend to be located
on the outside of the CpG island and in a region relatively far from the transcription start site. Additionally, we
observed that the methylation change of the sites in the low-CpG promoter region was remarkable. Finally, it was
shown that the correlation between the chronological age and ageing-associated methylation sites in ELOVL2 and
FHL2 in the LCLs was weaker than that in the PBCs.
Conclusions: The methylation levels of highly methylated sites of the low-CpG-density promoters in PBCs decreased
in the LCLs, suggesting that the methylation sites located in low-CpG-density promoters could be sensitive to
demethylation in LCLs. Despite being generated from a single cell type, LCLs may not always be a proxy for DNA from
PBCs in studies of epigenome-wide analysis attempting to elucidate the role of epigenetic change in disease risks.
Keywords: DNA methylation, Lymphoblastoid cell lines, Epigenome-wide analysis, Epigenetic epidemiology, Human
methylation array

DOI： 10.1186/s40246-017-0106-6

リポジトリ公開URL： https://hdl.handle.net/2324/7326341

記述言語：日本語   掲載種別：研究論文（大学，研究機関等紀要）  

CSTB(Cystatin B)遺伝子の異常リピートにより引き起こされる進行性ミオクローヌスてんかんの一病型であるウンフェルリヒト・ルントボルク病(Unverricht-Lundborg disease:ULD)の可能性のある検体の遺伝子解析研究である。進行性ミオクローヌスてんかんの中でCSTB(Cystatin B)遺伝子のリピート異常が原因の疾患はULDとして知られている。ULDを調べるために放射性同位体(Radioisotope:RI)を使用したサザンブロッティングによる解析が行われる。そこで本研究では、簡便なポリメラーゼ連鎖反応(Polymerase chain reaction: PCR)を使用してCSTBの異常リピートの検出を試み、診断手法の確立およびULDの診断に寄与できないか検討した。PCRの結果、健常者と比較して患者では異常リピートと考えられるDNA増幅を確認したがサンガーシークエンスによる配列確認により異常リピートではなく、別の配列の挿入が示唆される結論に至った。

リポジトリ公開URL： https://hdl.handle.net/2324/7329781

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Background: The evolutionary dynamics of repeat sequences is quite complex, with some duplicates never
having differentiated from each other. Two models can explain the complex evolutionary process for repeated
genes—concerted and birth-and-death, of which the latter is driven by duplications maintained by selection.
Copy number variations caused by random duplications and losses in repeat regions may modulate molecular
pathways and therefore affect phenotypic characteristics in a population, resulting in individuals that are able to
adapt to new environments. In this study, we investigated the filaggrin gene (FLG), which codes for filaggrin—an
important component of the outer layers of mammalian skin—and contains tandem repeats that exhibit copy
number variation between and within species. To examine which model best fits the evolutionary pathway for
the complete tandem repeats within a single exon of FLG, we determined the repeat sequences in crab-eating
macaque (Macaca fascicularis), orangutan (Pongo abelii), gorilla (Gorilla gorilla), and chimpanzee (Pan troglodytes)
and compared these with the sequence in human (Homo sapiens).
Results: In this study we compared concerted and birth-and-death evolution models, commonly used for gene
copies. We found that there is high nucleotide diversity between filaggrin repeat regions, which fits the birth-anddeath
model. Phylogenetic analyses also suggested that independent duplication events created the repeat sequences
in crab-eating macaques and orangutans, while different duplication and loss events created the repeats in gorillas,
chimpanzees, and humans. Comparison of the repeat sequences detected purifying selection within species and
lineage-specific duplications across species. We also found variation in the length of the repeated region within
species such as chimpanzee and crab-eating macaque.
Conclusions: We conclude that the copy number variation in the repeat sequences of FLG between primates
may be a consequence of species-specific divergence and expansion.
Keywords: Filaggrin, Copy number variation, Birth-and-death evolution, Duplication/loss

DOI： 10.1186/s12862-016-0851-5.

リポジトリ公開URL： https://hdl.handle.net/2324/7326340

記述言語：日本語   掲載種別：研究論文（大学，研究機関等紀要）  

本研究は、日本人の脊髄小脳失調症 (Spinocerebellar ataxia: SCA)症例の遺伝解析研究である。本症例は臨床的にSCAタイプ5に矛盾せず、頭部MRI画像では小脳萎縮が認められ、脳幹は保たれていた。遺伝学的解析により、SCA5の原因遺伝子であるβ-IIIスペクトリン遺伝子(SPTBN2)の新規非同義変異(c.924 G>C, p. E308D)が認められた。その遺伝子は細胞骨格たんぱく質をコードして 11番染色体に位置しており、E308Dの変異はホットスポットに局在していた。日本人健常者507人を検討した結果、9人が同様の変異を有していた。したがって、SCA5の責任遺伝子内のミスセンス変異であるE308Dが責任変異ではない可能性が示唆された。

リポジトリ公開URL： https://hdl.handle.net/2324/7329773

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.3390/toxins6123471

リポジトリ公開URL： https://hdl.handle.net/2324/7326138

記述言語：英語   掲載種別：研究論文（学術雑誌）  

The eggshells of 56 chelonians were examined by electron microscopy and X-ray diffractometry. They were classified into six types in terms of the matrix structure of their calcareous layer; type I was composed of a thin calcareous layer with minerals in an amorphous structure; type II with shell units composed of mammillary cores calcified with aragonite crystals; type III with shell units composed of mammillary cores, plus a single palisade layer also calcified with aragonite crystals, and with each shell unit separated; type IV with shell units the same as type III, but tightly packed together; type V with shell units composed of mammillary cores plus two palisade layers; and type VI with a cuticle layer calcified with calcite crystals over the same structure as that of type V. X-ray diffraction analyses at the outer surface of eggshells showed a gradual change in crystal disposition from the random disposition of type II to the single direction-oriented disposition of type V. The shell height was approximately parallel to the development of the palisade-layer matrix. The limiting membrane of all eggshell types was perforated with canals and that of type I was partially missing. Type I had a parchment shell, types II and III had a pliable shell (some were rigid) and types IV to VI had rigid shells. The present study showed that the hardness of eggshells can be determined by the composition of the shell matrices, as shell matrices are the framework for mineralization.

リポジトリ公開URL： https://hdl.handle.net/2324/7326132

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Risk alleles for complex diseases are spread widely throughout human populations. However, little is known about the geographic distribution of risk allele frequencies, which may contribute to geographic differences in disease susceptibility and prevalence. Here we focus on Crohn’s disease (CD) as a model for the evolutionary study of complex disease alleles. Recent genome-wide association studies and classical linkage analyses have identified more than 70 susceptible genomic regions for CD in Europeans, but only a few have been confirmed in non-European populations. Our analysis of eight European-specific susceptibility genes using HapMap data shows that at the NOD2 locus the CD-risk alleles are linked with a haplotype specific to CEU at a frequency that is significantly higher compared to the entire genome. We subsequently examined nine global populations and found that the CD-risk alleles spread through hitchhiking with a high-frequency haplotype (H1) exclusive to Europeans. To examine the neutrality of NOD2, we performed phylogenetic network analyses, coalescent simulation, protein structural prediction, characterization of mutation patterns, and estimations of population growth and time to most recent common ancestor (TMRCA). We found that while H1 was significantly prevalent in European populations, the H1 TMRCA predated human migration out of Africa. H1 is likely to have undergone negative selection because (i) the root of H1 genealogy is defined by a pre-existing amino acid substitution that causes serious conformational changes to the NOD2 protein, (ii) the haplotype has almost become extinct in Africa, and (iii) the haplotype has not been affected by the recent European expansion reflected in the other haplotypes. Nevertheless, H1 has survived in European populations, suggesting that the haplotype is advantageous to the populations. We propose that several CD-risk alleles, which destabilize and disrupt the NOD2 protein, have been maintained by natural selection on standing variation because the deleterious haplotype of NOD2 is advantageous in diploid individuals due to heterozygote advantage and/or intergenic interactions.

リポジトリ公開URL： https://hdl.handle.net/2324/7326126

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Spastic paraplegia type 4 (SPG4) is the most common autosomal dominant hereditary SPG caused by mutations in the SPAST gene. We studied the four- generation pedigree of a Japanese family with autosomal dominant hereditary SPG both clinically and genetically. Twelve available family members (ten affected; two unaffected) and two spouses were enrolled in the study. The clinical features were hyperreflexia in all four limbs, spasticity of the lower extremities, impaired vibration sense, mild cognitive impairment confirmed by the Wechsler Adult Intelligence Scale—Third Edition, and peripheral neuropathy confirmed by neurophysiological examinations. All four female patients experienced miscarriages. The cerebrospinal fluid tau levels were mildly increased in two of three patients examined. Linkage analyses revealed the highest logarithm of odds score of 2.64 at 2p23-p21 where the SPAST gene is located. Mutation scanning of the entire exonic regions of the SPAST gene by direct sequencing revealed no mutations. Exonic copy number analysis by real- time quantitative polymerase chain reaction revealed hetero- zygous deletion of exons 1 to 4 of the SPAST gene. Breakpoint analysis showed that the centromeric breakpoint was located within intron 4 of SPAST while the telomeric breakpoint was located within intron 3 of the neighboring DPY30 gene, causing a deletion of approximately 70 kb ranging from exons 1 to 3 of DPY30 to exons 1 to 4 of SPAST. To our knowledge, this is the first report of SPG4 associated with partial deletions of both the SPAST and DPY30 genes. The partial heterozygous deletion of DPY30 could modify the phenotypic expression of SPG4 patients with this pedigree.

リポジトリ公開URL： https://hdl.handle.net/2324/7326125

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Spastic paraplegia type 4 (SPG4) is the most common autosomal dominant hereditary SPG caused by mutations in the SPAST gene. We studied the four- generation pedigree of a Japanese family with autosomal dominant hereditary SPG both clinically and genetically. Twelve available family members (ten affected; two unaffected) and two spouses were enrolled in the study. The clinical features were hyperreflexia in all four limbs, spasticity of the lower extremities, impaired vibration sense, mild cognitive impairment confirmed by the Wechsler Adult Intelligence Scale—Third Edition, and peripheral neuropathy confirmed by neurophysiological examinations. All four female patients experienced miscarriages. The cerebrospinal fluid tau levels were mildly increased in two of three patients examined. Linkage analyses revealed the highest logarithm of odds score of 2.64 at 2p23-p21 where the SPAST gene is located. Mutation scanning of the entire exonic regions of the SPAST gene by direct sequencing revealed no mutations. Exonic copy number analysis by real- time quantitative polymerase chain reaction revealed hetero- zygous deletion of exons 1 to 4 of the SPAST gene. Breakpoint analysis showed that the centromeric breakpoint was located within intron 4 of SPAST while the telomeric breakpoint was located within intron 3 of the neighboring DPY30 gene, causing a deletion of approximately 70 kb ranging from exons 1 to 3 of DPY30 to exons 1 to 4 of SPAST. To our knowledge, this is the first report of SPG4 associated with partial deletions of both the SPAST and DPY30 genes. The partial heterozygous deletion of DPY30 could modify the phenotypic expression of SPG4 patients with this pedigree.

その他リンク： http://www.springerlink.com/content/d87437661v732711/

リポジトリ公開URL： https://hdl.handle.net/2324/7326123

記述言語：英語   掲載種別：研究論文（学術雑誌）  

リポジトリ公開URL： https://hdl.handle.net/2324/7326097

記述言語：英語   掲載種別：研究論文（学術雑誌）  

We studied a four-generation pedigree of a Japanese family with hereditary neuropathy to elucidate the genetic basis of this disease. Twelve members of the family were enrolled in this study. The clinical features were neurogenic muscle weakness with proximal dominancy in the lower extremities, sensory involvement, areflexia, fine postural tremors, painful muscle cramps, elevated creatine kinase levels, recurrent paroxysmal dry cough, and neurogenic bladder. We performed a genome-wide search using genetic loci spaced at about 13 Mb intervals. Although nine chromosomes (1, 3, 4, 5, 6, 10, 17, 19, and 22) had at least one region in which the logarithm of odds (LOD) score was over 1.0, no loci fulfilled the criteria for significant evidence of linkage. Moreover, we analyzed an extra 14 markers on 3p12–q13 (the locus of hereditary motor and sensory neuropathy, proximal dominant form) and an extra five markers on 3p22–p24 (the locus of hereditary sensory neuropathy with chronic cough) and observed LOD scores of b−3 on both 3p12–q13 and 3p22–p24. Mutation scanning of the entire coding regions of the MPZ and PMP22 genes revealed no mutations. We conclude that the disorder described here is a newly classified hereditary motor and sensory neuropathy with autosomal dominant inheritance.

リポジトリ公開URL： https://hdl.handle.net/2324/7326092

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Background: Based on the glutamatergic dysfunction hypothesis for schizophrenia pathogenesis, we have been performing systematic association studies of schizophrenia with the genes involved in glutametergic transmission. We report here association studies of schizophrenia with SLC1A4, SLC1A5 encoding neutral amino acid transporters ASCT1, ASCT2, and SLC6A5, SLC6A9 encoding glycine transporters GLYT2, GLYT1, respectively.
Methods: We initially tested the association of 21 single nucleotide polymorphisms (SNPs) distributed in the four gene regions with schizophrenia using 100 Japanese cases-control pairs and examined allele, genotype and haplotype association with schizophrenia. The observed nominal significance were examined in the full-size samples (400 cases and 420 controls).
Results: We observed nominally significant single-marker associations with schizophrenia in SNP2 (P = 0.021) and SNP3 (P = 0.029) of SLC1A4, SNP1 (P = 0.009) and SNP2 (P = 0.022) of SLC6A5. We also observed nominally significant haplotype associations with schizophrenia in the combinations of SNP2-SNP7 (P = 0.037) of SLC1A4 and SNP1-SNP4 (P = 0.043) of SLC6A5. We examined all of the nominal significance in the Full-size Sample Set, except one haplotype with insufficient LD. The significant association of SNP1 of SLC6A5 with schizophrenia was confirmed in the Full-size Sample Set (P = 0.018).
Conclusion: We concluded that at least one susceptibility locus for schizophrenia may be located within or nearby SLC6A5, whereas SLC1A4, SLC1A5 and SLC6A9 are unlikely to be major susceptibility genes for schizophrenia in the Japanese population.

リポジトリ公開URL： https://hdl.handle.net/2324/7325999

記述言語：英語   掲載種別：研究論文（学術雑誌）  

We have previously mapped autosomal dominant spinocerebellar ataxia (SCA) 16 to 3p26, overlapping with the locus of SCA15. Recently, partial deletions of ITPR1 and the neighbouring SUMF1 in the SCA15 and two additional families were reported. In the present study we determined the copy number of these genes by real time quantitative polymerase chain reaction (PCR) and found a heterozygous deletion of exons 1-48 of ITPR1, but not SUMF1 in SCA16. Breakpoint analysis revealed that the size of the deletion is 313,318 bp and the telomeric breakpoint is located in the middle of their intergenic region. Our data provide evidence that haploinsufficiency of ITPR1 alone causes SCA16 and SCA15.

リポジトリ公開URL： https://hdl.handle.net/2324/7326033

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Based on the glutamatergic dysfunction hypothesis for schizophrenia pathogenesis, we have been performing systematic association studies of schizophrenia with the glutamate receptor and transporter genes. We report here association studies of schizophrenia with three glutamate transporter genes SLC1A1, SLC1A3, and SLC1A6 encoding the glutamate transporters EAAT3, EAAT1, and EAAT4, respectively. We initially performed the screening of the total 25 single nucleotide polymorphisms (SNPs) distributed in the three gene regions using 100 out of 400 Japanese cases and 100 out of 420 Japanese controls. After controlling the false discovery rate (FDR) at level 0.05, we observed significant associations of schizophrenia with a genotype of SNP4 (rs2097837, P = 0.007) and with haplotypes of SNP2-SNP5 (P = 7.5 x 10(-5)) and SNP3-SNP5 (P = 9.0 x 10(-4)) in the SLC1A6 region. The haplotype of SNP2-SNP5 of SLC1A6 even showed marginally significant association with the disease in the full-size sample (400 cases and 420 controls, P = 0.031). We concluded that at least one susceptibility locus for schizophrenia may be located within or nearby SLC1A6, whereas SLC1A1 and SLC1A3 are unlikely to be major susceptibility genes for schizophrenia in the Japanese population.

リポジトリ公開URL： https://hdl.handle.net/2324/7326034

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Objective: To identify of the gene responsible for the onset of spinocerebellar ataxia type 16 (SCA16). Methods: We reanalyzed the linkage of the original Japanese pedigree using updated information, including three additional subjects. We then screened all exons located in the critical region. Results: We reassigned the locus of SCA16 to 3p26.2-pter (maximum logarithm-of-odds score 􏰂 5.177) and identified only one point mutation (4,256C¡T) in the 3= untranslated region of the contactin 4 gene (CNTN4) on chromosome 3p26.2-26.3, which cosegregated with the disease. This mutation was not detected in 520 control subjects; moreover, we revised the phenotype of SCA16 from pure to complicated SCA. Conclusion: The contactin 4 gene (CNTN4) is associated with cerebellar degeneration in spinocerebellar ataxia type 16. Additional studies are necessary to prove 4,256C¡T to be a causative mutation.

リポジトリ公開URL： https://hdl.handle.net/2324/7326080

記述言語：英語   掲載種別：研究論文（学術雑誌）  

The Japanese Schizophrenia Sib-Pair Linkage Group (JSSLG) is a multisite collaborative study group that was organ- ized to create a national resource for affected sib pair (ASP) studies of schizophrenia in Japan. We used a high- density single-nucleotide–polymorphism (SNP) genotyping assay, the Illumina BeadArray linkage mapping panel (version 4) comprising 5,861 SNPs, to perform a genomewide linkage analysis of JSSLG samples comprising 236 Japanese families with 268 nonindependent ASPs with schizophrenia. All subjects were Japanese. Among these families, 122 families comprised the same subjects analyzed with short tandem repeat markers. All the probands and their siblings, with the exception of seven siblings with schizoaffective disorder, had schizophrenia. After excluding SNPs with high linkage disequilibrium, we found significant evidence of linkage of schizophrenia to chromosome 1p21.2-1p13.2 (LOD p 3.39) and suggestive evidence of linkage to 14q11.2 (LOD p 2.87), 14q11.2- q13.2 (LOD p 2.33), and 20p12.1-p11.2 (LOD p 2.33). Although linkage to these regions has received little attention, these regions are included in or partially overlap the 10 regions reported by Lewis et al. that passed the two aggregate criteria of a meta-analysis. Results of the present study—which, to our knowledge, is the first genomewide analysis of schizophrenia in ASPs of a single Asian ethnicity that is comparable to the analyses done of ASPs of European descent—indicate the existence of schizophrenia susceptibility loci that are common to different ethnic groups but that likely have different ethnicity-specific effects.

リポジトリ公開URL： https://hdl.handle.net/2324/7331664

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Background: The occurrence of aberrant functional connectivity in the neuronal circuit is one of the integrative theories of the etiology of schizophrenia. Previous studies have reported that the protein and mRNA levels of the synapsin 2 (SYN2) and complexin 2 (CPLX2) genes were decreased in patients with schizophrenia. Synapsin 2 and complexin 2 are involved in synaptogenesis and the modulation of neurotransmitter release. This report presents a study of the association of polymorphisms of SYN2 and CPLX2 with schizophrenia in the Korean population.
Methods: Six single nucleotide polymorphisms (SNPs) and one 5-bp insertion/deletion in SYN2 and five SNPs in CPLX2 were genotyped in 154 Korean patients with schizophrenia and 133 control patients using direct sequencing or restriction fragment length polymorphism analysis. An intermarker linkage disequilibrium map was constructed for each gene.
Results: Although there was no significant difference in the genotypic distributions and allelic frequencies of either SYN2 or CPLX2 polymorphisms between the schizophrenia and control groups, the two-way haplotype analyses revealed significant associations with the disease (P < 0.05 after Bonferroni correction). The three-way haplotype analyses also revealed a significant association of SYN2 with schizophrenia (P < 0.001 after Bonferroni correction).
Conclusion: These results suggest that both SYN2 and CPLX2 may confer susceptibility to schizophrenia in the Korean population.

リポジトリ公開URL： https://hdl.handle.net/2324/7325991

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Metabotropic glutamate receptors (mGluRs) belong to the class of GTP-binding protein coupled receptors and consist of eight different subtypes. The subtype 2 metabotropic glutamate receptor (mGluR2) gene (GRM2) is one of the possible candidate genes for schizophrenia. Phencyclidine (PCP)-induced increase in glutamate efflux and schizophrenia-like behavioral abnormalities were reduced by pretreatment of the mGluRII agonist LY354740 in rats and its effects are mediated via mGluR2. To evaluate involvement of the mGluR2 gene in the pathogenesis of schizophrenia, we isolated the human mGluR2 gene and determined the transcription initiation site, the entire nucleotide sequence and the chromosomal localization. The hmGluR2 gene spans 13 kb with six exons, including one non-coding exon. The gene was mapped to chromosome 3 p12-p11 by Radiation Hybrid Panel analysis. We screened polymorphisms in the coding exons of the mGluR2 gene, using the SSCP procedure. The thirteen polymorphisms identified included ten missense, one silent mutation and two one-base substitutions in the 5'-untranslated region. We genotyped 213 Japanese schizophrenics and 220 controls to study the association of polymorphisms in the mGluR2 gene with schizophrenia. As we found no statistically significant differences in allele frequencies of each polymorphism, these polymorphisms apparently do not play a major role in schizophrenia.

DOI： 10.1038/sj.mp.4000841

リポジトリ公開URL： https://hdl.handle.net/2324/7325658

記述言語：英語   掲載種別：研究論文（学術雑誌）  

The human dopamine D4 receptor (DRD4) is of major interest in molccular studies of schizophrenia and personality traits. We examined the association of schizophrenia and polymorphisms in the upstream region of the DRD4 gene (-768G>A in the negative modulator region; -521C>T, -376C >T, and -291C>T in the cell type-specific promoter region; and -616C>G between the two regions) in 208 schizophrenic patients and 210 normal controls. No significant difference in genotype and allele frequencies was observed between the two groups, indicating that these polymorphisms do not make a major contribution to the pathogenesis of schizophrenia. We also studied the association of polymorphisms in the upstream region and a 48-bp repeat polymorphism in exon III of the DRD4 gene with personality traits in 173 Japanese individuals who completed the temperament and character inventory (TCI). The -768G>A polymorphism was significantly associated with reward dependence (P= 0.044), while no significant association was observed between novelty seeking and polymorphisms in the upstream region or the exon III repeat polymorphism of the DRD4 gene.

DOI： 10.1007/s100380170120

リポジトリ公開URL： https://hdl.handle.net/2324/7325700

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Ataxin-2, the gene product of the human spinocerebellar ataxia type 2 (SCA2) gene, is a protein of unknown function. Ataxin-2 interacts with ataxin-2-binding-protein 1 (A2BP1), a member of a novel family of putative RNA-binding proteins. Because the sequences of ataxin-2 and A2BP1 are evolutionarily conserved, we investigated functional aspects and expression pattern in the nematode Caenorhabditis elegans. Human ataxin-2 has 20.1% amino acid identity and 43.9% similarity to its C. elegans ortholog, designated ATX-2, that encodes a predicted 1026 aa protein. One of the worm orthologs of human A2BP1 is the numerator element FOX-1, with an overall 29.8% aa identity. We studied the expression pattern of atx-2 using the endogenous promotor coupled with a GFP expression vector. Atx-2 was widely expressed in the adult worm with strong expression in muscle and nervous tissue. It was also heavily expressed in the embryo. In order to elucidate the function of atx-2 and fox-1, we conducted RNA interference (RNAi) studies. The interfering dsRNA was introduced into larval L4 stage worms of the N2 strain by microinjection or soaking. DsRNA representing the full-length atx-2 gene resulted in arrested embryonic development in the offspring of all 58 microinjected worms. Nomarski imaging showed embryos in different stages of developmental arrest, indicating an essential role of atx-2 for early embryonic development. When fox-1 was targeted by RNAi, there was a marked reduction in the number of eggs per worm. The results presented here underline previous findings about the interaction of human ataxin-2 and A2BP1.

DOI： 10.1385/JMN:15:3:231

リポジトリ公開URL： https://hdl.handle.net/2324/7325621

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Thalassemia is a prevalent hereditary disorder characterized by impaired synthesis of globin chains. It has been suggested that the high frequency of thalassemia might reflect heterozygote advantage due to reduced susceptibility to malaria. In Nepal, malaria has often occurred in places below the altitude of 1,200m. We carried out a microepidemiological study on thalassemia in two neighboring populations in Nepal, the Danuwar and the Tamang. Settlements of the Danuwar are located below the limit of the malarial zone (1,200m in altitude), whereas those of the Tamang are found in malaria-free uplands. Three heterozygotes for hemoglobin E (HbE) were observed in the Danuwars. We detected one type (-alpha3.71) of alpha+-thalassemia that involves a deletion of 3.7kb, leading to a loss of one of two alpha-globin genes, in the Danuwars, at a high gene frequency of 63%, while the gene frequency in the Tamangs was only 5%. Analysis of the alpha-globin gene cluster revealed that four different haplotypes were associated with the type of alpha+-thalassemia in the Danuwars. Nucleotide sequences of the D-loop region in the mitochondrial DNA of the two populations indicated a similar nucleotide diversity in each population. The fixation index, FST, representing the degree of genetic differentiation estimated from mitochondrial DNA diversities (FST, 0.05), was smaller than that obtained from the gene frequencies of alpha-thalassemia (FST, 0.55). If we assume neutral molecular evolution in the D-loop region of mitochondrial DNA, these results suggest that the high frequency of alpha+-thalassemia may be due to biological adaptation to the malarial environment rather than to events such as a bottleneck.

DOI： 10.1007/s100380050198

リポジトリ公開URL： https://hdl.handle.net/2324/7182011

記述言語：英語   掲載種別：研究論文（学術雑誌）  

The spinocerebellar ataxia type 2 (SCA2) gene has been localized to chromosome 12q24.1. To characterize this region and to aid in the identification of the SCA2 gene, we have constructed a 3.9-Mb physical map, which covers markers D12S1328 and D12S1329 known to flank the gene. The map comprises a contig of 84 overlapping yeast artificial chromosomes (YACs), P1 artificial chromosomes (PACs), and bacterial artificial chromosomes (BACs) onto which we placed 82 PCR markers. We localized eight genes and expressed sequence tags on this map, many of which had not been precisely mapped before. In contrast to YACs, which showed a high degree of chimerism and deletions in this region, PACs and BACs were stable. Only 1 in 65 PACs contained a small deletion, and 2 in 18 BACs were chimeric. The high-resolution physical map, which was used in the identification of the SCA2 gene, will be useful for the positional cloning of other disease genes mapped to this region.

リポジトリ公開URL： https://hdl.handle.net/2324/7178702

記述言語：英語   掲載種別：研究論文（学術雑誌）  

The nucleotide sequences of the 5'-flanking regions of the duplicated Amy genes in eight sibling species belonging to the melanogaster species subgroup are analyzed. In Drosophila melanogaster, a region of about 450 bp immediately upstream of the translation initiation site of the two paralogous genes (the proximal and distal genes) has sequence similarities. However, we could not detect any significant sequence similarity in the region more upstream than -450. This result indicates that the coding regions of the ancestral Amy gene were duplicated together with 450 bp of the 5'-flanking region as one unit. Multiple alignment of these 450-bp sequences in the proximal and distal genes of all eight species revealed a mosaic pattern of highly conserved and divergent regions. The conserved regions included almost all the putative regulatory elements identified in previous analyses of the sequences. A phylogenetic analysis of the aligned sequences shows that these 450-bp sequences are clustered into the proximal and the distal groups. As a whole, the divergence between groups in this region is very large in contrast to that in the coding regions. Based on the divergence between groups, the 450-bp region is divided into two subregions. We found that the ratios of the divergence between groups to that within groups differ in the two subregions. From these observations, we discuss a possibility of positive selection acting on the subregion immediately upstream of the Amy coding region to cause divergence of regulatory elements of the paralogous genes.

リポジトリ公開URL： https://hdl.handle.net/2324/7178701

記述言語：英語   掲載種別：研究論文（学術雑誌）  

To infer the genealogical relationships of alpha-amylase electromorphs of Drosophila melanogaster, we determined the nucleotide sequences of a collection of electromorphs sampled throughout the world. On average there were 1.0 amino acid substitutions between identical electromorphs and 3.9 between different electromorphs, respectively. We found that the evolution of AMY1 through AMY6 electromorphs occurred by sequential accumulation of single amino acid substitutions each causing one charge difference. The nucleotide diversities at synonymous sites within Amy1,Amy2,Amy3,Amy4 and Amy6 were 0.0321, 0.0000, 0.0355, 0.0059 and 0.0030, respectively. We also obtained evidence of genetic exchanges, such as intrachromosomal recombination, interchromosomal recombination or gene conversion, between the two duplicated Amy genes as well as among the alleles.

リポジトリ公開URL： https://hdl.handle.net/2324/7177979

記述言語：英語   掲載種別：研究論文（学術雑誌）  

A comparative study was done on the enzymological features of alpha-amylase among six sibling species belonging to the Drosophila melanogaster species subgroup. The pH optima were 7.6 for D. melanogaster, D. mauritiana and D. simulans and 7.4 for D. erecta, D. teissieri and D. yakuba. The temperature optima were commonly 37 C in all species studied. However, there are two types of temperature dependence; a strict one as observed in D. melanogaster, D. mauritiana and D. simulans, and a flat one as observed in D. erecta, D. teissieri and D. yakuba. These separations are consistent with the general phylogeny within this species subgroup. The substrate dependence was almost the same in all the species studied. The Vmax and Km were also estimated for each species. We found clear differences in the enzymological features between the species. Thus these differences might reflect an adaptation of the amylase enzyme system to speciation in this species subgroup.

DOI： 10.1266/jjg.69.251

リポジトリ公開URL： https://hdl.handle.net/2324/7177978

担当ページ：ヒトは病気とともに進化した（長谷川真理子、太田博樹編）（「第七章: ヒトらしさの起源」の執筆を担当）   記述言語：日本語   著書種別：学術書

担当ページ：医学大辞典　伊藤正男、井村裕夫、高久史麿　総編集 ３項目   記述言語：日本語   著書種別：学術書

担当ページ：薬物動態・作用と遺伝子多型　澤田康文他編、pp74-86   記述言語：日本語   著書種別：学術書

担当ページ：新女性医学体系第28巻 遺伝の基礎と臨床　DNA・遺伝子診断の基礎　PCR法大濱紘三編、pp81-89   記述言語：日本語   著書種別：学術書

開催年月日： 2019年9月 - 2019年10月

記述言語：英語   会議種別：口頭発表（一般）  

開催地：Heidelberg   国名：ドイツ連邦共和国  

開催年月日： 2019年9月

記述言語：英語   会議種別：口頭発表（一般）  

開催地：Buenos Aires   国名：アルゼンチン共和国  

開催年月日： 2019年6月

記述言語：英語   会議種別：口頭発表（一般）  

開催地：Gothenburg   国名：スウェーデン王国  

開催年月日： 2019年6月

記述言語：英語   会議種別：口頭発表（一般）  

開催地：Gothenburg   国名：スウェーデン王国  

開催年月日： 2019年6月

記述言語：英語   会議種別：口頭発表（一般）  

開催地：National Tsing Hua University, Hsinchu   国名：台湾  

開催年月日： 2018年11月

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：麻布大学（相模原）   国名：日本国  

開催年月日： 2018年10月

記述言語：英語   会議種別：口頭発表（一般）  

開催地：Atlanta   国名：アメリカ合衆国  

開催年月日： 2018年9月

記述言語：英語   会議種別：口頭発表（一般）  

開催地：Yerevan   国名：アルメニア共和国  

開催年月日： 2018年7月

記述言語：英語   会議種別：口頭発表（一般）  

開催地：Yokohama   国名：日本国  

開催年月日： 2018年6月

記述言語：英語   会議種別：口頭発表（一般）  

開催地：Milan   国名：イタリア共和国  

開催年月日： 2017年12月

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：神戸ポートアイランド（神戸）   国名：日本国  

開催年月日： 2017年5月

記述言語：英語   会議種別：口頭発表（一般）  

開催地：Copenhagen   国名：デンマーク王国  

開催年月日： 2017年3月

記述言語：英語   会議種別：シンポジウム・ワークショップ パネル（公募）  

開催地：National Institute of Genetics, Shizuoka   国名：日本国  

開催年月日： 2017年3月

記述言語：英語   会議種別：口頭発表（一般）  

開催地：National Institute of Genetics, Shizuoka   国名：日本国  

開催年月日： 2016年11月 - 2016年12月

記述言語：日本語   会議種別：シンポジウム・ワークショップ パネル（公募）  

開催地：横浜、パシフィコ横浜   国名：日本国  

開催年月日： 2016年11月 - 2016年12月

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：横浜、パシフィコ横浜   国名：日本国  

開催年月日： 2016年11月

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：琉球大学   国名：日本国  

開催年月日： 2016年10月

記述言語：英語   会議種別：口頭発表（一般）  

開催地：Vancouver   国名：カナダ  

開催年月日： 2016年10月

記述言語：英語   会議種別：口頭発表（一般）  

開催地：Vancouver   国名：カナダ  

開催年月日： 2016年9月

記述言語：日本語   会議種別：シンポジウム・ワークショップ パネル（公募）  

開催地：仙台国際センター   国名：日本国  

Whole genome sequencing of a Japanese endemic pit viper, habu, Protobothrops flavoviridis reveals venom-related genes enriched in microchromosomal regions.

開催年月日： 2016年9月

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：日本大学国際関係学部北口校舎、三島、静岡   国名：日本国  

開催年月日： 2016年9月

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：日本大学国際関係学部北口校舎、三島、静岡   国名：日本国  

開催年月日： 2016年7月

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：ほほえみの宿 滝の湯、天童   国名：日本国  

開催年月日： 2016年4月

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：国立京都国際会館   国名：日本国  

開催年月日： 2015年12月

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：東邦大学習志野キャンパス   国名：日本国  

開催年月日： 2015年12月

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：神戸ポートアイランド   国名：日本国  

開催年月日： 2015年9月

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：東北大学   国名：日本国  

開催年月日： 2013年12月

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：札幌   国名：日本国  

開催年月日： 2013年11月

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：札幌   国名：日本国  

開催年月日： 2013年9月

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：日吉   国名：日本国  

開催年月日： 2013年8月

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：つくば   国名：日本国  

開催年月日： 2012年12月

記述言語：英語   会議種別：口頭発表（一般）  

開催地：福岡   国名：日本国  

開催年月日： 2012年12月

記述言語：英語   会議種別：口頭発表（一般）  

開催地：福岡   国名：日本国  

開催年月日： 2012年9月

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：福岡   国名：日本国  

開催年月日： 2012年3月

会議種別：口頭発表（一般）  

開催地：シドニー   国名：オーストラリア連邦  

開催年月日： 2011年10月

会議種別：口頭発表（一般）  

開催地：モントリオール   国名：カナダ  

開催年月日： 2010年12月

会議種別：口頭発表（一般）  

開催地：神戸   国名：日本国  

開催年月日： 2010年11月

会議種別：口頭発表（一般）  

開催地：ワシントンDC   国名：アメリカ合衆国  

開催年月日： 2010年10月

会議種別：口頭発表（一般）  

開催地：さいたま   国名：日本国  

開催年月日： 2010年10月

会議種別：口頭発表（一般）  

開催地：さいたま   国名：日本国  

開催年月日： 2010年9月

会議種別：口頭発表（一般）  

開催地：札幌   国名：日本国  

開催年月日： 2010年8月

会議種別：シンポジウム・ワークショップ パネル（公募）  

開催地：東京   国名：日本国  

開催年月日： 2010年7月 - 2010年8月

会議種別：口頭発表（一般）  

開催地：名古屋   国名：日本国  

開催年月日： 2010年3月

会議種別：口頭発表（一般）  

開催地：福岡   国名：日本国  

開催年月日： 2010年3月

会議種別：口頭発表（一般）  

開催地：福岡   国名：日本国  

開催年月日： 2009年12月

会議種別：口頭発表（一般）  

開催地：横浜   国名：日本国  

開催年月日： 2009年10月

会議種別：口頭発表（一般）  

開催地：ホノルル   国名：アメリカ合衆国  

開催年月日： 2009年10月

会議種別：口頭発表（一般）  

開催地：ホノルル   国名：アメリカ合衆国  

開催年月日： 2009年9月

会議種別：口頭発表（一般）  

開催地：東京   国名：日本国  

開催年月日： 2009年9月

会議種別：口頭発表（一般）  

開催地：東京   国名：日本国  

開催年月日： 2009年9月

会議種別：口頭発表（一般）  

開催地：松本   国名：日本国  

開催年月日： 2009年9月

会議種別：口頭発表（一般）  

開催地：札幌   国名：日本国  

開催年月日： 2009年6月

開催地：東京   国名：日本国  

Molecular Evolutionary Study Of The Ionotropic Glutamate-Receptor Gene Family As Schizophrenia Susceptibility Genes: Human-Specific Balancing Selection In GRIN2B Upstream Region

開催年月日： 2008年12月

開催地：神戸   国名：日本国  

開催年月日： 2008年11月

開催地：Philadelphia   国名：アメリカ合衆国  

開催年月日： 2008年10月

会議種別：口頭発表（一般）  

開催地：大阪   国名：日本国  

開催年月日： 2008年10月

開催地：大阪   国名：日本国  

開催年月日： 2008年9月

会議種別：口頭発表（一般）  

開催地：横浜   国名：日本国  

開催年月日： 2008年9月

会議種別：口頭発表（一般）  

開催地：名古屋   国名：日本国  

開催年月日： 2008年8月

会議種別：シンポジウム・ワークショップ パネル（公募）  

開催地：東京   国名：日本国  

開催年月日： 2008年7月

開催地：Berlin   国名：ドイツ連邦共和国  

会議種別：シンポジウム・ワークショップ パネル（公募）  

開催地：横浜   国名：日本国  

会議種別：口頭発表（一般）  

開催地：名古屋   国名：日本国  

会議種別：口頭発表（一般）  

開催地：東京   国名：日本国  

会議種別：口頭発表（一般）  

開催地：岡山   国名：日本国  

会議種別：シンポジウム・ワークショップ パネル（公募）  

開催地：国立遺伝学研究所、三島   国名：日本国  

開催地：米国サンディエゴ   国名：日本国  

開催年月日： 2023年10月 - 2023年11月

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：福岡国際会議場、マリンメッセ福岡   国名：日本国  

開催年月日： 2023年10月 - 2023年11月

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：福岡国際会議場、マリンメッセ福岡   国名：日本国  

開催年月日： 2023年10月

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：アマホーム PLAZA （奄美市市民交流センター）   国名：日本国  

開催年月日： 2023年10月

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：アマホーム PLAZA （奄美市市民交流センター）   国名：日本国  

開催年月日： 2023年9月

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：京都産業大学   国名：日本国  

開催年月日： 2023年9月

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：京都産業大学   国名：日本国  

開催年月日： 2023年9月

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：熊本大学   国名：日本国  

開催年月日： 2023年7月

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：神戸国際会議場   国名：日本国  

開催年月日： 2023年6月

記述言語：日本語   会議種別：シンポジウム・ワークショップ パネル（公募）  

開催地：慶應大学薬学部   国名：日本国  

開催年月日： 2023年5月 - 2023年6月

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：幕張メッセ   国名：日本国  

開催年月日： 2022年12月

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：神戸国際会議場   国名：日本国  

開催年月日： 2022年12月

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：神戸国際会議場   国名：日本国  

開催年月日： 2022年12月

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：神戸国際会議場   国名：日本国  

開催年月日： 2022年11月 - 2022年12月

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：幕張メッセ   国名：日本国  

開催年月日： 2022年11月 - 2022年12月

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：幕張メッセ   国名：日本国  

開催年月日： 2022年11月

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：琉球大学   国名：日本国  

開催年月日： 2022年9月

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：北海道大学   国名：日本国  

開催年月日： 2022年9月

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：北海道大学   国名：日本国  

開催年月日： 2022年9月

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：北海道大学   国名：日本国  

開催年月日： 2022年9月

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：北海道大学   国名：日本国  

開催年月日： 2022年9月

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：オンライン   国名：日本国  

開催年月日： 2021年12月

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：パシフィコ横浜   国名：日本国  

開催年月日： 2021年12月

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：パシフィコ横浜   国名：日本国  

開催年月日： 2021年9月

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：オンライン   国名：日本国  

開催年月日： 2021年9月

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：オンライン   国名：日本国  

開催年月日： 2021年9月

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：オンライン   国名：日本国  

開催年月日： 2020年12月

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：オンライン   国名：日本国  

開催年月日： 2020年12月

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：オンライン   国名：日本国  

開催年月日： 2020年9月

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：オンライン   国名：日本国  

開催年月日： 2020年9月

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：オンライン   国名：日本国  

開催年月日： 2019年12月

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：福岡   国名：日本国  

開催年月日： 2019年12月

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：福岡   国名：日本国  

開催年月日： 2019年12月

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：福岡   国名：日本国  

開催年月日： 2019年12月

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：福岡   国名：日本国  

開催年月日： 2019年11月

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：岡山理科大学、岡山   国名：日本国  

開催年月日： 2019年11月

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：長崎   国名：日本国  

開催年月日： 2019年10月

記述言語：英語   会議種別：口頭発表（一般）  

開催地：Houston, TX   国名：アメリカ合衆国  

開催年月日： 2019年10月

記述言語：英語   会議種別：口頭発表（一般）  

開催地：St. Louis, MO   国名：アメリカ合衆国  

開催年月日： 2019年9月

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：福井   国名：日本国  

開催年月日： 2019年9月

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：福井   国名：日本国  

開催年月日： 2019年2月

記述言語：英語   会議種別：口頭発表（一般）  

開催地：Las Vegas   国名：アメリカ合衆国  

開催年月日： 2018年11月

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：パシフィコ横浜（横浜）   国名：日本国  

開催年月日： 2018年11月

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：パシフィコ横浜（横浜）   国名：日本国  

開催年月日： 2018年11月

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：パシフィコ横浜（横浜）   国名：日本国  

開催年月日： 2018年11月

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：パシフィコ横浜（横浜）   国名：日本国  

開催年月日： 2018年10月

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：国立遺伝学研究所（三島）   国名：日本国  

開催年月日： 2018年10月

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：パシフィコ横浜（横浜）   国名：日本国  

開催年月日： 2018年10月

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：パシフィコ横浜（横浜）   国名：日本国  

開催年月日： 2018年9月

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：奈良先端科学技術大学院大学（奈良）   国名：日本国  

開催年月日： 2018年9月

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：奈良先端科学技術大学院大学（奈良）   国名：日本国  

開催年月日： 2018年9月

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：奈良先端科学技術大学院大学（奈良）   国名：日本国  

開催年月日： 2018年9月

記述言語：英語   会議種別：口頭発表（一般）  

開催地：Jena   国名：ドイツ連邦共和国  

開催年月日： 2018年7月

記述言語：英語   会議種別：口頭発表（一般）  

開催地：Yokohama   国名：日本国  

開催年月日： 2018年7月

記述言語：英語   会議種別：口頭発表（一般）  

開催地：Yokohama   国名：日本国  

開催年月日： 2018年5月

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：ロイトン札幌（札幌）   国名：日本国  

開催年月日： 2017年12月

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：神戸ポートアイランド（神戸）   国名：日本国  

開催年月日： 2017年12月

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：神戸ポートアイランド（神戸）   国名：日本国  

開催年月日： 2017年12月

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：神戸ポートアイランド（神戸）   国名：日本国  

開催年月日： 2017年12月

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：神戸ポートアイランド（神戸）   国名：日本国  

開催年月日： 2017年12月

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：神戸ポートアイランド（神戸）   国名：日本国  

開催年月日： 2017年12月

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：神戸ポートアイランド（神戸）   国名：日本国  

開催年月日： 2017年12月

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：神戸ポートアイランド（神戸）   国名：日本国  

開催年月日： 2017年11月

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：熊本大学（熊本）   国名：日本国  

開催年月日： 2017年11月

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：神戸国際会議場（神戸）   国名：日本国  

開催年月日： 2017年11月

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：神戸国際会議場（神戸）   国名：日本国  

開催年月日： 2017年11月

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：神戸国際会議場（神戸）   国名：日本国  

開催年月日： 2017年11月

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：東京大学本郷キャンパス（東京）   国名：日本国  

開催年月日： 2017年10月

記述言語：英語   会議種別：口頭発表（一般）  

開催地：Okinawa   国名：日本国  

開催年月日： 2017年10月

記述言語：英語   会議種別：口頭発表（一般）  

開催地：Orlando   国名：アメリカ合衆国  

開催年月日： 2017年10月

記述言語：英語   会議種別：口頭発表（一般）  

開催地：San Diego   国名：アメリカ合衆国  

開催年月日： 2017年9月

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：岡山大学   国名：日本国  

開催年月日： 2017年9月

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：岡山大学   国名：日本国  

開催年月日： 2017年9月

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：岡山大学   国名：日本国  

開催年月日： 2017年9月

記述言語：英語   会議種別：口頭発表（一般）  

開催地：Lisbon   国名：ポルトガル共和国  

開催年月日： 2017年8月

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：千里ライフサイエンスセンター（大阪府豊中市）   国名：日本国  

開催年月日： 2017年6月

記述言語：英語   会議種別：口頭発表（一般）  

開催地：San Diego   国名：アメリカ合衆国  

開催年月日： 2017年5月

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：仙台、仙台国際センター   国名：日本国  

開催年月日： 2017年5月

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：名古屋、名古屋国際会議場   国名：日本国  

開催年月日： 2017年4月

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：京都、ロームシアター京都   国名：日本国  

開催年月日： 2017年2月

記述言語：英語   会議種別：口頭発表（一般）  

開催地：Barcelona   国名：スペイン  

開催年月日： 2017年2月

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：はまぎんホール ヴィアマーレ、横浜   国名：日本国  

開催年月日： 2017年2月

記述言語：英語   会議種別：口頭発表（一般）  

開催地：Barcelona   国名：スペイン  

開催年月日： 2016年11月 - 2016年12月

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：横浜、パシフィコ横浜   国名：日本国  

開催年月日： 2016年11月 - 2016年12月

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：パシフィコ横浜、横浜   国名：日本国  

開催年月日： 2016年11月

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：琉球大学   国名：日本国  

Virgin pregnancy of Green anaconda (Eunectes murinus) in long-term captivity.

開催年月日： 2016年10月

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：かごしま県民交流センター   国名：日本国  

開催年月日： 2016年10月

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：産業技術総合研究所臨海副都心センター、東京   国名：日本国  

開催年月日： 2016年10月

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：産業技術総合研究所臨海副都心センター、東京   国名：日本国  

開催年月日： 2016年10月

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：産業技術総合研究所臨海副都心センター、東京   国名：日本国  

開催年月日： 2016年9月

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：和歌山県JAビル   国名：日本国  

開催年月日： 2016年7月

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：Gold Coast, QLD   国名：オーストラリア連邦  

開催年月日： 2015年12月

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：神戸ポートアイランド   国名：日本国  

開催年月日： 2015年12月

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：神戸ポートアイランド   国名：日本国  

開催年月日： 2015年10月

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：産業技術総合研究所 臨海副都心センター   国名：日本国  

開催年月日： 2015年10月

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：産業技術総合研究所 臨海副都心センター   国名：日本国  

開催年月日： 2015年7月

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：つくば国際会議場、筑波   国名：日本国  

開催年月日： 2015年5月

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：福岡大学、福岡   国名：日本国  

開催年月日： 2014年11月

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：パシフィコ横浜、横浜   国名：日本国  

開催年月日： 2014年10月

記述言語：英語   会議種別：口頭発表（一般）  

開催地：San Diego, CA   国名：アメリカ合衆国  

開催年月日： 2014年5月

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：琉球大学   国名：日本国  

開催年月日： 2013年12月

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：神戸   国名：日本国  

開催年月日： 2013年12月

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：神戸   国名：日本国  

開催年月日： 2012年12月

記述言語：英語   会議種別：口頭発表（一般）  

開催地：福岡   国名：日本国  

開催年月日： 2012年11月

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：愛知県豊田市   国名：日本国  

開催年月日： 2012年11月

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：愛知県豊田市   国名：日本国  

開催年月日： 2012年11月

記述言語：英語   会議種別：口頭発表（一般）  

開催地：San Francisco   国名：アメリカ合衆国  

開催年月日： 2012年10月

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：東京   国名：日本国  

開催年月日： 2012年9月

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：福岡   国名：日本国  

開催年月日： 2012年8月

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：東京   国名：日本国  

開催年月日： 2012年8月

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：東京   国名：日本国  

開催年月日： 2012年5月

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：福岡   国名：日本国  

開催年月日： 2012年5月

会議種別：口頭発表（一般）  

開催地：福岡   国名：日本国  

開催年月日： 2012年5月

会議種別：口頭発表（一般）  

開催地：福岡   国名：日本国  

開催年月日： 2012年5月

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：福岡   国名：日本国  

開催年月日： 2011年12月

会議種別：シンポジウム・ワークショップ パネル（公募）  

開催地：横浜   国名：日本国  

開催年月日： 2011年12月

会議種別：口頭発表（一般）  

開催地：横浜   国名：日本国  

開催年月日： 2011年11月

会議種別：口頭発表（一般）  

開催地：千葉   国名：日本国  

開催年月日： 2011年10月

会議種別：口頭発表（一般）  

開催地：モントリオール   国名：カナダ  

開催年月日： 2011年7月

会議種別：口頭発表（一般）  

開催地：京都   国名：日本国  

開催年月日： 2010年12月

会議種別：口頭発表（一般）  

開催地：神戸   国名：日本国  

開催年月日： 2010年11月

会議種別：口頭発表（一般）  

開催地：ワシントンDC   国名：アメリカ合衆国  

開催年月日： 2010年10月

会議種別：口頭発表（一般）  

開催地：さいたま   国名：日本国  

開催年月日： 2010年10月

会議種別：口頭発表（一般）  

開催地：サンフランシスコ   国名：アメリカ合衆国  

開催年月日： 2010年9月

会議種別：口頭発表（一般）  

開催地：京都   国名：日本国  

開催年月日： 2009年12月

会議種別：口頭発表（一般）  

開催地：横浜   国名：日本国  

開催年月日： 2009年12月

会議種別：口頭発表（一般）  

開催地：横浜   国名：日本国  

開催年月日： 2009年12月

会議種別：口頭発表（一般）  

開催地：横浜   国名：日本国  

開催年月日： 2009年9月

会議種別：口頭発表（一般）  

開催地：東京   国名：日本国  

開催年月日： 2008年12月

開催地：神戸   国名：日本国  

開催年月日： 2008年9月

開催地：横浜   国名：日本国  

会議種別：口頭発表（一般）  

開催地：Salt Lake City   国名：アメリカ合衆国  

会議種別：口頭発表（一般）  

開催地：福岡  

会議種別：口頭発表（一般）  

開催地：福岡  

会議種別：口頭発表（一般）  

開催地：福岡  

会議種別：口頭発表（一般）  

開催地：福岡  

会議種別：口頭発表（一般）  

開催地：福岡  

会議種別：口頭発表（一般）  

開催地：米子  

会議種別：口頭発表（一般）  

開催地：京都  

会議種別：口頭発表（一般）  

開催地：Brisbane   国名：オーストラリア連邦  

会議種別：口頭発表（一般）  

開催地：Hong Kong   国名：中華人民共和国  

会議種別：口頭発表（一般）  

開催地：米子   国名：日本国  

会議種別：口頭発表（一般）  

開催地：名古屋   国名：日本国  

会議種別：口頭発表（一般）  

開催地：東京   国名：日本国  

開催地：米国ニューヨーク   国名：日本国  

開催地：横浜   国名：日本国  

開催地：横浜   国名：日本国  

国名：日本国  

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：神戸山手大学   国名：日本国  

会議種別：口頭発表（一般）  

開催地：福岡   国名：日本国  

会議種別：口頭発表（一般）  

開催地：横浜   国名：日本国  

会議種別：口頭発表（一般）  

開催地：横浜   国名：日本国  

会議種別：口頭発表（一般）  

開催地：横浜   国名：日本国  

会議種別：口頭発表（一般）  

開催地：横浜   国名：日本国  

会議種別：口頭発表（一般）  

開催地：横浜   国名：日本国  

会議種別：口頭発表（一般）  

開催地：福岡   国名：日本国  

会議種別：シンポジウム・ワークショップ パネル（公募）  

開催地：福岡   国名：日本国  

会議種別：口頭発表（一般）  

開催地：Brussels   国名：ベルギー王国  

会議種別：口頭発表（一般）  

開催地：Pattaya   国名：タイ王国  

会議種別：口頭発表（一般）  

開催地：名古屋   国名：日本国  

会議種別：口頭発表（一般）  

開催地：名古屋   国名：日本国  

会議種別：口頭発表（一般）  

開催地：横浜   国名：日本国  

会議種別：口頭発表（一般）  

開催地：横浜   国名：日本国  

会議種別：口頭発表（一般）  

開催地：横浜   国名：日本国  

会議種別：口頭発表（一般）  

開催地：横浜   国名：日本国  

会議種別：口頭発表（一般）  

開催地：横浜   国名：日本国  

会議種別：口頭発表（一般）  

開催地：横浜   国名：日本国  

会議種別：口頭発表（一般）  

開催地：横浜   国名：日本国  

会議種別：口頭発表（一般）  

開催地：横浜   国名：日本国  

会議種別：口頭発表（一般）  

開催地：Cancun   国名：メキシコ合衆国  

会議種別：口頭発表（一般）  

開催地：Melbourne   国名：オーストラリア連邦  

会議種別：口頭発表（一般）  

開催地：福岡   国名：日本国  

会議種別：口頭発表（一般）  

開催地：Quebec   国名：カナダ  

会議種別：口頭発表（一般）  

開催地：長崎   国名：日本国  

会議種別：口頭発表（一般）  

開催地：長崎   国名：日本国  

会議種別：口頭発表（一般）  

開催地：長崎   国名：日本国  

服巻 保幸、柴田 弘紀、谷 綾子、藤井 洋、高木 宏美、平田 直嗣、菊田 るみこ、牧野 千絵子、柴田 篤志、二宮 英彰、田代 信維

会議種別：口頭発表（一般）  

開催地：Los Angeles   国名：日本国  

会議種別：口頭発表（一般）  

開催地：Los Angeles   国名：アメリカ合衆国  

会議種別：口頭発表（一般）  

開催地：神戸   国名：日本国  

会議種別：口頭発表（一般）  

開催地：神戸   国名：日本国  

会議種別：口頭発表（一般）  

開催地：神戸   国名：日本国  

会議種別：口頭発表（一般）  

開催地：神戸   国名：日本国  

会議種別：口頭発表（一般）  

開催地：神戸   国名：日本国  

会議種別：口頭発表（一般）  

開催地：東京   国名：日本国  

会議種別：口頭発表（一般）  

開催地：Toronto   国名：カナダ  

会議種別：口頭発表（一般）  

開催地：Biopolis   国名：シンガポール共和国  

会議種別：口頭発表（一般）  

開催地：神戸   国名：日本国  

会議種別：口頭発表（一般）  

開催地：神戸   国名：日本国  

会議種別：口頭発表（一般）  

開催地：神戸   国名：日本国  

会議種別：口頭発表（一般）  

開催地：神戸   国名：日本国  

会議種別：口頭発表（一般）  

開催地：京都   国名：日本国  

会議種別：口頭発表（一般）  

開催地：熊本   国名：日本国  

会議種別：口頭発表（一般）  

開催地：倉敷   国名：日本国