Soluble Klotho causes hypomineralization in Klotho-deficient mice

The type I transmembrane protein αKlotho (Klotho) serves as a coreceptor for the phosphaturic hormone fibroblast growth factor 23 (FGF23) in kidney, while a truncated form of Klotho (soluble Klotho, sKL) is thought to exhibit multiple activities, including acting as a hormone, but whose mode(s) of action in different organ systems remains to be fully elucidated. FGF23 is expressed primarily in osteoblasts/osteocytes and aberrantly high levels in the circulation acting via signaling through an FGF receptor (FGFR)-Klotho coreceptor complex cause renal phosphate wasting and osteomalacia. We assessed the effects of exogenously added sKL on osteoblasts and bone using Klotho-deficient (kl/kl) mice and cell and organ cultures. sKL induced FGF23 signaling in bone and exacerbated the hypomineralization without exacerbating the hyperphosphatemia, hypercalcemia and hypervitaminosis D in kl/kl mice. The same effects were seen in rodent bone models in vitro, in which we also detected formation of a sKL complex with FGF23-FGFR and decreased Phex (gene responsible for X-linked hypophosphatemic rickets (XLH)/osteomalacia) expression. Further, sKL-FGF23-dependent hypomineralization in vitro was rescued by soluble PHEX. These data suggest that exogenously added sKL directly participates in FGF23 signaling in bone and that PHEX is a downstream effector of the sKL-FGF23-FGFR axis in bone.This work was supported in part by grants from the Ministry of Education, Science, Sports and Culture, Japan (18592001 and 20592139 to Y Y and 21791788 to T M), and the Canadian Institutes of Health Research (MOP 83704 to J E A)

Assessment of Neutrophil Functional Activity following Prolonged Endurance Exercise

ntroduction: Neutrophils not only play an important role in host defense by migrating to the site of infection and producing reactive oxygen species (RO S), but also mediate pathological process in inflammatory tissue damage. Therefore, it is import ant not only to assess but also modulate neutrophil activities for disease prevention. We hav e reported that exhaustive exercise causes neutrophil priming (Suzuki et al. J. Appl. Physiol. , 81, 1213-1222, 1996) which might be associated wi th muscle damage (Suzuki et al. J. Appl. Physiol. , 87, 1360-1367, 1999), but antioxidant capacity is also activated following exercise (Suzuki et al. Med. Sci. Sports Exerc. , 35, 348-355, 2003). In the present study, we examined the effects of endurance exercis e on neutrophil activation in relation with muscle damage (Sugama et al. EIR , 18, 115-126, 2012) and report the ex vivo findings based on a newly- developed neutrophil activity measurement system (S uzuki et al. Anticancer Res, 32, 2369-2376, 2012). Methods: Fourteen male triathletes participated in a duathlo n race consisted of 5 km of running, 40 km of cycling and 5 km of running. Venous blood sam ples were collected before, immediately after, 1.5 h and 3 h after the race. A mixture of blood an d luminol was layered on hydrogel (Mebiol Co., Kanagawa, Japan) in each tube and incubated for 60 min. The cell counts in the hydrogel were quantified as the migratory activity of neutrophils , whereas the ROS production was measured by luminol-dependent chemiluminescence. Serum concentr ation of myoglobin (Mb) as a marker of muscle damage and plasma reactive oxygen metabolite s (d-ROMs) as a marker of oxidative stress were also measured. Results: The migratory activity of neutrophils was significa ntly elevated immediately after exercise, further increased 1.5 h, and slightly decreased but remained significantly elevated 3 h after the race . ROS production of neutrophils was significantly ele vated 3 h after the race. Serum Mb concentration increased significantly after exercise and correlat ed positively with the migratory activity of neutrophils, suggesting that neutrophils could infi ltrate into the injured muscle. On the other hand, plasma d-ROMs tended to correlate with ROS producti on, indicating that exercise-induced oxidative stress can be explained at least in part by the ROS production from neutrophils. Conclusions: This new method for measuring neutrophil activitie s can be applied not only for assessing the status of inflammation and oxidative stress in exhaustive exercise, but also as a method for evaluating the efficacy of antioxidant and anti -inflammatory substances for reducing muscle damage

Dual-GSE: Resource-efficient Generalized Quantum Subspace Expansion

Quantum error mitigation (QEM) is a class of hardware-efficient error reduction methods through additional modest quantum operations and classical postprocessing on measurement outcomes. The generalized quantum subspace expansion (GSE) has been recently proposed as a unified framework of two distinct QEM methods: quantum subspace expansion (QSE) and purification-based QEM. GSE takes over the advantages of these two methods, achieving the mitigation of both coherent and stochastic errors. However, GSE still requires multiple copies of quantum states and entangled measurements between the copies, as required in purification-based QEM. This is a significant drawback under the current situation of the restricted number and connectivity of qubits. In this work, we propose a resource-efficient implementation of GSE, which we name "Dual-GSE", circumventing significant overheads of state copies by constructing an ansatz of error-mitigated quantum states via dual-state purification. Remarkably, Dual-GSE can further simulate larger quantum systems beyond the size of available quantum hardware with a suitable ansatz construction inspired by those divide-and-conquer methods that forge entanglement classically. This also contributes to a significant reduction of the measurement overhead because we only need to measure subsystems' Pauli operators. The proposed method is demonstrated by numerical simulation of the eight-qubit transverse field Ising model, showing that our method estimates the ground state energy in high precision under gate noise with low mitigation overhead and practical sampling cost.Comment: 25 pages, 19 figure

Re-biopsy status among non-small cell lung cancer patients in Japan: A retrospective study

AbstractObjectiveDisease progression because of acquired resistance is common in advanced or metastatic epidermal growth factor receptor (EGFR)-mutation positive non-small cell lung cancer (NSCLC), despite initial response to EGFR-tyrosine kinase inhibitors (TKIs). In Japan, transbronchial tissue biopsy is the most common sampling method used for re-biopsy to identify patients eligible for treatment. We aimed to investigate the success rate of re-biopsy and re-biopsy status of patients with advanced or metastatic NSCLC completing first-line EGFR-TKI therapy.Patients and methodsThis was a retrospective, multi-center, Japanese study. The target patients in the study were EGFR mutation-positive NSCLC patients. The primary endpoint was the success rate (number of cases in which tumor cells were detected/total number of re-biopsies performed×100). Secondary endpoints included differences between the status of the first biopsy and that of the re-biopsy in the same patient population, and the details of cases in which re-biopsy could not be carried out. Re-biopsy-associated complications were also assessed.ResultsOverall, 395 patients were evaluated (median age 63 years), with adenocarcinoma being the most common tumor type. Re-biopsy was successful in 314 patients (79.5%). Compared with the sampling method at first biopsy, at re-biopsy, the surgical resection rate increased from 1.8% to 7.8%, and percutaneous tissue biopsy increased from 7.6% to 29.1%, suggesting the difficulty of performing re-biopsy. Approximately half of the patients had T790M mutations, which involved a Del19 mutation in 55.6% of patients and an L858R mutation in 43.0%. Twenty-three patients (5.8%) had re-biopsy- associated complications, most commonly pneumothorax.ConclusionsSuccess rate for re-biopsy in this study was approximately 80%. Our study sheds light on the re-biopsy status after disease progression in patients with advanced or metastatic NSCLC. This information is important to improve the selection of patients who may benefit from third-generation TKIs

認知症高齢者グループホーム職員の看取り体験の思い

This study explored caregiver perceptions related to experiences of end-of-life (EOL) care at group homes (GH) for elderly people with dementia. A self-administered questionnaire was designed to elicit GH staff perceptions by asking what they feel about their EOL care experiences at GH. Eighty one participants shared their perspectives. Results were classified into seven categories, “Anxiety and tension related to EOL care,” “Regret and condolence,” “Response of care provided,” “Respect for deceased people,” “Pride in providing EOL care,” “Creative view of life and death,” and “Familial sense of loss,”. Although staff members who experienced EOL care felt imperfect, they were satisfied with the care they provided. Moreover, they had positive views in terms of EOL care experiences, which seemed to engender their personal growth. The study also revealed a distinctive view of EOL care in GH, where caregivers felt as if they had lost a family member when they confronted a resident’s death

Fundamental physics activities with pulsed neutron at J-PARC(BL05)

"Neutron Optics and Physics (NOP/ BL05)" at MLF in J-PARC is a beamline for studies of fundamental physics. The beamline is divided into three branches so that different experiments can be performed in parallel. These beam branches are being used to develop a variety of new projects. We are developing an experimental project to measure the neutron lifetime with total uncertainty of 1 s (0.1%). The neutron lifetime is an important parameter in elementary particle and astrophysics. Thus far, the neutron lifetime has been measured by several groups; however, different values are obtained from different measurement methods. This experiment is using a method with different sources of systematic uncertainty than measurements conducted to date. We are also developing a source of pulsed ultra-cold neutrons (UCNs) produced from a Doppler shifter are available at the unpolarized beam branch. We are developing a time focusing device for UCNs, a so called "rebuncher", which can increase UCN density from a pulsed UCN source. At the low divergence beam branch, an experiment to search an unknown intermediate force with nanometer range is performed by measuring the angular dependence of neutron scattering by noble gases. Finally the beamline is also used for the research and development of optical elements and detectors. For example, a position sensitive neutron detector that uses emulsion to achieve sub-micrometer resolution is currently under development. We have succeeded in detecting cold and ultra-cold neutrons using the emulsion detector.Comment: 9 pages, 5 figures, Proceedings of International Conference on Neutron Optics (NOP2017