実験的歯の移動に伴う根尖部歯根吸収における抗炎症薬投与の影響

内容の要旨 , 審査の要旨広島大学(Hiroshima University)博士(歯学)Doctor of Philosophy in Dental Sciencedoctora

Fine definition of the pedigree haplotypes of closely related rice cultivars by means of genome-wide discovery of single-nucleotide polymorphisms

<p>Abstract</p> <p>Background</p> <p>To create useful gene combinations in crop breeding, it is necessary to clarify the dynamics of the genome composition created by breeding practices. A large quantity of single-nucleotide polymorphism (SNP) data is required to permit discrimination of chromosome segments among modern cultivars, which are genetically related. Here, we used a high-throughput sequencer to conduct whole-genome sequencing of an elite Japanese rice cultivar, Koshihikari, which is closely related to Nipponbare, whose genome sequencing has been completed. Then we designed a high-throughput typing array based on the SNP information by comparison of the two sequences. Finally, we applied this array to analyze historical representative rice cultivars to understand the dynamics of their genome composition.</p> <p>Results</p> <p>The total 5.89-Gb sequence for Koshihikari, equivalent to 15.7× the entire rice genome, was mapped using the Pseudomolecules 4.0 database for Nipponbare. The resultant Koshihikari genome sequence corresponded to 80.1% of the Nipponbare sequence and led to the identification of 67 051 SNPs. A high-throughput typing array consisting of 1917 SNP sites distributed throughout the genome was designed to genotype 151 representative Japanese cultivars that have been grown during the past 150 years. We could identify the ancestral origin of the pedigree haplotypes in 60.9% of the Koshihikari genome and 18 consensus haplotype blocks which are inherited from traditional landraces to current improved varieties. Moreover, it was predicted that modern breeding practices have generally decreased genetic diversity</p> <p>Conclusions</p> <p>Detection of genome-wide SNPs by both high-throughput sequencer and typing array made it possible to evaluate genomic composition of genetically related rice varieties. With the aid of their pedigree information, we clarified the dynamics of chromosome recombination during the historical rice breeding process. We also found several genomic regions decreasing genetic diversity which might be caused by a recent human selection in rice breeding. The definition of pedigree haplotypes by means of genome-wide SNPs will facilitate next-generation breeding of rice and other crops.</p

ロコモ マット トレーニング ガ コウレイシャ ノ タイリョク オヨビ ニンチ キノウ ニ オヨボス エイキョウ ニカンスル ケンキュウ

Preventing falls, declined locomotor and cognitive functionsare critical factors for maintaining independent life in older adults. Exercise intervention is known to bring a beneficial effect in their life. Here, we examined whether a home-based exercise using Locomo-mat affects physical and cognitive functions in elderlyor not. We measured physical performance tests （balance, time up and go test and walking speed） and cognitive test （working memory and dual task performances） in twenty-four older people. Twelve-subjects inthe exercise group performedfifteen minutes of Locomo-mat training about three times per week, whereasother subject in the control group did not perform any particular trainings. After two months of training, the exercise group significantly improved in balance, walking speed and dual task performances than in the control group. The results demonstratethat the home-based Locomo-mat exercise may be useful training for preventing age-related physical and cognitive decline in the elderly

Phosphorylation of the RSRSP stretch is critical for splicing regulation by RNA-Binding Motif Protein 20 (RBM20) through nuclear localization

RBM20 is a major regulator of heart-specific alternative pre-mRNA splicing of TTN encoding a giant sarcomeric protein titin. Mutation in RBM20 is linked to autosomal-dominant familial dilated cardiomyopathy (DCM), yet most of the RBM20 missense mutations in familial and sporadic cases were mapped to an RSRSP stretch in an arginine/serine-rich region of which function remains unknown. In the present study, we identified an R634W missense mutation within the stretch and a G1031X nonsense mutation in cohorts of DCM patients. We demonstrate that the two serine residues in the RSRSP stretch are constitutively phosphorylated and mutations in the stretch disturb nuclear localization of RBM20. Rbm20 S637A knock-in mouse mimicking an S635A mutation reported in a familial case showed a remarkable effect on titin isoform expression like in a patient carrying the mutation. These results revealed the function of the RSRSP stretch as a critical part of a nuclear localization signal and offer the Rbm20 S637A mouse as a good model for in vivo study

Genome-Wide Haplotype Changes Produced by Artificial Selection during Modern Rice Breeding in Japan

During the last 90 years, the breeding of rice has delivered cultivars with improved agronomic and economic characteristics. Crossing of different lines and successive artificial selection of progeny based on their phenotypes have changed the chromosomal constitution of the ancestors of modern rice; however, the nature of these changes is unclear. The recent accumulation of data for genome-wide single-nucleotide polymorphisms (SNPs) in rice has allowed us to investigate the change in haplotype structure and composition. To assess the impact of these changes during modern breeding, we studied 177 Japanese rice accessions, which were categorized into three groups: landraces, improved cultivars developed from 1931 to 1974 (the early breeding phase), and improved cultivars developed from 1975 to 2005 (the late breeding phase). Phylogenetic tree and structure analysis indicated genetic differentiation between non-irrigated (upland) and irrigated (lowland) rice groups as well as genetic structuring within the irrigated rice group that corresponded to the existence of three subgroups. Pedigree analysis revealed that a limited number of landraces and cultivars was used for breeding at the beginning of the period of systematic breeding and that 11 landraces accounted for 70% of the ancestors of the modern improved cultivars. The values for linkage disequilibrium estimated from SNP alleles and the haplotype diversity determined from consecutive alleles in five-SNP windows indicated that haplotype blocks became less diverse over time as a result of the breeding process. A decrease in haplotype diversity, caused by a reduced number of polymorphisms in the haplotype blocks, was observed in several chromosomal regions. However, our results also indicate that new haplotype polymorphisms have been generated across the genome during the breeding process. These findings will facilitate our understanding of the association between particular haplotypes and desirable phenotypes in modern Japanese rice cultivars

Uncovering of major genetic factors generating naturally occurring variation in heading date among Asian rice cultivars

To dissect the genetic factors controlling naturally occurring variation of heading date in Asian rice cultivars, we performed QTL analyses using F2 populations derived from crosses between a japonica cultivar, Koshihikari, and each of 12 cultivars originating from various regions in Asia. These 12 diverse cultivars varied in heading date under natural field conditions in Tsukuba, Japan. Transgressive segregation was observed in 10 F2 combinations. QTL analyses using multiple crosses revealed a comprehensive series of loci involved in natural variation in flowering time. One to four QTLs were detected in each cross combination, and some QTLs were shared among combinations. The chromosomal locations of these QTLs corresponded well with those detected in other studies. The allelic effects of the QTLs varied among the cross combinations. Sequence analysis of several previously cloned genes controlling heading date, including Hd1, Hd3a, Hd6, RFT1, and Ghd7, identified several functional polymorphisms, indicating that allelic variation at these loci probably contributes to variation in heading date. Taken together, the QTL and sequencing results indicate that a large portion of the phenotypic variation in heading date in Asian rice cultivars could be generated by combinations of different alleles (possibly both loss- and gain-of-function) of the QTLs detected in this study

Protection of Macaques with Diverse MHC Genotypes against a Heterologous SIV by Vaccination with a Deglycosylated Live-Attenuated SIV

HIV vaccine development has been hampered by issues such as undefined correlates of protection and extensive diversity of HIV. We addressed these issues using a previously established SIV-macaque model in which SIV mutants with deletions of multiple gp120 N-glycans function as potent live attenuated vaccines to induce near-sterile immunity against the parental pathogenic SIVmac239. In this study, we investigated the protective efficacy of these mutants against a highly pathogenic heterologous SIVsmE543-3 delivered intravenously to rhesus macaques with diverse MHC genotypes. All 11 vaccinated macaques contained the acute-phase infection with blood viral loads below the level of detection between 4 and 10 weeks postchallenge (pc), following a transient but marginal peak of viral replication at 2 weeks in only half of the challenged animals. In the chronic phase, seven vaccinees contained viral replication for over 80 weeks pc, while four did not. Neutralizing antibodies against challenge virus were not detected. Although overall levels of SIV specific T cell responses did not correlate with containment of acute and chronic viral replication, a critical role of cellular responses in the containment of viral replication was suggested. Emergence of viruses with altered fitness due to recombination between the vaccine and challenge viruses and increased gp120 glycosylation was linked to the failure to control SIV. These results demonstrate the induction of effective protective immune responses in a significant number of animals against heterologous virus by infection with deglycosylated attenuated SIV mutants in macaques with highly diverse MHC background. These findings suggest that broad HIV cross clade protection is possible, even in hosts with diverse genetic backgrounds. In summary, results of this study indicate that deglycosylated live-attenuated vaccines may provide a platform for the elucidation of correlates of protection needed for a successful HIV vaccine against diverse isolates

The Constrained Maximal Expression Level Owing to Haploidy Shapes Gene Content on the Mammalian X Chromosome.

X chromosomes are unusual in many regards, not least of which is their nonrandom gene content. The causes of this bias are commonly discussed in the context of sexual antagonism and the avoidance of activity in the male germline. Here, we examine the notion that, at least in some taxa, functionally biased gene content may more profoundly be shaped by limits imposed on gene expression owing to haploid expression of the X chromosome. Notably, if the X, as in primates, is transcribed at rates comparable to the ancestral rate (per promoter) prior to the X chromosome formation, then the X is not a tolerable environment for genes with very high maximal net levels of expression, owing to transcriptional traffic jams. We test this hypothesis using The Encyclopedia of DNA Elements (ENCODE) and data from the Functional Annotation of the Mammalian Genome (FANTOM5) project. As predicted, the maximal expression of human X-linked genes is much lower than that of genes on autosomes: on average, maximal expression is three times lower on the X chromosome than on autosomes. Similarly, autosome-to-X retroposition events are associated with lower maximal expression of retrogenes on the X than seen for X-to-autosome retrogenes on autosomes. Also as expected, X-linked genes have a lesser degree of increase in gene expression than autosomal ones (compared to the human/Chimpanzee common ancestor) if highly expressed, but not if lowly expressed. The traffic jam model also explains the known lower breadth of expression for genes on the X (and the Z of birds), as genes with broad expression are, on average, those with high maximal expression. As then further predicted, highly expressed tissue-specific genes are also rare on the X and broadly expressed genes on the X tend to be lowly expressed, both indicating that the trend is shaped by the maximal expression level not the breadth of expression per se. Importantly, a limit to the maximal expression level explains biased tissue of expression profiles of X-linked genes. Tissues whose tissue-specific genes are very highly expressed (e.g., secretory tissues, tissues abundant in structural proteins) are also tissues in which gene expression is relatively rare on the X chromosome. These trends cannot be fully accounted for in terms of alternative models of biased expression. In conclusion, the notion that it is hard for genes on the Therian X to be highly expressed, owing to transcriptional traffic jams, provides a simple yet robustly supported rationale of many peculiar features of X's gene content, gene expression, and evolution

Catholic Reformation and urban societies in France : the Jesuit Marian congregations in the 17th and 18th centuries

Apparues en 1563, sous la forme d’associations d’élèves de collèges jésuites, les congrégations mariales se développent rapidement dans le contexte de la Réforme catholique, en s’étendant à l’ensemble des fidèles, encadrés selon leur âge et milieu social. Encouragées par la papauté, les autorités civiles et religieuses, comme « un rempart contre les hérétiques », ces congrégations restent liées entre elles du fait de leur agrégation à la congrégation, initiale, du Collège romain (Prima Primaria). Ses membres suivent les mêmes Règles communes, et ils bénéficient de ses indulgences. En se soumettant à divers exercices, et en s’obligeant à une vie spirituelle exemplaire, ils créent l’émulation dans leur entourage familial et professionnel. En France, les congrégations mariales s’implantent prioritairement dans les lieux destinés à l’éducation et sur les frontières entre catholiques et protestants, en premier lieu, pour former les futures élites chrétiennes et gagner les élites urbaines. Fondée, vers 1630, dans la maison professe des jésuites de Paris, la Congrégation des Messieurs rassemble les dévots des classes dirigeantes de la capitale. Parmi ceux-ci, on relève plusieurs grandes figures qui s’inscrivent, conjointement, dans d’autres cercles dévots, comme la Compagnie du Saint-Sacrement. Souvent, au sortir de leurs études dans les collèges jésuites, s’étant élevé socialement, ces dévots poursuivent leur vie congréganiste, en s’appuyant sur leur parenté et leurs relations, pour s’efforcer d’agir dans la cité vers une perfection chrétienne. Cette sociabilité, poursuivie de génération en génération, est d’autant plus précieuse dans les milieux de l’artisanat. Le réseau ainsi créé, qui apporte un secours tant spirituel que matériel, constitue également une structure d’accueil dans leur mobilité.Y aurait-il un déclin général des congrégations mariales au siècle des Lumières ? Le nombre de leurs créations diminue, dans un premier temps. Puis, ces associations se trouvent affectées par les querelles qui se développent entre jésuites et jansénistes, autour de la bulle Unigenitus. À Paris, par exemple, on constate surtout un recul du nombre des magistrats des cours souveraines, compensé par une augmentation du nombre des ecclésiastiques antijansénistes et philojésuites. Pourtant, cet apparent déclin est loin d’être unanime, selon les milieux sociaux et les régions. On constate, durant la seconde moitié du XVIIe siècle et jusqu’au XVIIIe siècle, une augmentation des effectifs des Congrégations des Artisans, et même la multiplication de ces congrégations dans la province jésuite de Lyon. Cette extension vers des catégories sociales plus modestes passe également par l’accueil de femmes. On pourrait s’étonner, aussi, d’y constater la vitalité des demandes des messes pour les morts. Le cas de la Congrégation des Artisans de Montpellier est exemplaire. Cette sodalité conserve, en effet, une réelle attractivité dans la vie associative et religieuse montpelliéraine, même après l’expulsion de la Société de Jésus, et elle maintient le réseau tissé avec les autres congrégations mariales affiliées à la Primaria. Les congrégations mariales ont donc évolué : elles ne se limitent plus à des cercles de dévots mais, en s’étendant à des catégories sociales plus modestes, elles forment désormais une communauté de « bons chrétiens ». Elles nous offrent, alors, un nouvel éclairage sur le comportement religieux des sociétés urbaines au siècle des Lumières.The Marian congregations appeared in 1563, as association of Jesuit College students, and developed rapidly in the context of the Catholic Reformation, extending to all faithful, supervised according to their age and social backgrounds. Encouraged by the papacy, civil and religious authorities, as a "rampart against the heretics", these congregations remained interconnected because of their aggregation to the initial congregation of the Roman College (Prima Primaria). Its members followed the same Common Rules, and they benefited from its indulgences. By submitting to various exercises, and by committing themselves to an exemplary spiritual life, they created emulation in their family connections and professional relationships.In France, Marian congregations were firstly established in places for education and on the borders between Catholics and Protestants, their main purpose being to train the future Christian elites and to gain the urban elites. Founded around 1630 in the Jesuit professed house of Paris, the Congregation of Gentlemen (Messieurs), gathered the “dévots” of the ruling classes of the capital. Among these are several great figures which are jointly inscribed in other devout circles, such as the Company of the Holy Sacrament. Often, as a result of their studies in Jesuit colleges, having risen socially, these dévots pursued their congregation activity, relying on their kinship and their relations, to strive to act in the city towards a Christian perfection. This sociability pursued from generation to generation was all the more valuable among the artisans. The network thus created, which bring both spiritual and material assistance, was also a welcome structure in their mobility.Would there be a general decline of the Marian congregations in the Age of Enlightenment? Indeed, the number of newly created foundations decreased, at first. Then, these associations were affected by the conflict which had developed between Jesuits and Jansenists, around the bull Unigenitus. In Paris, for example, the number of sovereign courts magistrates, specifically, declined. This decrease was compensated by an increase in number of anti-Jansenist and philo-Jesuit clergy. However, this apparent decline is far from unanimous, depending on social categories and regions. Research shows, in the second half of the seventeenth century and up until the eighteenth century, an increase of the numbers of the Congregations of Artisans, and even the multiplication of these congregations in the Jesuit province of Lyon. This extension to more modest social categories also involves the reception of women. It is remarkable, too, to note the vitality of the demands of the masses for the dead. The case of the Congregation of the Artisans in Montpellier is exemplary. This sodality retained a real attractiveness in Montpellier's religious and associative life, even after the expulsion of the Society of Jesus, and it maintained the network with the other Marian congregations affiliated to the Primaria.Marian congregations have evolved: they are no longer confined to circles of dévots, but by extending to more modest social categories, they now form a community of "good Christians". They then give us a new insight into the religious behavior of urban societies during the Age of the Enlightenment