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1.  Genomic Prediction of Biological Shape: Elliptic Fourier Analysis and Kernel Partial Least Squares (PLS) Regression Applied to Grain Shape Prediction in Rice (Oryza sativa L.) 
PLoS ONE  2015;10(3):e0120610.
Shape is an important morphological characteristic both in animals and plants. In the present study, we examined a method for predicting biological contour shapes based on genome-wide marker polymorphisms. The method is expected to contribute to the acceleration of genetic improvement of biological shape via genomic selection. Grain shape variation observed in rice (Oryza sativa L.) germplasms was delineated using elliptic Fourier descriptors (EFDs), and was predicted based on genome-wide single nucleotide polymorphism (SNP) genotypes. We applied four methods including kernel PLS (KPLS) regression for building a prediction model of grain shape, and compared the accuracy of the methods via cross-validation. We analyzed multiple datasets that differed in marker density and sample size. Datasets with larger sample size and higher marker density showed higher accuracy. Among the four methods, KPLS showed the highest accuracy. Although KPLS and ridge regression (RR) had equivalent accuracy in a single dataset, the result suggested the potential of KPLS for the prediction of high-dimensional EFDs. Ordinary PLS, however, was less accurate than RR in all datasets, suggesting that the use of a non-linear kernel was necessary for accurate prediction using the PLS method. Rice grain shape can be predicted accurately based on genome-wide SNP genotypes. The proposed method is expected to be useful for genomic selection in biological shape.
PMCID: PMC4380318  PMID: 25825876
2.  Parainfectious encephalomyeloradiculitis associated with bacterial meningitis: a case report 
Acute disseminated encephalomyelitis in adulthood occurs in most cases after a viral infection. Acute disseminated encephalomyelitis associated with bacterial meningitis, however, is quite rare.
Case presentation
An 82-year-old Japanese woman presented with a fever and somnolence. Increased neutrophil count and protein content, and decreased glucose levels in her cerebrospinal fluid initially suggested bacterial meningitis. Brain magnetic resonance imaging on admission showed bilateral symmetrical lesions in her brainstem and her cerebellum. She was diagnosed with acute disseminated encephalomyelitis following bacterial meningitis. Even though appropriate antibiotic and steroid treatment improved her symptoms, she developed transverse myelitis and lumbosacral polyradiculitis on day 9.
Parainfectious encephalomyeloradiculitis, a variant of acute disseminated encephalomyelitis, is a unique neurological syndrome that may be caused by bacterial infection in the central nervous system.
PMCID: PMC4332421  PMID: 25889740
Acute disseminated encephalomyelitis; Bacterial meningitis; Encephalomyeloradiculitis; Polyradiculoneuropathy; Post-infectious
3.  Major QTLs associated with green stem disorder insensitivity of soybean (Glycine max (L.) Merr.) 
Breeding Science  2014;64(4):331-338.
Green stem disorder (GSD) is one of the most serious syndromes affecting soybean (Glycine max) cultivation in Japan. In GSD, stems remain green even when pods mature. When soybean plants develop GSD, seed surfaces are soiled by tissue fluid and seed quality is deteriorated during machine harvesting. We performed quantitative trait locus (QTL) analyses for GSD insensitivity using recombinant inbred lines (RILs; n = 154) derived from a cross between an insensitive line (‘Touhoku 129’) and a sensitive leading cultivar (‘Tachinagaha’) during a 6-year evaluation. Three effective QTLs were detected. The influences of these QTLs were in the following order: qGSD1 (LG_H) > qGSD2 (LG_F) > qGSD3 (LG_L). At these three QTLs, ‘Touhoku 129’ genotypes exhibited more GSD insensitivity than ‘Tachinagaha’ genotypes. The lower incidence of GSD for ‘Touhoku129’ was attributable primarily to these three QTLs because RILs harboring a ‘Touhoku 129’ genotype at the three QTLs exhibited a GSD incidence similar to that of ‘Touhoku 129.’ Although a limitation of this study is that only one mapping population was evaluated, this QTL information and the flanking markers of these QTLs would be effective tools for resolving GSD in soybean breeding programs.
PMCID: PMC4267307  PMID: 25914587
Glycine max (L.) Merr.; soybean; green stem disorder; qGSD1; maturity gene; QTL; DNA marker
4.  Identification of QTLs controlling harvest time and fruit skin color in Japanese pear (Pyrus pyrifolia Nakai) 
Breeding Science  2014;64(4):351-361.
Using an F1 population from a cross between Japanese pear (Pyrus pyrifolia Nakai) cultivars ‘Akiakari’ and ‘Taihaku’, we performed quantitative trait locus (QTL) analysis of seven fruit traits (harvest time, fruit skin color, flesh firmness, fruit weight, acid content, total soluble solids content, and preharvest fruit drop). The constructed simple sequence repeat-based genetic linkage map of ‘Akiakari’ consisted of 208 loci and spanned 799 cM; that of ‘Taihaku’ consisted of 275 loci and spanned 1039 cM. Out of significant QTLs, two QTLs for harvest time, one for fruit skin color, and one for flesh firmness were stably detected in two successive years. The QTLs for harvest time were located at the bottom of linkage group (LG) Tai3 (nearest marker: BGA35) and at the top of LG Tai15 (nearest markers: PPACS2 and MEST050), in good accordance with results of genome-wide association study. The PPACS2 gene, a member of the ACC synthase gene family, may control harvest time, preharvest fruit drop, and fruit storage potential. One major QTL associated with fruit skin color was identified at the top of LG 8. QTLs identified in this study would be useful for marker-assisted selection in Japanese pear breeding programs.
PMCID: PMC4267310  PMID: 25914590
Akiakari; fruit traits; genetic linkage map; quantitative trait locus; SSR marker; Taihaku
5.  Identification of QTLs for fruit quality traits in Japanese apples: QTLs for early ripening are tightly related to preharvest fruit drop 
Breeding Science  2014;64(3):240-251.
Many important apple (Malus × domestica Borkh.) fruit quality traits are regulated by multiple genes, and more information about quantitative trait loci (QTLs) for these traits is required for marker-assisted selection. In this study, we constructed genetic linkage maps of the Japanese apple cultivars ‘Orin’ and ‘Akane’ using F1 seedlings derived from a cross between these cultivars. The ‘Orin’ map consisted of 251 loci covering 17 linkage groups (LGs; total length 1095.3 cM), and the ‘Akane’ map consisted of 291 loci covering 18 LGs (total length 1098.2 cM). We performed QTL analysis for 16 important traits, and found that four QTLs related to harvest time explained about 70% of genetic variation, and these will be useful for marker-assisted selection. The QTL for early harvest time in LG15 was located very close to the QTL for preharvest fruit drop. The QTL for skin color depth was located around the position of MYB1 in LG9, which suggested that alleles harbored by ‘Akane’ are regulating red color depth with different degrees of effect. We also analyzed soluble solids and sugar component contents, and found that a QTL for soluble solids content in LG16 could be explained by the amount of sorbitol and fructose.
PMCID: PMC4154613  PMID: 25320559
fruit drop; genetic variance; harvest time; Malus × domestica; QTL analysis; skin color depth; sugar composition
6.  Genomic prediction of trait segregation in a progeny population: a case study of Japanese pear (Pyrus pyrifolia) 
BMC Genetics  2013;14:81.
In cross breeding, it is important to choose a good parental combination that has high probability of generating offspring with desired characteristics. This study examines a method for predicting the segregation of target traits in a progeny population based on genome-wide markers and phenotype data of parental cultivars.
The proposed method combines segregation simulation and Bayesian modeling for genomic selection. Marker segregation in a progeny population was simulated based on parental genotypes. Posterior marker effects sampled via Markov Chain Monte Carlo were used to predict the segregation pattern of target traits. The posterior distribution of the proportion of progenies that fulfill selection criteria was calculated and used for determining a promising cross and the necessary size of the progeny population. We applied the proposed method to Japanese pear (Pyrus pyrifolia Nakai) data to demonstrate the method and to show how it works in the selection of a promising cross. Verification using an actual breeding population suggests that the segregation of target traits can be predicted with reasonable accuracy, especially in a highly heritable trait. The uncertainty in predictions was reflected on the posterior distribution of the proportion of progenies that fulfill selection criteria. A simulation study based on the real marker data of Japanese pear cultivars also suggests the potential of the method.
The proposed method is useful to provide objective and quantitative criteria for choosing a parental combination and the breeding population size.
PMCID: PMC3847345  PMID: 24028660
Genomic selection; Selection of a parental combination; Segregation simulation; Bayesian modeling; Markov Chain Monte Carlo (MCMC); Genome-wide markers; Ordinal categorical scores
7.  Detection and verification of QTLs associated with heat-induced quality decline of rice (Oryza sativa L.) using recombinant inbred lines and near-isogenic lines 
Breeding Science  2013;63(3):339-346.
Decline in the apparent quality of rice (Oryza sativa L.) grain due to high temperatures during ripening recently became a major concern in many areas in Japan. The occurrence of white-back kernels (WBK) is one of the main problems of heat-induced quality decline. We identified QTLs associated with the occurrence of WBK using recombinant inbred lines (RILs) and verified their effects using near-isogenic lines (NILs). The QTL analysis used F7 and F8 RILs derived from ‘Hana-echizen’ (HE), which is tolerant to high temperature, × ‘Niigata-wase’ (NW), which is sensitive to high temperature. Four QTLs were identified on chromosomes 3, 4, 6, and 9 (qWB3, qWB4, qWB6 and qWB9). To verify the effects of qWB6 and qWB9, we developed two NILs in which qWB6 or both were introduced from HE into the NW background. The HE allele at qWB6 significantly decreased WBK under multiple environments. The combination of qWB6 and qWB9 in an F2 population derived from a cross between a NIL and NW showed that the NW allele at qWB9 significantly decreased WBK if the qWB6 allele was HE. These results will be of value in marker-assisted selection for the breeding of rice with tolerance to heat-induced quality decline.
PMCID: PMC3770562  PMID: 24273430
white-back kernels; rice breeding; QTL; high temperature; heat-induced quality decline
8.  Creation of Readily Accessible and Orally Active Analogue of Cortistatin A 
ACS Medicinal Chemistry Letters  2012;3(8):673-677.
Syntheses of structurally simplified analogues of cortistatin A (1), a novel antiangiogenic steroidal alkaloid from Indonesian marine sponge, and their biological activities were investigated. The analogues were designed by considering the 3-D structure of 1. Compound 30, in which the isoquinoline moiety was appended to the planar tetracyclic core structure, showed potent antiproliferative activity against human umbilical vein endothelial cells (HUVECs) together with high selectivity and also showed in vivo antiangiogenic activity and significant antitumor effect by oral administration.
PMCID: PMC4025756  PMID: 24900528
Cortistatin A; antiangiogenesis; marine sponge; analogue synthesis; structure−activity relationship
9.  Effects of co-administration of candesartan with pioglitazone on inflammatory parameters in hypertensive patients with type 2 diabetes mellitus: a preliminary report 
Angiotensin receptor blockers (ARBs) are reported to provide direct protection to many organs by controlling inflammation and decreasing oxidant stress. Pioglitazone, an anti-diabetic agent that improves insulin resistance, was also reported to decrease inflammation and protect against atherosclerosis. This study aimed to evaluate the utility of combination therapy with both medicines from the viewpoint of anti-inflammatory effects.
We administered candesartan (12 mg daily) and pioglitazone (15 mg daily) simultaneously for 6 months to hypertensive patients with type 2 diabetes mellitus (T2DM) and evaluated whether there were improvements in the serum inflammatory parameters of high-molecular-weight adiponectin (HMW-ADN), plasminogen activator inhibitor-1 (PAI-1), highly sensitive C-reactive protein (Hs-CRP), vascular cell adhesion molecule-1 (VCAM-1), and urinary-8-hydroxydeoxyguanosine (U-8-OHdG). We then analyzed the relationship between the degree of reductions in blood pressure and HbA1c values and improvements in inflammatory factors. Furthermore, we analyzed the relationship between pulse pressure and the degree of lowering of HbA1c and improvements in inflammatory factors. Finally, we examined predictive factors in patients who received benefits from the co-administration of candesartan with pioglitazone from the viewpoint of inflammatory factors.
After 6 months of treatment, in all patients significant improvements from baseline values were observed in HMW-ADN and PAI-1 but not in VCAM-1, Hs-CRP, and U-8-OHdG. Changes in HbA1c were significantly correlated with changes in HMW-ADN and PAI-1 in all patients, but changes in blood pressure were not correlated with any of the parameters examined. Correlation and multilinear regression analyses were performed to determine which factors could best predict changes in HbA1c. Interestingly, we found a significant positive correlation of pulse pressure values at baseline with changes in HbA1c.
Our data suggest that the pulse pressure value at baseline is a key predictive factor of changes in HbA1c. Co-administration of candesartan with pioglitazone, which have anti-inflammatory (changes in HMW-ADN and PAI-1) effects and protective effects on organs, could be an effective therapeutic strategy for treating hypertensive patients with type 2 diabetes mellitus.
Trial registration
UMIN-CTR: UMIN000010142
PMCID: PMC3663745  PMID: 23635096
Candesartan; Angiotensin receptor blockers; Type 2 diabetes mellitus; Inflammatory parameters; Pulse pressure
10.  Potential assessment of genome-wide association study and genomic selection in Japanese pear Pyrus pyrifolia 
Breeding Science  2013;63(1):125-140.
Although the potential of marker-assisted selection (MAS) in fruit tree breeding has been reported, bi-parental QTL mapping before MAS has hindered the introduction of MAS to fruit tree breeding programs. Genome-wide association studies (GWAS) are an alternative to bi-parental QTL mapping in long-lived perennials. Selection based on genomic predictions of breeding values (genomic selection: GS) is another alternative for MAS. This study examined the potential of GWAS and GS in pear breeding with 76 Japanese pear cultivars to detect significant associations of 162 markers with nine agronomic traits. We applied multilocus Bayesian models accounting for ordinal categorical phenotypes for GWAS and GS model training. Significant associations were detected at harvest time, black spot resistance and the number of spurs and two of the associations were closely linked to known loci. Genome-wide predictions for GS were accurate at the highest level (0.75) in harvest time, at medium levels (0.38–0.61) in resistance to black spot, firmness of flesh, fruit shape in longitudinal section, fruit size, acid content and number of spurs and at low levels (<0.2) in all soluble solid content and vigor of tree. Results suggest the potential of GWAS and GS for use in future breeding programs in Japanese pear.
PMCID: PMC3621438  PMID: 23641189
genome-wide association study (GWAS); genomic selection (GS); Japanese pear; ordinal categorical traits; harvest time; black spot resistance
11.  Respiratory Chain Analysis of Zymomonas mobilis Mutants Producing High Levels of Ethanol 
Applied and Environmental Microbiology  2012;78(16):5622-5629.
We previously isolated respiratory-deficient mutant (RDM) strains of Zymomonas mobilis, which exhibited greater growth and enhanced ethanol production under aerobic conditions. These RDM strains also acquired thermotolerance. Morphologically, the cells of all RDM strains were shorter compared to the wild-type strain. We investigated the respiratory chains of these RDM strains and found that some RDM strains lost NADH dehydrogenase activity, whereas others exhibited reduced cytochrome bd-type ubiquinol oxidase or ubiquinol peroxidase activities. Complementation experiments restored the wild-type phenotype. Some RDM strains seem to have certain mutations other than the corresponding respiratory chain components. RDM strains with deficient NADH dehydrogenase activity displayed the greatest amount of aerobic growth, enhanced ethanol production, and thermotolerance. Nucleotide sequence analysis revealed that all NADH dehydrogenase-deficient strains were mutated within the ndh gene, which includes insertion, deletion, or frameshift. These results suggested that the loss of NADH dehydrogenase activity permits the acquisition of higher aerobic growth, enhanced ethanol production, and thermotolerance in this industrially important strain.
PMCID: PMC3406159  PMID: 22660712
12.  A Bayesian method and its variational approximation for prediction of genomic breeding values in multiple traits 
BMC Bioinformatics  2013;14:34.
Genomic selection is an effective tool for animal and plant breeding, allowing effective individual selection without phenotypic records through the prediction of genomic breeding value (GBV). To date, genomic selection has focused on a single trait. However, actual breeding often targets multiple correlated traits, and, therefore, joint analysis taking into consideration the correlation between traits, which might result in more accurate GBV prediction than analyzing each trait separately, is suitable for multi-trait genomic selection. This would require an extension of the prediction model for single-trait GBV to multi-trait case. As the computational burden of multi-trait analysis is even higher than that of single-trait analysis, an effective computational method for constructing a multi-trait prediction model is also needed.
We described a Bayesian regression model incorporating variable selection for jointly predicting GBVs of multiple traits and devised both an MCMC iteration and variational approximation for Bayesian estimation of parameters in this multi-trait model. The proposed Bayesian procedures with MCMC iteration and variational approximation were referred to as MCBayes and varBayes, respectively. Using simulated datasets of SNP genotypes and phenotypes for three traits with high and low heritabilities, we compared the accuracy in predicting GBVs between multi-trait and single-trait analyses as well as between MCBayes and varBayes. The results showed that, compared to single-trait analysis, multi-trait analysis enabled much more accurate GBV prediction for low-heritability traits correlated with high-heritability traits, by utilizing the correlation structure between traits, while the prediction accuracy for uncorrelated low-heritability traits was comparable or less with multi-trait analysis in comparison with single-trait analysis depending on the setting for prior probability that a SNP has zero effect. Although the prediction accuracy with varBayes was generally lower than with MCBayes, the loss in accuracy was slight. The computational time was greatly reduced with varBayes.
In genomic selection for multiple correlated traits, multi-trait analysis was more beneficial than single-trait analysis and varBayes was much advantageous over MCBayes in computational time, which would outweigh the loss of prediction accuracy caused by the approximation procedure, and is thus considered a practical method of choice.
PMCID: PMC3574034  PMID: 23363272
Genomic selection; Multiple traits; Bayesian regression; MCMC iteration; Variational approximation
13.  Migraine prevalence in patients with atrial septal defect 
Patients with a patent foramen ovale have a high prevalence of migraine with aura (MA). However, whether patients with an atrial septal defect (ASD) have a high prevalence of migraine remains unclear. The present study aimed to determine the prevalence of migraine and its clinical characteristics in patients with ASD.
Ninety-five patients (age ≥ 20 years) who had undergone percutaneous ASD closure responded to a questionnaire used by neurologists to diagnose migraine either with or without aura. We diagnosed migraine before ASD closure according to the criteria of the International Headache Society. The overall prevalence of migraine seemed to be higher in the present study than in the Japanese general population (24.2% vs. 9.4%, respectively). All patients with MA were female and significantly younger than those without migraine (p < 0.01).
Our findings suggested that the susceptibility to the development of MA differs according to sex and age in patients with cardiac shunt.
PMCID: PMC3728011  PMID: 23883108
Atrial septal defect; Right-to-left shunt; Migraine
14.  Effects of candesartan in hypertensive patients with type 2 diabetes mellitus on inflammatory parameters and their relationship to pulse pressure 
Angiotensin receptor blockers (ARBs) are reported to provide direct protection to many organs by controlling inflammation and decreasing oxidant stress in patients without arteriosclerosis. This study aimed to evaluate (1) whether an ARB (candesartan) decreases values for inflammatory parameters in hypertensive patients with type 2 diabetes mellitus of long duration accompanied by arteriosclerosis and (2) whether there any predictors of which patients would receive the benefits of organ protection by candesartan.
We administered candesartan therapy (12 mg daily) for 6 months and evaluated whether there was improvement in serum inflammatory parameters high molecular weight adiponectin (HMW-ADN), plasminogen activator inhibitor-1 (PAI-1), highly sensitive C-reactive protein (Hs-CRP), vascular cell adhesion molecule-1 (VCAM-1) in serum and urinary-8-hydroxydeoxyguanosine (U-8-OHdG). We then analyzed the relationship between the degree of lowering of blood pressure and inflammatory factors and the relationship between pulse pressure and inflammatory factors. Finally, we analyzed predictive factors in patients who received the protective benefit of candesartan.
After 6 months of treatment, significant improvements from baseline values were observed in all patients in HMW-ADN and PAI-1 but not in Hs-CRP, VCAM-1 and U-8-OHdG. Multilinear regression analysis was performed to determine which factors could best predict changes in HMW-ADN and PAI-1. Changes in blood pressure were not significant predictors of changes in metabolic factors in all patients. We found that the group with baseline pulse pressure <60 mmHg had improved HMW-ADN and PAI-1 values compared with the group with baseline pulse pressure ≥ 60 mmHg. These results suggest that pulse pressure at baseline could be predictive of changes in HMW-ADN and PAI-1.
Candesartan improved inflammatory parameters (HMW-ADN and PAI-1) in hypertensive patients with type 2 diabetes mellitus of long duration independent of blood pressure changes. Patients with pulse pressure <60 mmHg might receive protective benefits by candesartan.
Trial registration
PMCID: PMC3489584  PMID: 23034088
Candesartan; Angiotensin receptor blockers; Type 2 diabetes mellitus; Inflammatory parameters; Pulse pressure
15.  Relationship between smoking and a new index of arterial stiffness, the cardio-ankle vascular index, in male workers: a cross-sectional study 
Tobacco Induced Diseases  2012;10(1):11.
Cigarette smoking is one of the major factors that increases arterial stiffness. The purpose of this study was to examine further the relationship between smoking status and arterial stiffness using a new index, the cardio-ankle vascular index (CAVI), in male Japanese workers.
This cross-sectional study included 4,729 male Japanese workers undergoing annual health checkups. CAVI was measured at the time of the annual health checkup between April 2007 and March 2008. The subjects were divided into three groups, smokers (n = 1,913), former smokers (n = 1,481) and non-smokers (n = 1,348) according to their responses to a questionnaire. We compared the CAVI in the three groups after adjusting for age. Multiple regression analysis was used to examine the association between CAVI and the number of cigarettes smoked per day in order to examine whether there was a dose–response relationship between smoking and CAVI.
The mean CAVI for each group was 7.81 ± 0.02 for smokers, 7.70 ± 0.02 for former smokers and 7.64 ± 0.02 for non-smokers. A significant difference was observed between each group. According to the results of multiple regression analysis, the standardized β of the number of cigarettes smoked per day was 0.09 (p < 0.01). This confirmed a positive association with CAVI.
Our study demonstrated that there is a significant association between the number of cigarettes smoked per day and arterial stiffness, as measured by CAVI.
PMCID: PMC3489890  PMID: 22839736
Cardio-ankle vascular index; Smoking; Arterial stiffness; Cardiovascular disease
16.  Low bone mineral density is associated with the onset of spontaneous osteonecrosis of the knee 
Acta Orthopaedica  2012;83(3):249-255.
Background and purpose
The primary event preceding the onset of symptoms in spontaneous osteonecrosis in the medial femoral condyle (SONK) may be a subchondral insufficiency fracture, which may be associated with underlying low bone mineral density (BMD). However, the pathogenesis of SONK is considered to be multifactorial. Women over 60 years of age tend to have higher incidence of SONK and low BMD. We investigated whether there may be an association between low BMD and SONK in women who are more than 60 years old.
We compared the BMD of 26 women with SONK within 3 months after the onset of symptoms to that of 26 control women with medial knee osteoarthritis (OA). All the SONK patients had typical clinical presentations and met specified criteria on MRI. The BMDs measured at the lumbar spine, ipsilateral femoral neck, and knee condyles and the ratios of medial condyle BMD to lateral condyle BMD (medial-lateral ratios) in the femur and tibia were compared between the two groups. The medial-lateral ratios were used as parameters for comparisons of the BMDs at both condyles.
The mean femoral neck, lateral femoral condyle, and lateral tibial condyle BMDs were between x% and y% lower in the SONK patients than in the OA patients (p < 0.001). The mean femoral and tibial medial-lateral ratios were statistically significantly higher in the SONK patients than in the OA patients.
A proportion of women over 60 years of age have low BMD that progresses rapidly after menopause and can precipitate a microfracture. These findings support the subchondral insufficiency fracture theory for the onset of SONK based on low BMD.
PMCID: PMC3369150  PMID: 22537352
17.  Emergency response technical work at Fukushima Dai-ichi nuclear power plant: occupational health challenges posed by the nuclear disaster 
PMCID: PMC3400146  PMID: 22499247
Radiation; heat; stress; injury; personal protective equipment; epidemiology; occupational health practice; communicable diseases; risk assessment
18.  The reverse, but coordinated, roles of Tor2 (TORC1) and Tor1 (TORC2) kinases for growth, cell cycle and separase-mediated mitosis in Schizosaccharomyces pombe 
Open biology  2011;1(3):110007.
Target of rapamycin complexes (TORCs), which are vital for nutrient utilization, contain a catalytic subunit with the phosphatidyl inositol kinase-related kinase (PIKK) motif. TORC1 is required for cell growth, while the functions of TORC2 are less well understood. We show here that the fission yeast Schizosaccharomyces pombe TORC2 has a cell cycle role through determining the proper timing of Cdc2 Tyr15 dephosphorylation and the cell size under limited glucose, whereas TORC1 restrains mitosis and opposes securin–separase, which are essential for chromosome segregation. These results were obtained using the previously isolated TORC1 mutant tor2-L2048S in the phosphatidyl inositol kinase (PIK) domain and a new TORC2 mutant tor1-L2045D, which harbours a mutation in the same site. While mutated TORC1 and TORC2 displayed diminished kinase activity and FKBP12/Fkh1-dependent rapamycin sensitivity, their phenotypes were nearly opposite in mitosis. Premature mitosis and the G2–M delay occurred in TORC1 and TORC2 mutants, respectively. Surprisingly, separase/cut1—securin/cut2 mutants were rescued by TORC1/tor2-L2048S mutation or rapamycin addition or even Fkh1 deletion, whereas these mutants showed synthetic defect with TORC2/tor1-L2045D. TORC1 and TORC2 coordinate growth, mitosis and cell size control, such as Wee1 and Cdc25 do for the entry into mitosis.
PMCID: PMC3352084  PMID: 22645648
target of rapamycin; rapamycin; Fkh1; Cdc2; separase
19.  Mis17 Is a Regulatory Module of the Mis6-Mal2-Sim4 Centromere Complex That Is Required for the Recruitment of CenH3/CENP-A in Fission Yeast 
PLoS ONE  2011;6(3):e17761.
The centromere is the chromosome domain on which the mitotic kinetochore forms for proper segregation. Deposition of the centromeric histone H3 (CenH3, CENP-A) is vital for the formation of centromere-specific chromatin. The Mis6-Mal2-Sim4 complex of the fission yeast S. pombe is required for the recruitment of CenH3 (Cnp1), but its function remains obscure.
Methodology/Principal Findings
Mass spectrometry was performed on the proteins precipitated with Mis6- and Mis17-FLAG. The results together with the previously identified Sim4- and Mal2-TAP precipitated proteins indicated that the complex contains 12 subunits, Mis6, Sim4, Mal2, Mis15, Mis17, Cnl2, Fta1-4, Fta6-7, nine of which have human centromeric protein (CENP) counterparts. Domain dissection indicated that the carboxy-half of Mis17 is functional, while its amino-half is regulatory. Overproduction of the amino-half caused strong negative dominance, which led to massive chromosome missegregation and hypersensitivity to the histone deacetylase inhibitor TSA. Mis17 was hyperphosphorylated and overproduction-induced negative dominance was abolished in six kinase-deletion mutants, ssp2 (AMPK), ppk9 (AMPK), ppk15 (Yak1), ppk30 (Ark1), wis4 (Ssk2), and lsk1 (P-TEFb).
Mis17 may be a regulatory module of the Mis6 complex. Negative dominance of the Mis17 fragment is exerted while the complex and CenH3 remain at the centromere, a result that differs from the mislocalization seen in the mis17-362 mutant. The known functions of the kinases suggest an unexpected link between Mis17 and control of the cortex actin, nutrition, and signal/transcription. Possible interpretations are discussed.
PMCID: PMC3061866  PMID: 21445296
20.  Identification of a second gene associated with variation in vertebral number in domestic pigs 
BMC Genetics  2011;12:5.
The number of vertebrae in pigs varies and is associated with body size. Wild boars have 19 vertebrae, but European commercial breeds for pork production have 20 to 23 vertebrae. We previously identified two quantitative trait loci (QTLs) for number of vertebrae on Sus scrofa chromosomes (SSC) 1 and 7, and reported that an orphan nuclear receptor, NR6A1, was located at the QTL on SSC1. At the NR6A1 locus, wild boars and Asian local breed pigs had the wild-type allele and European commercial-breed pigs had an allele associated with increased numbers of vertebrae (number-increase allele).
Here, we performed a map-based study to define the other QTL, on SSC7, for which we detected genetic diversity in European commercial breeds. Haplotype analysis with microsatellite markers revealed a 41-kb conserved region within all the number-increase alleles in the present study. We also developed single nucleotide polymorphisms (SNPs) in the 450-kb region around the QTL and used them for a linkage disequilibrium analysis and an association study in 199 independent animals. Three haplotype blocks were detected, and SNPs in the 41-kb region presented the highest associations with the number of vertebrae. This region encodes an uncharacterized hypothetical protein that is not a member of any other known gene family. Orthologs appear to exist not only in mammals but also birds and fish. This gene, which we have named vertnin (VRTN) is a candidate for the gene associated with variation in vertebral number. In pigs, the number-increase allele was expressed more abundantly than the wild-type allele in embryos. Among candidate polymorphisms, there is an insertion of a SINE element (PRE1) into the intron of the Q allele as well as the SNPs in the promoter region.
Genetic diversity of VRTN is the suspected cause of the heterogeneity of the number of vertebrae in commercial-breed pigs, so the polymorphism information should be directly useful for assessing the genetic ability of individual animals. The number-increase allele of swine VRTN was suggested to add an additional thoracic segment to the animal. Functional analysis of VRTN may provide novel findings in the areas of developmental biology.
PMCID: PMC3024977  PMID: 21232157
21.  Visceral Fat Area and Markers of Insulin Resistance in Relation to Colorectal Neoplasia 
Diabetes Care  2009;33(1):184-189.
Although abdominal obesity and related metabolic abnormalities are hypothesized to promote colorectal carcinogenesis, direct confirmation of this effect is required. Here, we examined the relation of early-stage colorectal neoplasia to visceral fat area and markers of insulin resistance.
Subjects were participants in a comprehensive health screening conducted at the Hitachi Health Care Center, Ibaraki, Japan. During a 3-year period (2004–2007), a total of 108 patients with early-stage colorectal neoplasia, including 22 with early cancer, were identified among individuals who received both colorectal cancer screening and abdominal computed tomography scanning. Three control subjects matched to each case subject were randomly selected from those whose screening results were negative. Conditional logistic regression analysis was used to examine the association of measures of obesity and markers of insulin resistance with colorectal neoplasia, with adjustment for smoking and alcohol drinking.
Visceral fat area, but not subcutaneous fat area, was significantly positively associated with colorectal cancer, with odds ratios (95% CI) for the lowest to highest tertile of visceral fat area of 1 (reference), 2.17 (0.45–10.46), and 5.92 (1.22–28.65), respectively (Ptrend = 0.02). Markers of insulin resistance, particularly fasting glucose, were also positively associated with colorectal cancer risk. In contrast, no associations were observed for colorectal adenomas.
These results suggest that visceral adipose tissue accumulation and insulin resistance may promote the development of early-stage cancer but not adenoma in the colorectum.
PMCID: PMC2797970  PMID: 19837793
22.  Fission Yeast Scm3 Mediates Stable Assembly of Cnp1 (CENP-A) into Centromeric Chromatin 
Molecular cell  2009;33(3):287-298.
Mis16 and Mis18 are subunits of a protein complex required for incorporation of the histone H3 variant CenH3 (Cnp1/CENP-A) into centromeric chromatin in Schizosaccharomyces pombe and mammals. How the Mis16-Mis18 complex performs this function is unknown. Here we report that the Mis16-Mis18 complex is required for centromere localization of Scm3Sp, a Cnp1-binding protein related to Saccharomyces cerevisiae Scm3. Scm3Sp is required for centromeric localization of Cnp1, whilst Scm3Sp localizes at centromeres independently of Cnp1. Like the Mis16-Mis18 complex but unlike Cnp1, Scm3Sp dissociates from centromeres during mitosis. Inactivation of Scm3Sp or Mis18 increases centromere localization of histones H3 and H2A/H2B, which are largely absent from centromeres in wild type cells. Whereas S. cerevisiae Scm3 is proposed to replace histone H2A/H2B in centromeric nucleosomes, the dynamic behavior of S. pombe Scm3 suggests that it acts as a Cnp1 assembly/maintenance factor that directly mediates the stable deposition of Cnp1 into centromeric chromatin.
PMCID: PMC2677390  PMID: 19217403
23.  EM algorithm for Bayesian estimation of genomic breeding values 
BMC Genetics  2010;11:3.
In genomic selection, a model for prediction of genome-wide breeding value (GBV) is constructed by estimating a large number of SNP effects that are included in a model. Two Bayesian methods based on MCMC algorithm, Bayesian shrinkage regression (BSR) method and stochastic search variable selection (SSVS) method, (which are called BayesA and BayesB, respectively, in some literatures), have been so far proposed for the estimation of SNP effects. However, much computational burden is imposed on the MCMC-based Bayesian methods. A method with both high computing efficiency and prediction accuracy is desired to be developed for practical use of genomic selection.
EM algorithm applicable for BSR is described. Subsequently, we propose a new EM-based Bayesian method, called wBSR (weighted BSR), which is a modification of BSR incorporating a weight for each SNP according to the strength of its association to a trait. Simulation experiments show that the computational time is much reduced with wBSR based on EM algorithm and the accuracy in predicting GBV is improved by wBSR in comparison with BSR based on MCMC algorithm. However, the accuracy of predicted GBV with wBSR is inferior to that with SSVS based on MCMC algorithm which is currently considered to be a method of choice for genomic selection.
EM-based wBSR method proposed in this study is much advantageous over MCMC-based Bayesian methods in computational time and can predict GBV more accurately than MCMC-based BSR. Therefore, wBSR is considered a practical method for genomic selection with a large number of SNP markers.
PMCID: PMC2845064  PMID: 20092655
24.  A case of hypoxic encephalopathy with delayed exacerbation 
Most patients contract hypoxic encephalopathy after suffering a cardiac arrest. They usually endure severe neurological sequelae and the temporal profile of the disease progression remains unclear. This case study shows how the effects of hypoxic encephalopathy continue to progress for several years after the initial event. Up to eight years after the hypoxic insult, the patient’s intellect steadily deteriorated, and brain atrophy progressed. As the hypoxic insult on the brain is only transient, the neurological disability seems not to be exacerbated for years. However, our case indicates that this disorder may have a long progression.
PMCID: PMC2840540  PMID: 20428410
dementia; encephalopathy; hypoxia; MRI
25.  Fabp7 Maps to a Quantitative Trait Locus for a Schizophrenia Endophenotype 
PLoS Biology  2007;5(11):e297.
Deficits in prepulse inhibition (PPI) are a biological marker for schizophrenia. To unravel the mechanisms that control PPI, we performed quantitative trait loci (QTL) analysis on 1,010 F2 mice derived by crossing C57BL/6 (B6) animals that show high PPI with C3H/He (C3) animals that show low PPI. We detected six major loci for PPI, six for the acoustic startle response, and four for latency to response peak, some of which were sex-dependent. A promising candidate on the Chromosome 10-QTL was Fabp7 (fatty acid binding protein 7, brain), a gene with functional links to the N-methyl-D-aspartic acid (NMDA) receptor and expression in astrocytes. Fabp7-deficient mice showed decreased PPI and a shortened startle response latency, typical of the QTL's proposed effects. A quantitative complementation test supported Fabp7 as a potential PPI-QTL gene, particularly in male mice. Disruption of Fabp7 attenuated neurogenesis in vivo. Human FABP7 showed altered expression in schizophrenic brains and genetic association with schizophrenia, which were both evident in males when samples were divided by sex. These results suggest that FABP7 plays a novel and crucial role, linking the NMDA, neurodevelopmental, and glial theories of schizophrenia pathology and the PPI endophenotype, with larger or overt effects in males. We also discuss the results from the perspective of fetal programming.
Author Summary
A startle response to an unexpected, strong startling stimulus can be suppressed by an immediately preceding low-intensity stimulus, thereby eliciting little behavioral response. This phenomenon, called prepulse inhibition (PPI), has been observed in all mammals tested and is thought to reflect sensory-motor gating functions in organisms. PPI is diminished in human schizophrenia, raising the possibility that PPI might serve as a potential biological marker for the disease. Once the genes regulating PPI in lower animals are identified, it is expected that the human orthologs will be strong candidate genes for schizophrenia. In this study, we first performed a genetic dissection of mouse PPI using quantitative trait loci analysis, which detects chromosomal regions harboring causative genes. Further analyses including those of knockout mice, allowed us to identify one potential causative gene, Fabp7 (fatty acid binding protein 7, brain), a chaperon for the essential fatty acid docosahexaenoic acid. Human studies showed that the FABP7 gene is modestly associated with schizophrenia and that transcript expression levels are up-regulated in schizophrenic brains. From these results, we propose that a FABP7 protein-mediated disturbance of essential lipid metabolism in developing brains may be one risk factor in the development of schizophrenia, with a greater effect in males.
The search for responsible genes for prepulse inhibition, a measure deemed to be a biological trait in schizophrenia, has exposed a gene encoding essential fatty acid-binding protein.
PMCID: PMC2071943  PMID: 18001149

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