Iguratimod suppresses sclerostin and receptor activator of NF-κB ligand production via the extracellular signal-regulated kinase/early growth response protein 1/tumor necrosis factor alpha pathway in osteocytes and ameliorates disuse osteoporosis in mice.

Disuse osteoporosis is a prevalent complication among patients afflicted with rheumatoid arthritis (RA). Although reports have shown that the antirheumatic drug iguratimod (IGU) ameliorates osteoporosis in RA patients, details regarding its effects on osteocytes remain unclear. The current study examined the effects of IGU on osteocytes using a mouse model of disuse-induced osteoporosis, the pathology of which crucially involves osteocytes. A reduction in distal femur bone mass was achieved after 3 weeks of hindlimb unloading in mice, which was subsequently reversed by intraperitoneal IGU treatment (30 mg/kg; five times per week). Histology revealed that hindlimb-unloaded (HLU) mice had significantly increased osteoclast number and sclerostin-positive osteocyte rates, which were suppressed by IGU treatment. Moreover, HLU mice exhibited a significant decrease in osteocalcin-positive cells, which was attenuated by IGU treatment. In vitro, IGU suppressed the gene expression of receptor activator of NF-κB ligand (RANKL) and sclerostin in MLO-Y4 and Saos-2 cells, which inhibited osteoclast differentiation of mouse bone marrow cells in cocultures. Although IGU did not affect the nuclear translocation or transcriptional activity of NF-κB, RNA sequencing revealed that IGU downregulated the expression of early growth response protein 1 (EGR1) in osteocytes. HLU mice showed significantly increased EGR1- and tumor necrosis factor alpha (TNFα)-positive osteocyte rates, which were decreased by IGU treatment. EGR1 overexpression enhanced the gene expression of TNFα, RANKL, and sclerostin in osteocytes, which was suppressed by IGU. Contrarily, small interfering RNA-mediated suppression of EGR1 downregulated RANKL and sclerostin gene expression. These findings indicate that IGU inhibits the expression of EGR1, which may downregulate TNFα and consequently RANKL and sclerostin in osteocytes. These mechanisms suggest that IGU could potentially be used as a treatment option for disuse osteoporosis by targeting osteocytes.

An investigation of the differential therapeutic effects of romosozumab on postmenopausal osteoporosis patients with or without rheumatoid arthritis complications: a case-control study.

The impact of ROMO on the width of anabolic windows and the increase in BMD was reduced in the RA group compared to the non-RA group, and this reduction was associated with correlations to RA-related factors. PURPOSE: To investigate the effects of romosozumab (ROMO) in postmenopausal osteoporosis, with and without comorbid rheumatoid arthritis (RA). METHODS: In this retrospective, case-controlled, multicenter study, 171 postmenopausal patients who did not receive oral glucocorticoid, comprising 59 in the RA group and 121 in the non-RA group, received uninterrupted ROMO treatment for 12 months. Propensity score matching was employed to ensure comparability in clinical backgrounds, resulting in 41 patients in each group. Baseline characteristics were as follows: overall (mean age, 76.3 years; T-score of lumbar spine (LS), - 3.0; 45.1% were treatment-naive for osteoporosis); RA group (anti-cyclic citrullinated peptide antibody (ACPA) positivity, 80.5%; titer, 206.2 U/ml; clinical disease activity index (CDAI), 13.6; health assessment questionnaire disability index (HAQ-DI), 0.9). Bone mineral density (BMD) and serum bone turnover markers were monitored over a 12-month period. RESULTS: The rate of increase in the bone formation marker, PINP, and the rates of decrease in the bone resorption marker, TRACP-5b, exhibited a trend toward smaller changes in the RA group compared to the non-RA group, implying a smaller anabolic window. After 12 months, the RA group displayed lower BMD increases in the LS (9.1% vs. 12.6%; P = 0.013) and total hip (2.4% vs. 4.8%; P = 0.025) compared to the non-RA group. Multiple regression analysis in the all RA group (n = 59) for the association between RA-specific factors and 12-month BMD changes revealed negative correlations between ACPA titer and LS BMD and between HAQ-DI and femoral neck BMD. CONCLUSIONS: The efficacy of ROMO may be attenuated by RA-related factors.

Anti-NF-κB peptide derived from nuclear acidic protein attenuates ovariectomy-induced osteoporosis in mice.

NF-κB is a transcription factor that is activated with aging. It plays a key role in the development of osteoporosis by promoting osteoclast differentiation and inhibiting osteoblast differentiation. In this study, we developed a small anti-NF-κB peptide called 6A-8R from a nuclear acidic protein (also known as macromolecular translocation inhibitor II, Zn2+-binding protein, or parathymosin) that inhibits transcriptional activity of NF-κB without altering its nuclear translocation and binding to DNA. Intraperitoneal injection of 6A-8R attenuated ovariectomy-induced osteoporosis in mice by inhibiting osteoclast differentiation, promoting osteoblast differentiation, and inhibiting sclerostin production by osteocytes in vivo with no apparent side effects. Conversely, in vitro, 6A-8R inhibited osteoclast differentiation by inhibiting NF-κB transcriptional activity, promoted osteoblast differentiation by promoting Smad1 phosphorylation, and inhibited sclerostin expression in osteocytes by inhibiting myocyte enhancer factors 2C and 2D. These findings suggest that 6A-8R has the potential to be an antiosteoporotic therapeutic agent with uncoupling properties.

Basic fibroblast growth factor promotes meniscus regeneration through the cultivation of synovial mesenchymal stem cells via the CXCL6-CXCR2 pathway.

OBJECTIVE: To investigate the efficacy of basic fibroblast growth factor (bFGF) in promoting meniscus regeneration by cultivating synovial mesenchymal stem cells (SMSCs) and to validate the underlying mechanisms. METHODS: Human SMSCs were collected from patients with osteoarthritis. Eight-week-old nude rats underwent hemi-meniscectomy, and SMSCs in pellet form, either with or without bFGF (1.0 × 106 cells per pellet), were implanted at the site of meniscus defects. Rats were divided into the control (no transplantation), FGF (-) (pellet without bFGF), and FGF (+) (pellet with bFGF) groups. Different examinations, including assessment of the regenerated meniscus area, histological scoring of the regenerated meniscus and cartilage, meniscus indentation test, and immunohistochemistry analysis, were performed at 4 and 8 weeks after surgery. RESULTS: Transplanted SMSCs adhered to the regenerative meniscus. Compared with the control group, the FGF (+) group had larger regenerated meniscus areas, superior histological scores of the meniscus and cartilage, and better meniscus mechanical properties. RNA sequencing of SMSCs revealed that the gene expression of chemokines that bind to CXCR2 was upregulated by bFGF. Furthermore, conditioned medium derived from SMSCs cultivated with bFGF exhibited enhanced cell migration, proliferation, and chondrogenic differentiation, which were specifically inhibited by CXCR2 or CXCL6 inhibitors. CONCLUSION: SMSCs cultured with bFGF promoted the expression of CXCL6. This mechanism may enhance cell migration, proliferation, and chondrogenic differentiation, thereby resulting in superior meniscus regeneration and cartilage preservation.

Laser-driven multi-MeV high-purity proton acceleration via anisotropic ambipolar expansion of micron-scale hydrogen clusters.

Multi-MeV high-purity proton acceleration by using a hydrogen cluster target irradiated with repetitive, relativistic intensity laser pulses has been demonstrated. Statistical analysis of hundreds of data sets highlights the existence of markedly high energy protons produced from the laser-irradiated clusters with micron-scale diameters. The spatial distribution of the accelerated protons is found to be anisotropic, where the higher energy protons are preferentially accelerated along the laser propagation direction due to the relativistic effect. These features are supported by three-dimensional (3D) particle-in-cell (PIC) simulations, which show that directional, higher energy protons are generated via the anisotropic ambipolar expansion of the micron-scale clusters. The number of protons accelerating along the laser propagation direction is found to be as high as 1.6 [Formula: see text] [Formula: see text] 10[Formula: see text]/MeV/sr/shot with an energy of 2.8 [Formula: see text] MeV, indicating that laser-driven proton acceleration using the micron-scale hydrogen clusters is promising as a compact, repetitive, multi-MeV high-purity proton source for various applications.

Discriminative detection of laser-accelerated multi-MeV carbon ions utilizing solid state nuclear track detectors.

A new diagnosis method for the discriminative detection of laser-accelerated multi-MeV carbon ions from background oxygen ions utilizing solid-state nuclear track detectors (SSNTDs) is proposed. The idea is to combine two kinds of SSNTDs having different track registration sensitivities: Bisphenol A polycarbonate detects carbon and the heavier ions, and polyethylene terephthalate detects oxygen and the heavier ions. The method is calibrated with mono-energetic carbon and oxygen ion beams from the heavy ion accelerator. Based on the calibration data, the method is applied to identify carbon ions accelerated from multilayered graphene targets irradiated by a high-power laser, where the generation of high-energy high-purity carbon ions is expected. It is found that 93 ± 1% of the accelerated heavy ions with energies larger than 14 MeV are carbons. The results thus obtained support that carbon-rich heavy ion acceleration is achieved.

Experimental investigation on the temporal contrast of pre-pulses by post-pulses in a petawatt laser facility.

We experimentally explore the generation of pre-pulses by post-pulses, created through internal reflection in the optical components, by the nonlinear process associated with the B-integral in the laser chain of the petawatt (PW) facility J-KAREN-P. At a large time delay between the main and the post-pulses, we have found that the pre-pulses are not generated from their counterpart post-pulses at an identical time difference before the main pulse, and the temporal shapes of the pre-pulses are greatly distorted asymmetrically. We have also observed that the peak intensities of the pre-pulses are drastically suppressed compared to the expected value at a small time delay. We briefly describe the origins of the pre-pulses generated by the post-pulses and demonstrate the removal of the pre-pulses by switching to optical components with a small wedge angle at our PW laser facility.

Dynamics of the boundary layer created by the explosion of a dense object in an ambient dilute gas triggered by a high power laser.

The dynamics of the boundary layer in between two distinct collisionless plasmas created by the interaction between a dense object modeling a cluster and a short laser pulse in the presence of an ambient gas is studied with two dimensional relativistic particle-in-cell simulations, which are found to be described by three successive processes. In the first phase, a collisionless electrostatic shock wave, launched near the cluster expansion front, reflects the ambient gas ions at a contact surface as a moving wall, which allows a particle acceleration with a narrower energy spread. In the second phase, the contact surface disappears and the compressed surface of the ambient gas ions passes over the shock potential, forming an overlapping region between the cluster expansion front and the compressed surface of the ambient gas. Here, another type of nonlinear wave is found to be evolved, leading to a relaxation of the shock structure, while continuing to reflect the ambient gas ions. The nonlinear wave exhibits a bipolar electric field structure that is sustained for a long timescale coupled with slowly evolving ion dynamics, suggesting that a quasistationary kinetic equilibrium dominated by electron vortices in the phase space is established. In the third phase, a rarefaction wave is triggered and evolves at the compressed surface of ambient gas. This is because some of the ambient gas ions tend to pass over the potential of the bipolar electric field. Simultaneously, a staircase structure, i.e., a kind of internal shock, is formed in the cluster due to the deceleration of cluster ions. Such structure formations and successive dynamics accompanied by the transitions from the shock wave phase through the overlapping phase to the rarefaction wave phase are considered to be a unique nature at the boundary layer created by an explosion of a dense plasma object in an ambient dilute plasma.

Quasimonoenergetic Proton Bunch Acceleration Driven by Hemispherically Converging Collisionless Shock in a Hydrogen Cluster Coupled with Relativistically Induced Transparency.

An approach for accelerating a quasimonoenergetic proton bunch via a hemispherically converging collisionless shock created in laser-cluster interactions at the relativistically induced transparency (RIT) regime is studied using three-dimensional particle-in-cell simulations. By the action of focusing a petawatt class laser pulse onto a micron-size spherical hydrogen cluster, a crescent-shaped collisionless shock is launched at the laser-irradiated hemisphere and propagates inward. The shock converges at the sphere center in concurrence with the onset of the RIT, thereby allowing the proton bunch to be pushed out from the shock surface in the laser propagation direction. The proton bunch experiences further acceleration both inside and outside of the cluster to finally exhibit a quasimonoenergetic spectral peak around 300 MeV while maintaining a narrow energy spread (∼10%) and a small half-divergence angle (∼5°) via the effect of the RIT. This mechanism works for finite ranges of parameters with threshold values concerning the laser peak intensity and the cluster radius, resulting from the synchronization of the multiple processes in a self-consistent manner. The present scheme utilizing the internal and external degrees of freedom ascribed to the spherical cluster leads to the proton bunch alternative to the plain target, which allows the operation with a high repetition rate and impurity free.

Unified Total Synthesis, Stereostructural Elucidation, and Biological Evaluation of Sarcophytonolides.

Sarcophytonolides are cembranolide diterpenes isolated from the soft corals of genus Sarcophyton. Unified total synthesis of sarcophytonolides C, E, F, G, H, and J and isosarcophytonolide D was achieved. The synthetic routes feature NaHMDS- or SmI2-mediated fragment coupling, alkoxycarbonylallylation, macrolactonization, and transannular ring-closing metathesis. These total syntheses led to the absolute configurational confirmation of sarcophytonolide H, elucidation of sarcophytonolides C, E, F, and G, and revision of sarcophytonolide J and isosarcophytonolide D. We also evaluated the antifouling activity and toxicity of the synthetic sarcophytonolides H and J and their analogues as well as the cytotoxicity of the synthetic sarcophytonolides and the key synthetic intermediates.

High-contrast high-intensity repetitive petawatt laser.

We report the generation of 63 J of broadband pulse energies at 0.1 Hz from the J-KAREN-P laser, which is based on an OPCPA/Ti:sapphire hybrid architecture. Pulse compression down to 30 fs indicates a peak power of over 1 PW. High temporal contrast of 1012 prior to the main pulse has been demonstrated with 10 J output energy. High intensities of 1022 W/cm2 on target by focusing a 0.3 PW laser with an f/1.3 off-axis parabolic mirror have been achieved. Fundamental processes of laser matter interaction at over 1022 W/cm2 intensities belong to a new branch of science that will be the principal research task of our infrastructure.

Approaching the diffraction-limited, bandwidth-limited Petawatt.

J-KAREN-P is a high-power laser facility aiming at the highest beam quality and irradiance for performing state-of-the art experiments at the frontier of modern science. Here we approached the physical limits of the beam quality: diffraction limit of the focal spot and bandwidth limit of the pulse shape, removing the chromatic aberration, angular chirp, wavefront and spectral phase distortions. We performed accurate measurements of the spot and peak fluence after an f/1.3 off-axis parabolic mirror under the full amplification at the power of 0.3 PW attenuated with ten high-quality wedges, resulting in the irradiance of ~1022 W/cm2 and the Strehl ratio of ~0.5.

Ion pinhole imaging diagnostics on fast ion source in femtosecond laser plasma of cluster targets.

The spatial configuration of the ion source generated under femtosecond laser interaction with clusters is investigated. While intense laser pulses (36 fs, 60 mJ, intensity of 4 × 1017 W/cm2) propagated in CO2 cluster (~0.22 µm in diameter) media, the shape of the obtained plasma ion source was registered for the first time by means of pinhole imaging method. The remarkable decrease in fast ion yield in the vicinity of the assumed best laser focus near the gas cluster jet axis is observed. Such observed anisotropy of the ion source is suggested to originate from the influence of the laser prepulse destroying clusters in advance to the arrival of the main pulse. The assumption is confirmed by optical shadowgraphy images of the plasma channel and is important for further development of an efficient laser-plasma-based fast ion source. Following the observed geometry of the ion source, the laser intensity limit allowing to accelerate ions to ~100 keV energy range was estimated.

Late-stage divergent synthesis and antifouling activity of geraniol-butenolide hybrid molecules.

Hybrid molecules consisting of geraniol and butenolide were designed and synthesized by the late-stage divergent strategy. In the synthetic route, ring-closing metathesis was utilized for the construction of a butenolide moiety. A biological evaluation of the eight synthetic hybrid compounds revealed that these molecules exhibit antifouling activity against the cypris larvae of the barnacle Balanus (Amphibalanus) amphitrite with EC50 values of 0.30-1.31 µg mL-1. These results show that hybridization of the geraniol and butenolide structural motifs resulted in the enhancement of the antifouling activity.

Total Synthesis of Sarcophytonolide H and Isosarcophytonolide D: Structural Revision of Isosarcophytonolide D and Structure-Antifouling Activity Relationship of Sarcophytonolide H.

The first total syntheses of sarcophytonolide H and the originally proposed and correct structures of isosarcophytonolide D have been achieved via transannular ring-closing metathesis (RCM). These total syntheses culminated in the stereostructural confirmation of sarcophytonolide H and the reassignment of isosarcophytonolide D, respectively. The antifouling activity of the synthetic sarcophytonolide H and its analogues was also evaluated.

Revealing the second harmonic generation in a femtosecond laser-driven cluster-based plasma by analyzing shapes of Ar XVII spectral lines.

We present experiments dealing with a femtosecond laser-driven cluster-based plasma, where by analyzing the nonlinear phenomenon of satellites of spectral lines of Ar XVII, we revealed the nonlinear phenomenon of the generation of the second harmonic of the laser frequency. For performing this analysis we developed new results in the theory of satellites of spectral lines. From such lineshape analysis we found, in particular, that the efficiency of converting the short (40 fs) intense (3x10¹8 W/cm²) incident laser light into the second harmonic was 2%. This result is in the excellent agreement with the 2-Dimensional Particle-In-Cell (2D PIC) simulation that we also performed. There is also an order of magnitude agreement between the thresholds for the SHG found from the line shape analysis and from the 2D PIC simulations.

Managing Type 2 Diabetes Mellitus through Periodical Hospital Visits in the Aftermath of the Great East Japan Earthquake Disaster: A Retrospective Case Series.

AIMS: To assess the impact of the Great East Japan Earthquake Disaster on daily diabetes practice and to determine the feasibility of controlling type 2 diabetes mellitus in an outpatient department. METHODS: We retrospectively reviewed the data on disaster-affected patients with type 2 diabetes who periodically attended outpatient department of Soma Central Hospital. There were 767 patients with type 2 diabetes mellitus in total. The primary outcome measure was the change in HbA1c. RESULTS: HbA1c levels of 58 patients with periodical hospital visits did not deteriorate after the disasters. Moreover, there observed no significant difference in the mean of HbA1c levels among all age and sex throughout the year. While several changes in diabetes medication usage occurred, DPP4-inhibitor was the only oral diabetic agent that increased in frequency (+60%). CONCLUSIONS: Patients with type 2 diabetes who were managed with periodical hospital visits did not show significant deterioration in HbA1c levels.

Observation and theory of X-ray mirages.

The advent of X-ray lasers allowed the realization of compact coherent soft X-ray sources, thus opening the way to a wide range of applications. Here we report the observation of unexpected concentric rings in the far-field beam profile at the output of a two-stage plasma-based X-ray laser, which can be considered as the first manifestation of a mirage phenomenon in X-rays. We have developed a method of solving the Maxwell-Bloch equations for this problem, and find that the experimentally observed phenomenon is due to the emergence of X-ray mirages in the plasma amplifier, appearing as phase-matched coherent virtual point sources. The obtained results bring a new insight into the physical nature of amplification of X-ray radiation in laser-induced plasma amplifiers and open additional opportunities for X-ray plasma diagnostics and extreme ultraviolet lithography.

Soft x-ray free-electron laser imaging by LiF crystal and film detectors over a wide range of fluences.

LiF crystal and film detectors were used to measure the far-field fluence profile of a self-amplified spontaneous-emission free-electron laser beam and diffraction imaging with high spatial resolution. In these measurements the photoluminescence (PL) response of LiF crystal and film was compared over a wide range of soft x-ray fluences. It was found that the soft x-ray fluence dependences of LiF crystal and film differ. At low fluence, the LiF crystal shows higher PL response compared to LiF film, while this comparison is the opposite at higher fluence. Accurate measurement of LiF crystal and film PL response is important for precise characterization of the spatial, spectral, and coherence features of x-ray beams across the full profile and in localized areas. For such measurements, crucial LiF detector attributes are high spatial resolution and high dynamic range.