No description available.

No description available.

No description available.

京都大学 / 新制・課程博士 / 博士(医学) / 甲第23774号 / 医博第4820号 / 新制||医||1057(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 伊佐 正, 教授 高橋 淳, 教授 井上 治久 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

<p>Giant cell tumour of bone (GCT) is an aggressive primary bone tumour with an unclear etiology that presents with significant local osteolysis due in part to the accumulation of multinucleated osteoclast-like giant cells. However, it is the neoplastic spindle-like stromal cells within GCT that largely direct the pathogenesis of the tumour. I hypothesize that parathyroid hormone-related protein (PTHrP) is a key mediator within GCT that promotes the characteristic osteolytic phenotype by stimulating both bone resorption and giant cell formation. The work presented in this thesis collectively demonstrates that the stromal cells express PTHrP and its receptor, the parathyroid hormone type 1 receptor (PTH1R), and that PTHrP acts in an autocrine/paracrine manner within the tumour to stimulate expression of factors that promote bone resorption. Data are presented that demonstrate that PTHrP stimulates stromal cell expression of the receptor activator of nuclear factor-κB ligand (RANKL), a known essential regulator of osteoclastogenesis, which results in increased formation of multinucleated cells from murine monocytes. Moreover, the GCT stromal cells express matrix metalloproteinase (MMP)-1 and MMP-13. These results suggest that the stromal cells may participate directly in bone resorption through the degradation of type I collagen, the promotion of osteoclast activity, or through a combination of these elements. PTHrP also regulates the expression of MMP-13 by the stromal cells. Experiments with CD40 ligand show that local factors present within the tumour can influence PTHrP expression by the stromal cells and potentiate its catabolic effects by stimulation of RANKL and MMP-13 expression. Together, this thesis presents evidence that suggests PTHrP is an important factor in the pathophysiology of GCT by its actions on promoting catabolism within the tumour. The role of PTHrP in normal physiology and the mechanisms of action presented here suggest that research into the effects of PTHrP within GCT may provide invaluable information that enhances our understanding of the biology of this particularly aggressive bone tumour.</p> / Doctor of Philosophy (PhD)

<p> The conditions ideally suited for blue straggler star formation are for the most part unknown, though there is mounting evidence to suggest that the preferred blue straggler formation pathway, whether it be via the coalescence of a primordial binary system or through the collision of two single main-sequence stars, depends largely on the cluster environment. In this thesis we are trying to isolate the preferred blue straggler formation mechanism(s) operating in various globular cluster environments by comparing relative blue straggler frequencies to global cluster properties.</p> <p> We define a series of selection rules to isolate the blue stragglers from main-sequence turn-off and extended horizontal branch stars in the colour-magnitude diagrams of 57 globular clusters taken from HST images of their central cores. The boundary conditions were defined using only the main-sequence turn-off as a point of reference, and are hence applied consistently from cluster to cluster. We chose to count only those stars found within one core radius of the cluster center in an effort to obtain a sample that is approximately representative of a uniform cluster environment where, ideally, a single blue straggler formation mechanism is predominantly operating. Relative frequencies of blue straggler stars are then found using the red giant branch for normalization and are subsequently analyzed. We confirm the anticorrelation between relative blue straggler frequency and total integrated cluster luminosity previously observed by Piotto et al. (2004), and find a new anticorrelation between relative blue straggler frequency and the central velocity dispersion, as well as a weak anticorrelation with the half-mass relaxation time. We find no other statistically significant trends. Observational implications pertaining to blue straggler formation mechanisms are then discussed.</p> <p> We present a very simple, semi-analytic model designed in an attempt to reproduce the observed trends in the core. Using estimates for the collisional timescales, we find that only a small percentage of the blue stragglers produced are a direct result of collisions. The majority of the blue stragglers created in our model are thus products of mass-transfer in tight, low-mass binary systems. We were surprised to find a reasonably good agreement between the data and our predictions, given the simplicity of our model. Our results suggest that the binary fraction could be a crucial parameter in shaping blue straggler populations, and hence better and more abundant observations of binary systems and their numbers could prove an important step in gaining a better understanding of blue straggler formation mechanisms.</p> / Thesis / Master of Science (MSc)

Astrophysical phenomena such as exploding primordial black holes (PBHs), gamma-ray bursts (GRBs), compact object mergers, and supernovae, are expected to produce a single pulse of electromagnetic radiation detectable at the low-frequency end of the radio spectrum. Detection of any of these pulses would be significant for the study of the objects themselves, their host environments, and the interstellar/intergalactic medium. Furthermore, a detection of a radio transient from an exploding PBH could be a signature of an extra spatial dimension, which would drastically alter our perception of spacetime. However, even upper limits on the existence of PBHs, from transient searches, would be important to discussions of cosmology. We describe a method to carry out an agnostic single-dispersed-pulse search, and apply it to data collected with the Eight-meter-wavelength Transient Array (ETA). ETA is a radio telescope dedicated to searching for transient pulses. It consists of 12 crossed-dipole antenna stands with Galactic-noise-limited performance from 29-47 MHz. There is a vast amount of data collected from an ETA observation. It is therefore greatly beneficial to use a computer cluster, which works in parallel on different parts of a data set, in order to carry out a single-pulse search quickly and efficiently. Each spectrogram in a data set needs to be analyzed individually, without reference to the rest, in order to utilize a computer cluster's capabilities. The data reduction software has been developed for single-dispersed-pulse searches, and is described in this thesis. The data reduction involves sweeping through the collected data with a dedispersion routine assuming a range of dispersion measures. The resulting time series are searched with multiple matched filters for signals above a signal-to-noise threshold. Applying the single pulse search to ~ 30 hours of ETA data did not yield a compelling detection of an astrophysical signal. However, from ≈ 5 hours of interference-free data we find an observational upper limit to the rate of exploding PBHs of r ≈ 4.8 × 10⁻⁷ pc⁻³ y⁻¹ for a PBH with a fireball Lorentz-factor f = 10^4.3. This limit is applicable to PBHs in the halo of the Galaxy to distances ≲ 2 kpc, and dispersion measures ≲ 80 pc cm⁻³ . We also find a source-agnostic rate limit ≲ 0.25 events y⁻¹ deg⁻² for pulses of duration < 3 s, and having apparent energy densities ≳ 2.6 × 10⁻²³ J m⁻² Hz⁻¹ at 38 MHz. / Ph. D.

Herbicide combinations are common in corn production in the United States to control broadleaf and grass weed species. Studies were conducted in 1995 and 1996 to: (1) investigate the interactions of 2,4-D and dicamba with halosulfuron-methyl on common lambsquarters and common ragweed control in corn, (2) determine the effect of 2,4-D on the foliar absorption, translocation, and metabolism of 14C halosulfuron-methyl in common lambsquarters, (3) examine the interactions of 2,4-D, dicamba, and ALS-inhibitor herbicides with rimsulfuron plus thifensulfuron-methyl (RT) and with sethoxydim on giant foxtail, common ragweed, and common lambsquarters control in corn. Combinations of halosulfuron-methyl with 2,4-D or dicamba were generally additive in their effects on common lambsquarters and common ragweed control, and were occasionally synergistic on common lambsquarters. Synergistic herbicide interactions in the greenhouse were observed with 2,4-D (17 g/ha ) and halosulfuron-methyl (18 g/ha) and 2,4-D (70 g/ha ) in combination with halosulfuron-methyl at 4.5 and 36 g/ha, respectively. Absorption and translocation of 14C-halosulfuron-methyl were not influenced by the addition of 2,4-D, with absorption increasing with time. Three unknown halosulfuron-methyl metabolites (M1, M2, and M3) with Rf values of 0.0, 0.97, and 0.94, respectively, were isolated. The addition of 2,4-D increased the level of M3 at the 18 g/ha halosulfuron-methyl rate, which may contribute to common lambsquarters phytotoxicity. Antagonism on giant foxtail control was observed with all combinations of RT and 2,4-D. Tank mixtures of RT with flumetsulam plus clopyralid plus 2,4-D, atrazine, 2,4-D, and dicamba plus atrazine controlled giant foxtail £ 78% 65 (DAT). RT mixed with flumetsulam plus clopyralid plus 2,4-D injured corn 26%, and yields were reduced 34% when compared to RT alone. Giant foxtail control from sethoxydim tank-mixed with bentazon plus atrazine with urea ammonium nitrate (UAN), or with ALS-inhibiting herbicides except halosulfuron-methyl in combination with 2,4-D was 24% lower when averaged over treatments. Yields of sethoxydim-resistant (SR) corn treated with sethoxydim mixed with combinations of sulfonylurea herbicides plus 2,4-D were low, with the exception of the combination halosulfuron-methyl with sethoxydim and 2,4-D. These studies indicate that thoroughly understanding postemergence (POST) corn herbicide tank mixtures is crucial for effective weed management. / Ph. D.

<p dir="ltr">We present a model describing an impact jetting origin for the formation of chondrules, the mm– scale, igneous components of chondritic meteorites which originated during the first few million years of solar system history. The ubiquity of chondrules in both non-carbonaceous and carbonaceous chondrites suggests their formation persisted throughout the protoplanetary disk, but their formation mechanism is debated and largely unexplored in the outer disk.<b> </b>Using the iSALE2D shock physics code, we generate models of the process of impact jetting during mixed material (dunite and water ice) impacts that mimic accretionary impacts that form giant planet cores. We show that the process of impact jetting provides the conditions necessary to satisfy critical first-order constraints on chondrule characteristics (size, shape, thermal history). We then explore the implications of chondrule formation by impact jetting during the formation of giant planet cores by combining the original results with simulations of giant planet core accretion generated using a Lagrangian Integrator for Planetary Accretion and Dynamics (LIPAD) code.</p><p dir="ltr">The second closest Galilean satellite to Jupiter is Europa, an ocean world with an outer ice shell and subsurface water ocean encapsulating its rocky core. The surface of Europa is covered in double ridges. These features are defined by two topographic highs about 100 meters tall, with a central trough between them, which extend for hundreds of kilometers over the surface of the moon. Accurate models for the formation of features as prominent as double ridges will help to further constrain the interior structure and dynamics of the interior of the body. We use analytical and numerical finite element models to show that the incremental growth of an ice wedge within the ice shell can cause deformation matching the observed size and shape of observed double ridges on Europa. These models indicate that the total height and width of the ridges correspond to the depth of the wedge, so that deeper wedges create shorter and broader ridges. We consider different sources for the wedge material and ultimately argue in favor of local sources of liquid water within the ice shell.</p>

Nucleocytoplasmic large DNA viruses (NCLDVs) have genome sizes that range from around 100 kilobases (kb) to up to 2.5 megabases, and virion sizes that can reach up to 1.5 μm. Their large size in both of these contexts is atypical and defies the traditional view that viruses are streamlined, "filterable infectious agents". NCLDVs include many diverse groups, including Poxviruses, Asfarviruses, Iridoviruses, Mimiviruses, and Marseilleviruses. Poxviruses are perhaps the most well-studied; these viruses have 135-360 kbp genomes with about half of the genes encoding essential replication genes and the other half encoding genes related to host-virus interactions. Many of the genes involved in host-virus interactions are involved in immunomodulatory processes and have homology to proteins encoded by the host. These viral genes, often referred to as "mimics", are therefore believed to be the result of host-to-virus gene transfer. In this study I sought to examine if common poxvirus immunomodulatory genes were found in other NCLDV lineages, and if so, to analyze the evolutionary history of these genes. I identified 5 protein families of immunomodulatory genes that were found in both poxviruses and other NCLDV lineages, and I used phylogenetic tools to compare viral immunomodulatory genes of NCLDVs to their eukaryotic orthologs to evaluate the number of times different NCLDV lineages have acquired these genes. Our phylogenetic analyses showed that several viral immunomodulatory genes were acquired multiple times by different NCLDV lineages, while others appear to have been transferred between viral groups. Interestingly, some NCLDV genes clustered together with homologs from the unrelated Herpesviridae family, suggesting that inter-viral gene exchange can traverse vast evolutionary distances. The vast diversity of hosts infected by different NCLDV lineages suggests that these immunomodulatory genes play key roles that are useful to viruses in a variety of contexts. This research provides insight into how giant viruses acquire host genes, which contribute to their large genome size, and how those genes evolved to subvert antiviral defenses. / Master of Science / Giant viruses are a relatively recent discovery, from the beginning of this century. Nucleocytoplasmic large DNA viruses (NCLDVs) are a classification of multiple giant virus families. These viruses have large genomes from around 100 kilobases to 2.5 megabases of DNA. For reference, the genome size of the flu virus is approximately 13 kilobases. Most viruses cannot be seen by the human eye, even with microscopes, but giant viruses can get as big as bacteria, which can be seen with microscopes. It is unknown how or why these viruses get so large. One explanation is that they steal genes from their host and those genes evolve to work against the host. In this thesis, I explored some of the genes that these viruses have picked up. I curated a set of 49 previously characterized viral genes to analyze in this context. These genes have to do with modulating the host immune system and are known as "immunomodulatory genes". Viral immunomodulatory genes are often mimics of the host genes which function to help the immune system. However, a virus evolves faster than a host and the virus mimic gene can evolve to work against the immune system. This change can be visualized using phylogenetic tools; the viral genes will be more similar to each other than to the host genes and cluster separately on a phylogenetic tree. About half of the genes of Poxviruses, a giant virus family that has viruses that infect humans, are related to virus-host interactions, and include viral mimic genes. Poxviruses have been far better studied than other NCLDV families because of their public health importance. Variola virus, the virus that causes smallpox, is a poxvirus. Other NCLDV infect animals, algae, and amoeba. Though their hosts are different, their genomes have similar features. I set out to discover whether some of these previously characterized viral immunomodulatory genes that exist in poxviruses also exist in other NCLDV families. I utilized phylogenetic tools and a database of giant virus sequences to figure out which genes are being picked up by which family of NCLDV. I also sought to determine whether the individual NCLDV families have their own acquired immunomodulatory gene or have a gene very similar to all other families, suggesting an ancient acquisition. If the gene is very similar, it suggests that an ancestor of the NCLDV acquired the gene and it has stuck around as the group diverged into families. It is also interesting if different families stole the same type of gene multiple times because that indicates the importance of that gene in subverting the antiviral immune system for viral replication. This work provides insight into how giant viruses acquire host genes, which contribute to their large genome size, and how they evolved those genes to subvert antiviral defenses.