Search

J-domain proteins (JDPs) are the largest family of chaperones in most organisms, but much of how they function within the network of other chaperones and protein quality control machineries is still an enigma. Here, we report on the latest findings related to JDP functions presented at a dedicated JDP workshop in Gdansk, Poland. The report does not include all (details) of what was shared and discussed at the meeting, because some of these original data have not yet been accepted for publication elsewhere or represented still preliminary observations at the time.

J-domain proteins (JDPs) are the largest family of chaperones in most organisms, but much of how they function within the network of other chaperones and protein quality control machineries is still an enigma. Here, we report on the latest findings related to JDP functions presented at a dedicated JDP workshop in Gdansk, Poland. The report does not include all (details) of what was shared and discussed at the meeting, because some of these original data have not yet been accepted for publication elsewhere or represented still preliminary observations at the time.

J-domain proteins (JDPs) are the largest family of chaperones in most organisms, but much of how they function within the network of other chaperones and protein quality control machineries is still an enigma. Here, we report on the latest findings related to JDP functions presented at a dedicated JDP workshop in Gdansk, Poland. The report does not include all (details) of what was shared and discussed at the meeting, because some of these original data have not yet been accepted for publication elsewhere or represented still preliminary observations at the time.

Myelopathy with atlantoaxial instability is a relatively rare condition. It is treated with various surgical methods to treat upper cervical problems, including atlantoaxial fusion, occipitocervical fusion, and C1 laminectomy. However, the choice of surgical method, especially in highly aged （≥80 years） patients, is controversial. This case report describes the difficulty of selecting the appropriate surgical procedure for upper cervical and occipitocervical diseases in highly aged patients. An 85-year-old woman complained of neck pain and bilateral hand numbness. The Japanese Orthopedic Association score for cervical myelopathy （C-JOA） of the patient was 9 out of a possible score of 17. Plain radiographs showed atlantoaxial subluxation （AAS） and vertical subluxation （VS）, whereas magnetic resonance imaging showed spinal cord compression and myelomalacia at C1-2. The patient underwent a C1 laminectomy to minimize invasive procedures. After surgery, her symptoms improved, and her C-JOA score increased to 12. Fifteen months after surgery, her neurological conditions gradually deteriorated again. Her VS progressed postoperatively, with spinal canal restenosis at the craniovertebral junction. After an additional occipitocervical fusion, her symptoms improved, and she had no evidence of recurrence at her final follow-up. Although surgeons tend to choose less-invasive procedures when treating highly aged patients, appropriate surgical procedures may be required （even if invasive for the patient） when less-invasive treatments failed. Hence, it is important to avoid over-selecting less-invasive surgical procedures for highly aged patients.

Proper control of gene expression levels upon various perturbations is a fundamental aspect of cellular robustness. Protein-level dosage compensation is one mechanism buffering perturbations to stoichiometry of multiprotein complexes through accelerated proteolysis of unassembled subunits. Although N-terminal acetylation- and ubiquitin-mediated proteasomal degradation by the Ac/N-end rule pathway enables selective compensation of excess subunits, it is unclear how widespread this pathway contributes to stoichiometry control. Here we report that dosage compensation depends only partially on the Ac/N-end rule pathway. Our analysis of genetic interactions between 18 subunits and 12 quality control factors in budding yeast demonstrated that multiple E3 ubiquitin ligases and N-acetyltransferases are involved in dosage compensation. We find that N-acetyltransferases-mediated compensation is not simply predictable from N-terminal sequence despite their sequence specificity for N-acetylation. We also find that the compensation of Pop3 and Bet4 is due in large part to a minor N-acetyltransferase NatD. Furthermore, canonical NatD substrates histone H2A/H4 were compensated even in its absence, suggesting N-acetylation-independent stoichiometry control. Our study reveals the complexity and robustness of the stoichiometry control system. Author summary Quality control of multiprotein complexes is important for maintaining homeostasis in cellular systems that are based on functional complexes. Proper stoichiometry of multiprotein complexes is achieved by the balance between protein synthesis and degradation. Recent studies showed that translation efficiency tends to scale with stoichiometry of their subunits. On the other hand, although protein N-terminal acetylation- and ubiquitin-mediated proteolysis pathway is involved in selective degradation of excess subunits, it is unclear how widespread this pathway contributes to stoichiometry control due to the lack of a systematic inve

Koki Tsuchiya,1 Koji Ishikawa,1 Soji Tani,1 Yusuke Oshita,2 Takuma Kuroda,1 Ryo Yamamura,1 Haruka Emori,1 Hiroshi Maruyama,1 Akira Matsuoka,1 Yoshifumi Kudo,1 Toshiyuki Shirahata,1 Tomoaki Toyone,1 Takashi Nagai,1 Katsunori Inagaki11Department of Orthopaedic Surgery, Showa University School of Medicine, Tokyo 142-8666, Japan; 2Department of Orthopaedic Surgery, Yamanashi Red Cross Hospital, Yamanashi, JapanAbstract: Discontinuation of denosumab during osteoporosis treatment leads to rapid loss of bone mineral density and induces a bone turnover rebound effect. Previous studies have reported analysis based on dual-energy X-ray absorptiometry scanning (DXA). Here, we report the first case involving analysis of three-dimensional bone mineral density and bone strength, measured by quantitative computed tomography (QCT) after discontinuation of denosumab. An 82-year-old woman who discontinued denosumab because of patient’s wish was administered the fifth dose after a gap of 14 months. Her bone mineral density evaluated by DXA and QCT, bone strength, and bone turnover marker levels showed significant rebound phenomenon. The levels of the cortical parameters of the hip were also decreased indicating an increased risk of femoral fractures after denosumab interruption. Our case highlights the increased risk of fractures after discontinuation of denosumab. Therefore, denosumab must be used judiciously without interruption in the dosage schedule.Keywords: lumbar spine, femoral neck, bone turnover markers, cortical bone, biomechanical analysis

Koji Ishikawa,1–3 Takashi Nagai,1 Koki Tsuchiya,1 Yusuke Oshita,3 Takuma Kuroda,1 Hiroshi Ito,1 Soji Tani,1 Yusuke Dodo,1 Tomoaki Toyone,1 Katsunori Inagaki1 1Department of Orthopaedic Surgery, Showa University School of Medicine, Tokyo, Japan; 2Department of Orthopaedic and Spine Surgery, Sanraku Hospital, Tokyo, Japan; 3Department of Orthopaedic Surgery, Yamanashi Red Cross Hospital, Yamanashi, Japan Abstract: Denosumab is a fully human monoclonal antibody against the receptor activator of nuclear factor-κB ligand (RANKL) that is used for the treatment of osteoporosis. Denosumab-induced hypocalcemia is a rare but important adverse event, which is usually asymptomatic in patients with osteoporosis. It is also known that hypocalcemia is common in patients with bone metastases and severe renal impairment. Here we report a case of symptomatic hypocalcemia following administration of 60 mg of denosumab in a patient with high bone turnover and no renal impairment (estimated glomerular filtration rate [eGFR], 71 mL/min), despite prophylactic oral vitamin D administration. This report supports our observation that there is a risk of protracted and marked denosumab-induced hypocalcemia in patients with high bone turnover, irrespective of their degree of renal impairment. Keywords: denosumab, symptomatic hypocalcemia, high bone turnover, no renal impairment

Koji Ishikawa,1 Takashi Nagai,1 Keizo Sakamoto,1 Kenji Ohara,2 Takeshi Eguro,1,2 Hiroshi Ito,1 Yoichi Toyoshima,1 Akatsuki Kokaze,3 Tomoaki Toyone,1 Katsunori Inagaki1 1Department of Orthopaedic Surgery, Showa University School of Medicine, Tokyo, 2Department of Orthopaedic Surgery, Yamanashi Red Cross Hospital, Yamanashi, 3Department of Public Health, Showa University School of Medicine, Tokyo, Japan Abstract: Hypocalcemia is the most common major adverse event in patients with osteoporosis receiving the bone resorption inhibitor denosumab; however, limited information is available regarding risk factors of hypocalcemia. Therefore, this study aimed to identify the risk factors of hypocalcemia induced by denosumab treatment for osteoporosis. We retrospectively reviewed the records of patients who had received initial denosumab supplemented with activated vitamin D for osteoporosis. Serum levels of the following bone turnover markers (BTMs) were measured at baseline: bone-specific alkaline phosphatase (BAP), total N-terminal propeptide of type 1 procollagen (P1NP), tartrate-resistant acid phosphatase 5b (TRACP-5b), and urinary cross-linked N-telopeptide of type 1 collagen (NTX). Of the 85 denosumab-treated patients with osteoporosis studied, 22 (25.9%) developed hypocalcemia. Baseline serum total P1NP, TRACP-5b, and urinary NTX were significantly higher in patients with hypocalcemia than in those with normocalcemia following denosumab administration (all P<0.01). Multivariate logistic regression analysis revealed that patients with total P1NP >76.5 µg/L, TRACP-5b >474 mU/dL, or urinary NTX >49.5 nmol bone collagen equivalent/mmol creatinine had a higher risk of hypocalcemia (P<0.01). Our study suggests that denosumab may have a greater impact on serum calcium levels in patients with postmenopausal osteoporosis with higher baseline bone turnover than in patients with postmenopausal osteop

Takashi Nagai, Keizo Sakamoto, Koji Ishikawa, Emi Saito, Takuma Kuroda, Katsunori Inagaki Department of Orthopaedic Surgery, Showa University School of Medicine, Shinagwa-ku, Tokyo, Japan Abstract: Bisphosphonate excessively inhibits bone resorption and results in pathological fracture of the femur or ilium. The subject of this study was administered risedronate for 7 years; we suspected an easy fracture of the femoral diaphysis. In this study, we report the results of this patient's bone biopsy and bone morphometric analysis. A 76-year-old female patient presented with right femoral pain. Bone mineral density of the anteroposterior surface of the 2nd to 4th lumbar vertebrae (L2-L4) was decreased and levels of bone turnover markers were high. Therefore, we initiated treatment with risedronate. As she continued the medication, urinary levels of cross-linked N-terminal telopeptides of type I collagen and alkaline phosphatase (bone-type isozyme) were found to be within the normal ranges. After 7 years of administration, the patient experienced pain when she put weight on the right femur and right femoral pain while walking. Plain radiographic examination revealed polypoid stress fracture-like lesions on the right femoral diaphysis and on the slightly distal-lateral cortical bone. Similar lesions were observed on magnetic resonance imaging and bone scintigraphy. We suspected severely suppressed bone turnover. Bone biopsy was obtained after labeling with tetracycline, and bone morphometric analysis was performed. On microscopic examination, slight double tetracycline labeling was observed. The trabeculae were narrow, and the numbers of osteoblasts and osteoclasts were decreased. Further, rates of bone calcification and bone formation were slow. Hence, we diagnosed fracture as a result of low turnover osteopathy. Risedronate was withdrawn, and Vitamin D3 was administered to improve the bone turnover. At 6 months, abnormal signals on magnetic resonance imaging had

99Moの新しい製造方法として提案している溶液照射法では、照射ターゲットであるモリブデン酸塩水溶液がキャプセル中を流動する。しかしながら、流動するモリブデン酸塩水溶液とキャプセルや配管の構造材料との両立性は、明らかではなかった。そこで、両者の両立性を調べるために、腐食性確認試験装置を設計・製作した。また、製作した試験装置を用いて予備試験を行った結果、目的の試験が行えることを確認した。, In the solution irradiation method, which is proposed as new 99Mo production method, the molybdate solution of an irradiation target flows in a capsule. However, the compatibility between the flowing aqueous molybdate solution and the structural materials of capsules and pipes was not clear. Therefore, test apparatuses for the investigation of the compatibility were designed and fabricated. Preliminary tests with the test apparatuses were also carried out, and it was confirmed that planed tests could be carried out., 著者所属: 日本原子力研究開発機構(JAEA), JAEA-Testing 2009-004

本研究では、99Mo製造のための溶液照射法で用いる照射ターゲットの候補として選定した2種類のモリブデン酸塩水溶液(モリブデン酸アンモニウム水溶液及びモリブデン酸カリウム水溶液)を用い、gamma線照射下において、選定水溶液と構造材料との両立性,選定水溶液の化学的安定性,循環特性,放射線分解及びgamma発熱について調べた。これらに加えて、gamma線照射下におけるPZCの健全性について調べた。その結果、次のことがわかった。(1)選定水溶液とステンレス鋼の両立性は良好である。(2)選定水溶液は化学的に安定であり、水溶液の循環は滞りなく行われる。(3)選定水溶液の放射線分解によって発生したガス中における水素成分割合は、純水の場合と比べて高くなる。(4)選定水溶液に対するgamma発熱の影響は、水の場合と同程度である。(5)PZCの健全性は維持される。, In the present study, using two kinds of aqueous molybdate solutions (an aqueous ammonium molybdate solution and an aqueous potassium molybdate solution) selected as candidates for the irradiation target of the solution irradiation method for 99Mo production, the compatibility between the solutions and structural materials, the chemical stability, circulation characteristics, radiolysis and gamma heating of the solutions were investigated under gamma-ray irradiation. In addition, the integrity of PZC was investigated under gamma-ray irradiation. As a result, the following were found: (1) the compatibility between the solutions and stainless steel is very well, (2) the solutions are chemically stable and have a smooth circulation, (3) the ratios of hydrogen in the gases generated by the radiolysis of the solutions are higher than that of pure water, (4) the effect of gamma heating on the solutions is the same level as that on pure water, and (5) the integrity of PZC is maintained., 著者所属: 日本原子力研究開発機構(JAEA), JAEA-Technology 2009-013

The impurity concentration in both (NH4)6Mo7O24 and K2MoO4 solutions, which are selected as advanced targets of Mo-solution irradiation method for 99Mo production, was determined by the Instrumental Neutron Activation Analysis (NAA) using k0-standardization method. As a result, Na, Mn and W were identified as impurities in the as received molybdate. After the compatibility test with structural material (SUS304) under gamma-ray irradiation, activation analysis of molybdate solutions was also carried out. It was found that the identified impurity concentration was stably staying in solutions and no element comes from the structural material by the NAA method. However, small corrosion of structural material was observed from the ICP measurement., The impurity concentration in both (NH4)6Mo7O24 and K2MoO4 solutions, which are selected as advanced targets of Mo-solution irradiation method for 99Mo production, was determined by the Instrumental Neutron Activation Analysis (NAA) using k0-standardization method. As a result, Na, Mn and W were identified as impurities in the as received molybdate. After the compatibility test with structural material (SUS304) under gamma-ray irradiation, activation analysis of molybdate solutions was also carried out. It was found that the identified impurity concentration was stably staying in solutions and no element comes from the structural material by the NAA method. However, small corrosion of structural material was observed from the ICP measurement., 著者所属: 日本原子力研究開発機構(JAEA), JAEA-Technology 2009-039

本研究では、溶液照射法を用いた99Mo製造システムの概略構成を検討し、溶液照射法で用いる照射ターゲットの候補として2種類のモリブデン酸塩水溶液(モリブデン酸アンモニウム水溶液及びモリブデン酸カリウム水溶液)を選定した後、未照射下において、選定水溶液を用いたPZCのモリブデン吸着性能,選定水溶液のもととなるモリブデン酸塩の性状・熱物性,選定水溶液と構造材料との両立性及び選定水溶液の化学的安定性について調べた。その結果、モリブデン酸カリウム水溶液が、モリブデン含有量,構造材料との両立性及び化学的安定性の観点から、照射ターゲットとして有望であることがわかった。また、モリブデン酸アンモニウム水溶液に関しては、pH調整を行うことにより、照射ターゲットとしての適性を持つことがわかった。さらに、選定水溶液との両立性が良好なステンレス鋼を、キャプセルや配管等の構造材料として使用できる見通しを得た。, In the present study, the schematic structure of the 99Mo production system with the solution irradiation method was investigated, and two kinds of aqueous molybdate solutions (an aqueous ammonium molybdate solution and an aqueous potassium molybdate solution) were selected as candidates for the irradiation target of the solution irradiation method, and then the molybdenum adsorption performance of PZC with the solutions, the properties of the molybdates to be materials of the solutions, the compatibility between the solutions and structural materials, and the chemical stability of the solutions were investigated under unirradiation. As a result, it was found that the aqueous potassium molybdate solution is promising as the target in terms of the molybdenum content, the compatibility with the structural materials, and the chemical stability and that the aqueous ammonium molybdate solution with suitable pH adjustment has an aptitude for the target. In addition, it became clear that stainless steel having good compatibility with the solutions has a potential as the structural material of capsules, pipes and so on., 著者所属: 日本原子力研究開発機構(JAEA), JAEA-Technology 2009-012