出生後軟骨膜におけるIKKβはMCP-5の発現抑制を介して成長板内軟骨性骨化を間接的に制御する

京都大学0048新制・課程博士博士(医学)甲第19223号医博第4022号新制||医||1010(附属図書館)32222京都大学大学院医学研究科医学専攻(主査)教授 妻木 範行, 教授 開 祐司, 教授 松田 秀一学位規則第4条第1項該当Doctor of Medical ScienceKyoto UniversityDFA

Chiral phonons: circularly polarized Raman spectroscopy and ab initio\textit{ab initio} calculations in a chiral crystal tellurium

Recently, phonons with chirality (chiral phonons) have attracted significant attention. Chiral phonons exhibit angular and pseudo-angular momenta. In circularly polarized Raman spectroscopy, the peak split of the $\Gamma_3$ mode is detectable along the principal axis of the chiral crystal in the backscattering configuration. In addition, peak splitting occurs when the pseudo-angular momenta of the incident and scattered circularly polarized light are reversed. Until now, chiral phonons in binary crystals have been observed, whereas those in unary crystals have not been observed. Here, we observe chiral phonons in a chiral unary crystal Te. The pseudo-angular momentum of the phonon is obtained in Te by an $\textit{ab initio}$ calculation. From this calculation, we verified the conservation law of pseudo-angular momentum in Raman scattering. From this conservation law, we determined the handedness of the chiral crystals. We also evaluated the true chirality of the phonons using a measure with symmetry similar to that of an electric toroidal monopole

Higher incidence of aseptic loosening caused by a lower canal filling ratio with a modified modular stem in total hip arthroplasty

Purpose: Although a cementless modular prosthesis has shown reliable results, cases of unstable fixation and revision due to aseptic loosening were observed in our institute. The purpose of this study was to clarify the causes of unstable fixation of the prosthesis.Methods: A total of 144 patients (154 hips) who underwent total hip arthroplasty using the modular prosthesis were retrospectively investigated. For the cohort study, 97 patients (104 hips) were included. The femoral component survival rate and sleeve fixation were assessed at a minimum follow-up of 5 years. Patients were divided into 2 groups, including stable and unstable fixation groups,by sleeve fixation. Clinical and radiographic outcomes were compared. Results: The Kaplan-Meier survival rate at 9 years was 93% with revision for any reason as the endpoint in study cohort. The reasons for revision were recurrent dislocation (1 hip) and aseptic loosening of the stem (5 hips). A total of 88 hips (84.6%) showed stable fixation, and 16 hips (15.4%) showed unstable fixation at final follow-up. There was no significant difference in clinical outcomes between the 2 groups at final follow-up. The canal flare index was significantly higher, and the canal filling ratio was significantly lower in the unstable fixation group. Conclusion: Although the modified modular prosthesis was useful for treating anatomically difficult patients, we need to pay attention to both proximal/distal mismatch of the intramedullary canal and the canal filling ratio to achieve stable fixation and good long-term results

The Nutrient-Responsive Molecular Chaperone Hsp90 Supports Growth and Development in Drosophila

Animals can sense internal nutrients, such as amino acids/proteins, and are able to modify their developmental programs in accordance with their nutrient status. In the fruit fly, Drosophila melanogaster, amino acid/protein is sensed by the fat body, an insect adipose tissue, through a nutrient sensor, target of rapamycin (TOR) complex 1 (TORC1). TORC1 promotes the secretion of various peptide hormones from the fat body in an amino acid/protein-dependent manner. Fat-body-derived peptide hormones stimulate the release of insulin-like peptides, which are essential growth-promoting anabolic hormones, from neuroendocrine cells called insulin-producing cells (IPCs). Although the importance of TORC1 and the fat body-IPC axis has been elucidated, the mechanism by which TORC1 regulates the expression of insulinotropic signal peptides remains unclear. Here, we show that an evolutionarily conserved molecular chaperone, heat shock protein 90 (Hsp90), promotes the expression of insulinotropic signal peptides. Fat-body-selective Hsp90 knockdown caused the transcriptional downregulation of insulinotropic signal peptides. IPC activity and systemic growth were also impaired in fat-body-selective Hsp90 knockdown animals. Furthermore, Hsp90 expression depended on protein/amino acid availability and TORC1 signaling. These results strongly suggest that Hsp90 serves as a nutrient-responsive gene that upregulates the fat body-IPC axis and systemic growth. We propose that Hsp90 is induced in a nutrient-dependent manner to support anabolic metabolism during the juvenile growth period

High risk of elevated metal concentrations with 9/10-mm stem trunnions and highly cross-linked polyethylene grafted with poly(2-methacryloyloxyethyl phosphorylcholine) in total hip arthroplasty

Background: The risks of metal release due to fretting and corrosion at the head–neck junction and consequent adverse local tissue reaction (ALTR) have concerns in metal-on-polyethylene (MoP) total hip arthroplasty (THA). Although trunnions have become thinner in diameter to increase the range of motion, it has remained unclear whether this change affects metal release and ALTR in vivo. This study aimed to investigate serum metal concentrations and the prevalence of ALTR in MoP THA with a 9/10-mm stem trunnion.Patients and methods: A consecutive series of 37 hips that underwent THA using MoP grafted with poly(2-methacryloyloxyethyl phosphorylcholine) (PMPC) with a 9/10-mm trunnion stem were retrospectively reviewed. Serum metal levels were assessed and compared with those in MoP THA with a 10/12-mm trunnion stem. ALTR was diagnosed with serum metal levels and cross-sectional images. The factors associated with serum metal levels were also assessed.Results: The median serum cobalt and chromium levels were 1.5 μg/L and 1.0 μg/L in the 9/10-mm group and 0.2 μg/L and 0.4 μg/L in the 10/12-mm group, respectively. ALTR was found in 5 hips of 3 patients. Revision surgery was performed in 4 hips, and all stem trunnions and femoral heads showed severe corrosion. Postoperative walking ability was associated with serum metal levels.Conclusion: It was found that a 9/10-mm stem trunnion with MoP grafted with PMPC had high risks of metal release in primary THA. Careful follow-up and cross-sectional imaging are needed to detect ALTR for early revision

Cooling Stability Test of MgB₂ Wire Immersed in Liquid Hydrogen under External Magnetic Field

11th European Conference on Applied Superconductivity (EUCAS2013)Liquid hydrogen (LH₂), which has large latent heat, low viscosity coefficient, is expected to be a candidate for a cryogen for superconducting wires, not only MgB₂ but also other HTC superconductors. LH₂ cooled superconducting wires are expected to have excellent electro-magnetic characteristics, which is necessary to be clear for cooling stability design of LH₂ cooled superconducting device, however, due to handling difficulties of LH₂, there are only few papers on the properties of LH₂ cooled superconductors, especially under external magnetic field. We designed and made an experimental setup which can energize superconducting wires immersed in LH₂ with the current of up to 500A under the condition of external magnetic field up to 7 T and pressure up to 1.5 MPa. In order to confirm experimental method and safety operation of the setup, over current tests were carried out using MgB₂ superconducting wires under various external magnetic field conditions. Critical current of the test wire at the temperature 21, 24, 27, 29 K under external magnetic fields up to 1.2 T was successfully measured. The resistance of the wire also was measured, while the transport current exceeded the critical current of the wire

The fungal metabolite (+)-terrein abrogates osteoclast differentiation via suppression of the RANKL signaling pathway through NFATc1

Pathophysiological bone resorption is commonly associated with periodontal disease and involves the excessive resorption of bone matrix by activated osteoclasts. Receptor activator of nuclear factor (NF)-κB ligand (RANKL) signaling pathways have been proposed as targets for inhibiting osteoclast differentiation and bone resorption. The fungal secondary metabolite (+)-terrein is a natural compound derived from Aspergillus terreus that has previously shown anti-interleukin-6 properties related to inflammatory bone resorption. However, its effects and molecular mechanism of action on osteoclastogenesis and bone resorption remain unclear. In the present study, we showed that 10 µM synthetic (+)-terrein inhibited RANKL-induced osteoclast formation and bone resorption in a dose-dependent manner and without cytotoxicity. RANKL-induced messenger RNA expression of osteoclast-specific markers including nuclear factor of activated T-cells cytoplasmic 1 (NFATc1), the master regulator of osteoclastogenesis, cathepsin K, tartrate-resistant acid phosphatase (Trap) was completely inhibited by synthetic (+)-terrein treatment. Furthermore, synthetic (+)-terrein decreased RANKL-induced NFATc1 protein expression. This study revealed that synthetic (+)-terrein attenuated osteoclast formation and bone resorption by mediating RANKL signaling pathways, especially NFATc1, and indicated the potential effect of (+)-terrein on inflammatory bone resorption including periodontal disease

The Fungal Metabolite (+)-Terrein Abrogates Ovariectomy-Induced Bone Loss and Receptor Activator of Nuclear Factor-kappa B Ligand-Induced Osteoclastogenesis by Suppressing Protein Kinase-C alpha/beta II Phosphorylation

Osteoporosis is a common disease characterized by a systemic impairment of bone mass and microarchitecture that results in fragility fractures. Severe bone loss due to osteoporosis triggers pathological fractures and consequently decreases the daily life activity and quality of life. Therefore, prevention of osteoporosis has become an important issue to be addressed. We have reported that the fungal secondary metabolite (+)-terrein (TER), a natural compound derived from Aspergillus terreus, has shown receptor activator of nuclear factor-kappa B ligand (RANKL)-induced osteoclast differentiation by suppressing nuclear factor of activated T-cell 1 (NFATc1) expression, a master regulator of osteoclastogenesis. TER has been shown to possess extensive biological and pharmacological benefits; however, its effects on bone metabolism remain unclear. In this study, we investigated the effects of TER on the femoral bone metabolism using a mouse-ovariectomized osteoporosis model (OVX mice) and then on RANKL signal transduction using mouse bone marrow macrophages (mBMMs). In vivo administration of TER significantly improved bone density, bone mass, and trabecular number in OVX mice (p < 0.01). In addition, TER suppressed TRAP and cathepsin-K expression in the tissue sections of OVX mice (p < 0.01). In an in vitro study, TER suppressed RANKL-induced phosphorylation of PKC alpha/beta II, which is involved in the expression of NFATc1 (p < 0.05). The PKC inhibitor, GF109203X, also inhibited RANKL-induced osteoclastogenesis in mBMMs as well as TER. In addition, TER suppressed the expression of osteoclastogenesis-related genes, such as Ocstamp, Dcstamp, Calcr, Atp6v0d2, Oscar, and Itgb3 (p < 0.01). These results provide promising evidence for the potential therapeutic application of TER as a novel treatment compound against osteoporosis

Lactobacillus delbrueckii subsp. bulgaricus 2038 and Streptococcus thermophilus 1131 Induce the Expression of the REG3 Family in the Small Intestine of Mice via the Stimulation of Dendritic Cells and Type 3 Innate Lymphoid Cells

Accumulating evidence clarifies that intestinal barrier function, for example, by the mucus layer, antimicrobial peptides, immune systems, and epithelial tight junctions, plays crucial roles in maintaining our health. We reported previously that yogurt fermented with Lactobacillus delbrueckii subsp. bulgaricus 2038 and Streptococcus thermophilus 1131 induced the gene expression of the regenerating family member 3 (REG3) family, which encodes antimicrobial peptides in the small intestine, although it was unclear how the yogurt activated the intestinal cells related to it. Here, we evaluated the cytokine production from the intestinal immune cells stimulated by these strains in vitro and in vivo to elucidate the mechanism for the induction of the REG3 family by the yogurt. The results showed that stimulation by both strains induced interleukin (IL)-23 production from bone marrow-derived dendritic cells (DCs) and IL-22 production from small intestinal lamina propria (LP) cells. In addition, oral administration of these strains to mice increased IL-23p19+ LPDCs and IL-22+ type 3 innate lymphoid cells and induced the expression of Reg3g in small intestinal tissue. Moreover, we showed that the activities for the induction of IL-23 by DCs were strain dependent on L. bulgaricus and S. thermophilus and that S. thermophilus 1131, which is the predominant species in the yogurt, exhibited relatively higher activity compared to the other strains of S. thermophilus. Our findings suggested that these yogurt starter strains, L. bulgaricus 2038 and S. thermophilus 1131, have the potential to maintain and improve intestinal barrier function by stimulating immune cells in the LP