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Purpose: Indoleamine 2,3-dioxygenase 1 (IDO1: IDO), an enzyme catabolizing tryptophan (Trp) into the kynurenine (Kyn) pathway, is increasingly being recognized as an important microenvironmental factor suppressing antitumor immune responses. The purpose of the present study was to determine the prognostic significance of Trp catabolism in adult T-cell leukemia/lymphoma (ATL).Experimental Design: We quantified serum Trp and Kyn in 96 ATL patients, 38 human T-cell lymphotropic virus type-1 asymptomatic carriers (HTLV-1 ACs), and 40 healthy adult volunteer controls. The relationships between various clinical parameters including overall survival were analyzed. IDO expression was evaluated in the affected lymph nodes of ATL patients.Results: Serum Kyn concentrations and Kyn/Trp ratios were significantly higher in HTLV-1 ACs than healthy controls. Both increased significantly with progression from HTLV-1 AC to ATL. However, there were no significant differences in the serum Trp concentrations between ATL patients, HTLV-1 ACs, and controls. IDO was possibly produced by ATL and/or cells of the microenvironment. Multivariate analyses demonstrated that a high serum Kyn/Trp ratio and high Kyn level, but not a high Trp level, were significantly independent detrimental prognostic factors in ATL, as well as in that subset of patients with aggressive variant ATL.Conclusions: Quantification of serum Kyn and Trp is useful for predicting prognosis of an individual ATL patient. Furthermore, ATL, especially in patients with a high serum Kyn/Trp ratio, is an appropriate disease for testing novel cancer immunotherapies targeting IDO. Clin Cancer Res; 21(12); 2830–9. ©2015 AACR.

Supplementary Figure 1, Tables S1-6. Supplementary Fig. S1. IDO expression scores in ATL cells Supplementary Table S1. Clinical characteristics of ATL patients Supplementary Table S2. Univariate Cox proportional hazard analysis for survival according to the serum level of Kyn, Trp, or Kyn/Trp ratio Supplementary Table S3. Multivariate analysis for OS in ATL patients Supplementary Table S4. Multivariate analysis for OS in ATL patients Supplementary Table S5. Multivariate analysis for OS in aggressive ATL patients Supplementary Table S6. Multivariate analysis for OS in aggressive ATL patients

We investigate the characteristics of a dust-devil-like vortex (DDLV) observed using thermal image velocimetry (TIV) at a sports ground in Tokyo. Thermal image velocimetry provides unique observations of the two-dimensional velocity distribution for a DDLV with high spatio–temporal resolution (i.e., tens of cm s−1) near the ground. Two DDLVs were detected, one each in summer and winter, and the quantitative features of the larger, stronger DDLV in the winter are examined. The size and strength of the detected DDLV, which are quantified using TIV, are within the ranges reported in past observations and numerical simulations of dust devils. The vortex appears at the boundary of a cold-air current near a 55-m building wall, and persists for more than 3 min.

A double-distribution-function lattice Boltzmann model for large-eddy simulations of a passive scalar field in a neutrally stratified turbulent flow is described. In simulations of the scalar turbulence within and above a homogeneous plant canopy, the model’s performance is found to be comparable with that of a conventional large-eddy simulation model based on the Navier–Stokes equations and a scalar advection–diffusion equation in terms of the mean turbulence statistics, budgets of the second moments, power spectra, and spatial two-point correlation functions. For a top-down scalar, for which the plant canopy serves as a distributed sink, the variance and flux of the scalar near the canopy top are predominantly determined by sweep motions originating far above the canopy. These sweep motions, which have spatial scales much larger than the canopy height, penetrate deep inside the canopy and cause scalar sweep events near the canopy floor. By contrast, scalar ejection events near the canopy floor are induced by coherent eddies generated near the canopy top. The generation of such eddies is triggered by the downward approach of massive sweep motions to existing wide regions of weak ejective motions from inside to above the canopy. The non-local transport of scalars from above the canopy to the canopy floor, and vice versa, is driven by these eddies of different origins. Such non-local transport has significant implications for the scalar variance and flux budgets within and above the canopy, as well as the transport of scalars emitted from the underlying soils to the atmosphere.

Malignant lymphoma developing during anti-PD-1 antibody treatment is extremely rare. A 74-year-old female was admitted with left hypochondrial pain. She was diagnosed with squamous cell carcinoma of the right upper lobe of the lung, and had undergone surgery and postoperative chemotherapy three years prior. Needle biopsy of a mediastinal lymph node revealed recurrent lung cancer (LC). Pembrolizumab (PEM) monotherapy was started as salvage treatment. Although her lymphadenopathy improved, thrombocytopenia and splenomegaly developed during treatment with nine doses of PEM. Laboratory findings included anemia, increased lactate dehydrogenase, and soluble interleukin-2 receptor levels of 6379 U/mL. Flow cytometry of peripheral blood and bone marrow showed CD20+, κ ≪ λ cell populations. IGH-BCL2 fusion was detected by fluorescence in situ hybridization in bone marrow. Positron emission tomography showed abnormal uptake in tonsils, both cervical lymph nodes, mediastinum (different location from the recurrent LC), spleen, and abdominal cavity. Follicular lymphoma (FL) grade 1/2 was histologically diagnosed by tonsillar biopsy. She achieved a complete metabolic response (CMR) after rituximab monotherapy on PEM discontinuation. Relapsed FL was diagnosed by submandibular gland biopsy four months after restarting PEM and she achieved a second CMR after rituximab-containing chemotherapy. We describe the first case of newly diagnosed FL during PEM treatment.

Respiratory tract infections (RTIs) are the most common diseases globally among children. This study aimed to assess the epidemiology of admission-requiring pediatric RTI cases and evaluate the effect of the pathogen type on the length of hospital stay (LOS) using the FilmArray® respiratory panel, a multiplex PCR test. The age-specific distribution and seasonality of viruses were investigated between March 26, 2018 and April 12, 2019. Multivariable linear regression analyses were performed to evaluate the effect of pathogen type and coinfection on LOS. Among 153 hospitalized RTI patients, respiratory syncytial virus was the leading cause of hospitalization in infants < 12 months of age (27.7%). Human metapneumovirus and parainfluenza virus were also major causes of hospitalization in patients aged 2-3 years (22.6% and 22.6%, respectively). In the multivariable linear regression model excluding rhinovirus/enterovirus, there was a significant association between viral coinfection and longer LOS (p = 0.012), while single viral infection of any type was not positively correlated with LOS. This study revealed the epidemiology of admission-requiring pediatric RTIs.

Previous genomic studies have revealed the genomic landscape of myeloma cells. Although some of the genomic abnormalities shown are believed to be correlated to the molecular pathogenesis of multiple myeloma and/or clinical outcome, these correlations are not fully understood. The aim of this study is to elucidate the correlation between genomic abnormalities and clinical characteristics by targeted capture sequencing in the Japanese multiple myeloma cohort. We analysed 154 patients with newly diagnosed multiple myeloma. The analysis revealed that the study cohort consisted of a less frequent hyperdiploid subtype (37·0%) with relatively high frequencies of KRAS mutation (36·4%) and IGH-CCND1 translocation (26·6%) compared with previous reports. Moreover, our targeted capture sequencing strategy was able to detect rare IGH-associated chromosomal translocations, such as IGH-CCND2 and IGH-MAFA. Interestingly, all 10 patients harboured MAX mutations accompanied by 14q23 deletion. The patients with del(17p) exhibited an unfavourable clinical outcome, and the presence of KRAS mutation was associated with shorter survival in patients with multiple myeloma, harbouring IGH-CCND1. Thus, our study provides a detailed landscape of genomic abnormalities, which may have potential clinical application for patients with multiple myeloma.

A central-moments-based lattice Boltzmann model for large-eddy simulation of neutrally-stratified turbulent flows is described. Through comparative simulations of the airflow within and above a homogeneous plant canopy, the performance of the model is evaluated with respect to a conventional large-eddy-simulation model based on the incompressible Navier–Stokes equations. Simulated turbulence statistics, such as the mean velocity, velocity variances, velocity skewness, and power spectra, are shown to be almost identical between the two models. The spatial structure of coherent eddies and their maintenance processes are also confirmed to be properly represented by the lattice Boltzmann method through analysis of the turbulence kinetic energy budget and spatial two-point correlation functions. Using the simulated results, the energetics of the streamwise-elongated streaky structures commonly observed over vegetation and urban canopies are examined. While the short-wavelength components of the shear-generated streamwise kinetic energy are redirected rapidly by pressure to the lateral and vertical velocity components, long-wavelength energy tends to remain in the streamwise velocity component, which is dissipated in relatively slower processes. Consequently, the streaky structures persist in the streamwise velocity component.

Objective Existing cross-sectional observational studies indicate that patients with multiple myeloma experience negative physical and psychological symptoms and low health-related quality of life. The study aim was to determine symptom prevalence, health-related quality of life and symptoms associated with health-related quality of life in patients with newly diagnosed multiple myeloma. Methods This multicenter longitudinal cohort study was conducted in four hospitals in Japan. Patients with newly diagnosed multiple myeloma were asked to report their symptom intensity and health-related quality of life using validated questionnaires at three points: at diagnosis (T1), 1 month (T2) and 12 months after diagnosis (T3). Symptoms associated with health-related quality of life were explored using a mixed-effects model. Results A total of 106 patients completed the assessment at T1. The symptoms more than 30% of patients reported were pain, disturbed sleep and distress at T1, pain, dry mouth, disturbed sleep and fatigue at T2, fatigue, numbness of tingling and pain and numbness or tingling at T3. Pain and depression were significantly associated with health-related quality of life negatively. Conclusions The finding suggests that more than 30% of multiple myeloma patients suffered from pain and various symptoms and they received suboptimal palliative care within a year after starting initial chemotherapy. Pain and depression should be the main targets of interventions to improve health-related quality of life in this population.

Urban geometry and materials combine to create complex spatial, temporal and directional patterns of longwave infrared (LWIR) radiation. Effective anisotropy (or directional variability) of thermal radiance causes remote sensing (RS) derived urban surface temperatures to vary with RS view angles. Here a new and novel method to resolve effective thermal anisotropy processes from LWIR camera observations is demonstrated at the Comprehensive Outdoor Scale MOdel (COSMO) test site. Pixel-level differences of brightness temperatures reach 18.4 K within one hour of a 24-h study period. To understand this variability, the orientation and shadowing of surfaces is explored using the Discrete Anisotropic Radiative Transfer (DART) model and Blender three-dimensional (3D) rendering software. Observed pixels and the entire canopy surface are classified in terms of surface orientation and illumination. To assess the variability of exitant longwave radiation (M_LW) from the 3D COSMO surface (M_LW^3D), the observations are prescribed based on class. The parameterisation is tested by simulating thermal images using a camera view model to determine camera perspectives of M_LW^3D fluxes. The mean brightness temperature differences per image (simulated and observed) are within 0.65 K throughout a 24-h period. Pixel-level comparisons are possible with the high spatial resolution of M_LW^3D and DART camera view simulations. At this spatial scale (< 0.10 m), shadow hysteresis, surface sky view factor and building edge effects are not completely resolved by M_LW^3D. By simulating apparent brightness temperatures from multiple view directions, effective thermal anisotropy of M_LW^3D is shown to be up to 6.18 K. The developed methods can be extended to resolve some of the identified sources of sub-facet variability in realistic urban settings. The extension of DART to the interpretation of ground-based RS is shown to be promising.

We used numerical simulations to investigate the general relationship between urban morphology and the intensity of wind gusts in built-up areas at the pedestrian level. The simulated urban boundary layer developed over a 19.2 km (length) $$\times $$ 4.8 km (width) $$\times $$ 1.0 km (height) simulation domain, with 2-m resolution in all directions, to explicitly resolve the detailed shapes of buildings and the flow at the pedestrian level. This complex computation was accomplished using the lattice Boltzmann method and by implementing a large-eddy simulation model. To generalize the results, a new parameter that expresses the intensity of gusts (the gust index, $${\tilde{U}}_{ max})$$ was defined as the local maximum wind speed divided by the freestream velocity. In addition, this parameter was decomposed into the mean wind-speed ratio, $${\tilde{U}} $$ and turbulent gust ratio, $${\tilde{U}}^{{\prime }}$$ to evaluate the qualities of gusts. These parameters were useful for quantitatively comparing the gust intensities within urban canopies at different locations or even among different experiments. In addition, the entire horizontal domain was subdivided into homogeneous square patches, in which both the simulated gust parameters and the morphological characteristics of building geometries were averaged. This procedure masked the detailed structure of individual buildings but retained the bulk characteristics of the urban morphology. At the pedestrian level, the gust index decreased with increasing building cover. Compared to $${\tilde{U}} $$ , the quantity $${\tilde{U}}^{{\prime }}$$ notably contributed to the index throughout the range of plan area index $$(\lambda _p)$$ values. The dependences of all normalized wind-speed ratios transiently changed at $$\lambda _p =~0.28$$ . In cases where $$\lambda _p < 0.28, {\tilde{U}} $$ decreased with increasing $$\lambda _p $$ , although $${\tilde{U}}^{{\prime }}$$ was almost constant. In cases where $$\lambda _p > 0.28, {\tilde{U}}$$ was almost constant and $${\tilde{U}}^{{\prime }}$$ decreased with increasing $$\lambda _p $$ . This was explained by the change in flow regimes within the building canyon. At a higher elevation above the canopy layer, $$\lambda _p $$ becomes less relevant to normalized wind-speed ratios, and instead the aerodynamic roughness length became important.

The applicability of outer-layer scaling is examined by numerical simulation of a developing neutral boundary layer over a realistic building geometry of Tokyo. Large-eddy simulations are carried out over a large computational domain $$(19.2\hbox { km} \times 4.8 \hbox { km}\times 1 \hbox { km}$$ in the streamwise, spanwise, and vertical directions, respectively), with a fine grid spacing (2 m) using the lattice-Boltzmann method with massively parallel graphics processing units. The simulation produces a ratio of the boundary-layer height to the average building height of more than 50. Results from simulations show that outer-layer features are maintained for turbulence statistics in the upper part of the boundary layer, as well as the width of predominant streaky structures throughout the entire boundary layer, despite the very large roughness. This is caused by the existence of very large streaky structures extending throughout the entire boundary layer, which follow outer-layer scaling with a self-preserving development. We assume the top-down mechanism in the physical interpretation of results.

Observations using a three-dimensional scanning coherent Doppler lidar in an urban area revealed the characteristics of streaky structures above a rough, inhomogeneous surface for a high-Reynolds-number flow. The study focused on two points: (1) the frequency of occurrence and conditions required for the presence of streaky structures, and (2) the universal scaling of the spacing of streaky structures ( $$\lambda )$$ . The horizontal snapshots of the radial velocity were visually classified into six groups: Streak, Mixed, Fishnet, No streak, Front, and Others. The Streak category accounted for more than 50% of all possible flows and occurred when the horizontal wind speed was large and the atmospheric stratification was near-neutral. The spacing ( $$\lambda )$$ was estimated from the power spectral density of the streamwise velocity fluctuations along the spanwise direction. The spacing $$\lambda $$ decreased with an increase in the local velocity gradient. Furthermore, it was revealed that the local velocity gradient normalized by the friction velocity and the boundary-layer height ( $$z_i )$$ comprehensively predicts $$\lambda /z_i $$ under various experimental and environmental conditions, in terms of the scale of motion (i.e., indoor and outdoor scales), thermal stratification (i.e., from weakly unstable to stable stratification), and surface roughness (i.e., from flat to very rough surfaces).

t(14;20)(q32;q11)/IGH-MAFB is a rare chromosomal abnormality in plasma cell myeloma (PCM), accounting for 1-2% of PCM cases. Patients with this translocation may have a poor prognosis. However, the clinicopathological features and response to novel agents have not been well clarified. We present a 63-year-old Japanese female with PCM positive for t(14;20). The tumor responded well to a proteasome inhibitor, bortezomib, and the patient achieved complete remission. Six months after remission, tumor relapse was noted in the left cerebellum and the right frontal lobe of the cerebrum. After whole brain radiation therapy, the tumor masses decreased in size. The patient was followed up with best-care support, but died of the disease 29 months after the initial PCM diagnosis. t(14;20)-positive PCM responded well to bortezomib at the time of the initial treatment. The CNS tumor involvement, which is rare in PCM, may be associated with the clinical aggressiveness of the t(14;20)-positive form of this myeloma.

Sea breeze is closely related to the living environment in coastal-urban regions. Therefore, the framework for sea-breeze detection is crucial. We proposed a framework to derive a two-dimensional distribution of sea-breeze front (SBF) using geostationary satellite images. The framework includes the application of morphological snake algorithm into visible band images for automated detection of the cumulus cloud-lines associated with SBF. The verification was undertaken by comparing the passage time of the cloud-line with the arrival time of the SBF estimated from ground observation. The results show that the cloud-line was reasonably able to represent the arrival time of the SBF with a bias time of 20 min and within a distance of 3 km. The mean penetration speed obtained from the cloud-lines passage was slightly slower than that estimated from the arrival time of SBF (1.4 ms−1 and 1.5 ms−1, respectively). In certain cases, the cloud-lines passage was found to be behind the SBF more than 5 km, particularly in the city center. This indicated the enhanced updraft due to urban-heat-island circulation potentially caused the delayed of cloud-line propagation in certain prevailing wind condition.

Introduction There is limited evidence regarding the impact of updated Charlson comorbidity index (CCI) on survival in patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL) receiving rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) regimen. Methods We retrospectively reviewed 125 patients with newly diagnosed DLBCL receiving R-CHOP as a first-line immunochemotherapy who were admitted to Nagoya City West Medical Center between May 2011 and December 2018. We evaluated the association between their survival and the 5 following baseline indexes: CCI, age-adjusted CCI, updated CCI, Barthel index and mini-nutritional assessment (MNA-SF). Result Baseline characteristics of the 125 patients with newly diagnosed DLBCL were as follows: median age was 75 years; 84% was >60 years; 70% had high LDH (> upper limit of normal); 33% had ECOG-PS ≥2; Ann Arbor stage of I, II, III, IV was 14%, 21%, 18% and 48%, respectively; 39% had extranodal site ≥2; 11% had high BNP levels (BNP≥100 pg/mL). None of CCI, age-adjusted CCI and updated CCI was associated with the survival, although both a lower Barthel index and malnutrition were significantly associated with shorter overall survival. The patients with high BNP levels had worse prognosis compared to those with low levels. Multivariate analysis revealed that age >60 years, extranodal site ≥2 and malnutrition (MNA-SF ≤7) were independent risk factors for survival (adjusted hazard ratios, 2.9, 2.2 and 2.0, respectively; p Conclusion In our cohort, none of CCI, age-adjusted CCI and updated CCI had impact on survival in patient with DLBCL receiving R-CHOP treatment, whereas malnutrition (MNA-SF ≤7) had negative impact on survival in those patients. Well-designed clinical trials are warranted to identify not only lymphoma-related factors but also host factors for survival.

Scintillometer measurements of turbulent fluxes of momentum and sensible heat in the roughness sublayer over a regular array of cubes in an outdoor environment were tested with direct measurement from sonic anemometers. The dissipation rate, e, and temperature structure parameter, C T 2 , obtained from the scintillometer agreed well with those from four sonic anemometers located along the scintillometer path. The fluxes measured by the scintillometer also corresponded well to those from the line-averaged eddy covariance approach, although this agreement was greatly influenced by the choice of the zero-plane displacement length and the form of the similarity function used in the scintillometer software. A guide for choosing the appropriate similarity function for the urban roughness sublayer is proposed.

Purpose: Indoleamine 2,3-dioxygenase 1 (IDO1: IDO), an enzyme catabolizing tryptophan (Trp) into the kynurenine (Kyn) pathway, is increasingly being recognized as an important microenvironmental factor suppressing antitumor immune responses. The purpose of the present study was to determine the prognostic significance of Trp catabolism in adult T-cell leukemia/lymphoma (ATL). Experimental Design: We quantified serum Trp and Kyn in 96 ATL patients, 38 human T-cell lymphotropic virus type-1 asymptomatic carriers (HTLV-1 ACs), and 40 healthy adult volunteer controls. The relationships between various clinical parameters including overall survival were analyzed. IDO expression was evaluated in the affected lymph nodes of ATL patients. Results: Serum Kyn concentrations and Kyn/Trp ratios were significantly higher in HTLV-1 ACs than healthy controls. Both increased significantly with progression from HTLV-1 AC to ATL. However, there were no significant differences in the serum Trp concentrations between ATL patients, HTLV-1 ACs, and controls. IDO was possibly produced by ATL and/or cells of the microenvironment. Multivariate analyses demonstrated that a high serum Kyn/Trp ratio and high Kyn level, but not a high Trp level, were significantly independent detrimental prognostic factors in ATL, as well as in that subset of patients with aggressive variant ATL. Conclusions: Quantification of serum Kyn and Trp is useful for predicting prognosis of an individual ATL patient. Furthermore, ATL, especially in patients with a high serum Kyn/Trp ratio, is an appropriate disease for testing novel cancer immunotherapies targeting IDO. Clin Cancer Res; 21(12); 2830–9. ©2015 AACR.

Average horizontal wind velocity in an urban canopy is mainly determined by a balance between flow deceleration caused by the drag force of buildings and flow acceleration from the momentum flux gradient in the canopy. To express the transport of momentum in an urban canopy, mixing length is often used to calculate diffusivity there. A new parametrization for mixing length is introduced for a one-dimensional multilayer urban canopy model (UCM). A database from large-eddy simulations using actual urban morphology for Tokyo is used for this parametrization. The derived mixing length is described as a function of the non-dimensional height raised to the power of $$q$$ , where $$q < 1$$ . The $$q$$ value and constants of the function also depend on the selection of canopy height. The mixing length profile is closely related to that of the average plane area index of the buildings in the study area. Recalculation of mean horizontal wind velocity using the new parametrization of mixing length for Tokyo slightly improved the multilayer UCM results.

The spatial variability of flow and turbulence properties above an outdoor scale model of regular cube roughness under neutral stability is investigated using eight simultaneously employed sonic anemometers which are characterized by an extra short transducer span (0.05 m) and high sampling rate (50 Hz). Measurements are conducted in a layer between the top of the cubes with a plan area density of 0.25 and two times the height of the roughness, $$H$$ . Large spatial variability (horizontal and vertical) is observed at the two lowest measurement levels ( $$z=H$$ and $$1.25H$$ ) for all variables considered which include mean wind, Reynolds stress, integral statistics, (co)spectra, budget of turbulent kinetic energy and a spatial quadrant analysis of the momentum transfer. The spatial inhomogeneity almost disappears at $$z = 1.5H$$ where normalized variables attain homogeneous surface layer values for neutral stratification. The present results support a new conceptual framework to explain the turbulence behavior just above the canopy consisting of two sublayers which develop in response to the strongly varying surface. Although an individual measurement location below $$z = 1.5H$$ is unable to produce representative turbulence statistics above the present bluff body roughness, averaging across a sufficient number of measurement locations to achieve complete spatial sampling of all surface characteristics (canyon spaces, rooftops, etc.), produces representative statistics even at heights which are probably still within the roughness sublayer with values close to the respective inertial subrange predictions.

This study conducted large-eddy simulations (LES) of fully developed turbulent flow within and above explicitly resolved buildings in Tokyo and Nagoya, Japan. The more than 100 LES results, each covering a 1,000 $$\times $$ 1,000 m $$^{2}$$ area with 2-m resolution, provide a database of the horizontally-averaged turbulent statistics and surface drag corresponding to various urban morphologies. The vertical profiles of horizontally-averaged wind velocity mostly follow a logarithmic law even for districts with high-rise buildings, allowing estimates of aerodynamic parameters such as displacement height and roughness length using the von Karman constant $$=$$ 0.4. As an alternative derivation of the aerodynamic parameters, a regression of roughness length and variable Karman constant was also attempted, using a displacement height physically determined as the central height of drag action. Although both the regression methods worked, the former gives larger (smaller) values of displacement height (roughness length) by 20–25 % than the latter. The LES database clearly illustrates the essential difference in bulk flow properties between real urban surfaces and simplified arrays. The vertical profiles of horizontally-averaged momentum flux were influenced by the maximum building height and the standard deviation of building height, as well as conventional geometric parameters such as the average building height, frontal area index, and plane area index. On the basis of these investigations, a new aerodynamic parametrization of roughness length and displacement height in terms of the five geometric parameters described above was empirically proposed. The new parametrizations work well for both real urban morphologies and simplified model geometries.

Background: A RANKL-binding peptide WP9QY (W9) is known to inhibit osteoclastogenesis. Results: W9 showed an anabolic effect on cortical bone in mice. W9 bound RANKL and differentiated osteoblasts with production of autocrine factors like BMP-4. Conclusion: Signaling through RANKL is involved in part in the W9-induced osteoblast differentiation. Significance: The RANKL pathway could be a novel mechanism in osteoblast differentiation., To date, parathyroid hormone is the only clinically available bone anabolic drug. The major difficulty in the development of such drugs is the lack of clarification of the mechanisms regulating osteoblast differentiation and bone formation. Here, we report a peptide (W9) known to abrogate osteoclast differentiation in vivo via blocking receptor activator of nuclear factor-κB ligand (RANKL)-RANK signaling that we surprisingly found exhibits a bone anabolic effect in vivo. Subcutaneous administration of W9 three times/day for 5 days significantly augmented bone mineral density in mouse cortical bone. Histomorphometric analysis showed a decrease in osteoclastogenesis in the distal femoral metaphysis and a significant increase in bone formation in the femoral diaphysis. Our findings suggest that W9 exerts bone anabolic activity. To clarify the mechanisms involved in this activity, we investigated the effects of W9 on osteoblast differentiation/mineralization in MC3T3-E1 (E1) cells. W9 markedly increased alkaline phosphatase (a marker enzyme of osteoblasts) activity and mineralization as shown by alizarin red staining. Gene expression of several osteogenesis-related factors was increased in W9-treated E1 cells. Addition of W9 activated p38 MAPK and Smad1/5/8 in E1 cells, and W9 showed osteogenesis stimulatory activity synergistically with BMP-2 in vitro and ectopic bone formation. Knockdown of RANKL expression in E1 cells reduced the effect of W9. Furthermore, W9 showed a weak effect on RANKL-deficient osteoblasts in alkaline phosphatase assay. Taken together, our findings suggest that this peptide may be useful for the treatment of bone diseases, and W9 achieves its bone anabolic activity through RANKL on osteoblasts accompanied by production of several autocrine factors.

We examine the similarity of turbulent organized structures over smooth and very rough wall flows. Turbulent flow fields in horizontal cross-sections were measured using particle image velocimetry, and the characteristics of turbulent organized structures over four types of surfaces were investigated. Measurements were conducted at several measurement heights across the internal boundary layer. The length and width of turbulence structures were quantified using a two-point correlation method. We selected two thresholds of two-point correlation coefficients to consider both large-scale and small-scale structures; the validity of these choices was examined through the analyses using proper orthogonal decomposition. For large-scale structures, the length and aspect ratios (streamwise length/spanwise width) of structures were highly correlated with the velocity gradient for each measurement height and boundary-layer thickness. This relationship was also examined in the results of previous studies, and the scaling of the aspect ratio with the non-dimensional velocity gradient again showed the importance of the velocity gradient, with slight differences found between smooth and rough surfaces. In contrast, the small-scale structures exhibited weak dependency on the velocity gradient and boundary-layer thickness. Instantaneous snapshots of turbulent organized structures at the same shear level also displayed differences in small-scale structures, but the structures of the organized motions resembled each other, as in the results of the two-point correlation method.

Instantaneous flow structures “within” a cubical canopy are investigated via large-eddy simulation. The main topics of interest are, (1) large-scale coherent flow structures within a cubical canopy, (2) how the structures are coupled with the turbulent organized structures (TOS) above them, and (3) the classification and quantification of representative instantaneous flow patterns within a street canyon in relation to the coherent structures. We use a large numerical domain (2,560 m × 2,560 m × 1,710 m) with a fine spatial resolution (2.5 m), thereby simulating a complete daytime atmospheric boundary layer (ABL), as well as explicitly resolving a regular array of cubes (40 m in height) at the surface. A typical urban ABL is numerically modelled. In this situation, the constant heat supply from roof and floor surfaces sustains a convective mixed layer as a whole, but strong wind shear near the canopy top maintains the surface layer nearly neutral. The results reveal large coherent structures in both the velocity and temperature fields “within” the canopy layer. These structures are much larger than the cubes, and their shapes and locations are shown to be closely related to the TOS above them. We classify the instantaneous flow patterns in a cavity, specifically focusing on two characteristic flow patterns: flushing and cavity-eddy events. Flushing indicates a strong upward motion, while a cavity eddy is characterized by a dominant vortical motion within a single cavity. Flushing is clearly correlated with the TOS above, occurring frequently beneath low-momentum streaks. The instantaneous momentum and heat transport within and above a cavity due to flushing and cavity-eddy events are also quantified.

We report four cases of adult-onset Langerhans cell histiocytosis (LCH) with central nervous system (CNS) lesions in the hypothalamic-pituitary region. The first clinical symptoms were diabetes insipidus (two patients), hypothyroidism (one patient), and decreased libido/erectile dysfunction (one patient). Diagnosis was delayed as the CNS lesion was not initially suspected to be secondary to LCH, with a median time from symptom onset to treatment of 3.0 (range

We investigate the spatial characteristics of urban-like canopy flow by applying particle image velocimetry (PIV) to atmospheric turbulence. The study site was a Comprehensive Outdoor Scale MOdel (COSMO) experiment for urban climate in Japan. The PIV system captured the two-dimensional flow field within the canopy layer continuously for an hour with a sampling frequency of 30 Hz, thereby providing reliable outdoor turbulence statistics. PIV measurements in a wind-tunnel facility using similar roughness geometry, but with a lower sampling frequency of 4 Hz, were also done for comparison. The turbulent momentum flux from COSMO, and the wind tunnel showed similar values and distributions when scaled using friction velocity. Some different characteristics between outdoor and indoor flow fields were mainly caused by the larger fluctuations in wind direction for the atmospheric turbulence. The focus of the analysis is on a variety of instantaneous turbulent flow structures. One remarkable flow structure is termed 'flushing', that is, a large-scale upward motion prevailing across the whole vertical cross-section of a building gap. This is observed intermittently, whereby tracer particles are flushed vertically out from the canopy layer. Flushing phenomena are also observed in the wind tunnel where there is neither thermal stratification nor outer-layer turbulence. It is suggested that flushing phenomena are correlated with the passing of large-scale low-momentum regions above the canopy.

Hyperphosphorylated paratarg-7 (pP-7) is a frequent target of paraproteins in German patients with monoclonal gammopathy of undetermined significance (MGUS)/multiple myeloma (MM). The frequency of MGUS/MM is lower in Japan than in Europe. As pP-7, the first molecularly defined autosomal-dominant risk factor for any hematological neoplasm, is inherited in a dominant fashion, we determined the incidence of the pP-7 carrier state in a Japanese population, and compared the frequency of pP-7-specific paraproteins and the pP-7 carrier state in Japanese and German patients with MGUS/MM. Peripheral blood from 111 Japanese patients with MGUS/MM and 278 healthy blood donors was analyzed for the pP-7 carrier state by isoelectric focusing and for pP-7-specific antibodies by ELISA. The Japanese group was compared with 252 German MGUS/MM patients and 200 healthy controls. Five of 111 (4.5%) Japanese and 35/252 (13.9%) German IgA/IgG MGUS/MM patients had a pP-7-specific paraprotein (P=0.009). The prevalence of healthy pP-7 carriers in the Japanese study group was 1/278 (0.36%), whereas it was 4/200 in the German group (P=0.166). The relative risk for pP-7 carriers developing MGUS/MM had an odds ratio of 13.1 in the Japanese and 7.9 in the German group. In conclusion, the fraction of pP-7 carriers with a pP-7-specific paraprotein is lower among Japanese than in German patients with MGUS/MM, but pP-7 carriers in both ethnic groups have a high risk of developing MGUS/MM.

A large-eddy simulation of the atmospheric boundary layer, large enough to contain both an urban surface layer and a convective mixed layer, was performed to investigate inner-layer and outer-layer scale motions. The objective was to determine the applicability of Monin–Obukhov similarity theory to inner-layer motions, to investigate the influence of outer-layer motions on surface-layer structure, as well as to assess the interaction of the two scales of motion. The urban surface roughness consisted of square-patterned cubic buildings of dimension H (40 m). A spatial filter was used to decompose the two scales in the inertial sublayer. The horizontal square filter of size 10H was effective in separating the inner-layer (surface-layer height ≈ 2 H) and outer-layer scales (boundary-layer height δ ≈ 30H), where the Reynolds stress contribution of the inner layer dominates in the logarithmic layer (depth 2H). Similarity coefficients for velocity fluctuations were successfully determined for inner-layer motions in the surface layer, proving the robustness of Monin–Obukhov similarity for surface-layer turbulence. The inner-layer structures exhibit streaky structures that have similar streamwise length but narrower spanwise width relative to the streamwise velocity fluctuation field, consistent with observations from an outdoor scale model. The outer-layer motions to some extent influence the location of ejections and sweeps through updraft and downdraft motions, respectively, thus, disturbing the homogeneity and similarity of inner-layer motions. Although the horizontal averages of the variances and covariance of motions reveal that the Reynolds stresses are dominated by inner-layer structures, the localized influence of the interaction of outer-layer horizontal and inner-layer vertical motions on the Reynolds stress is not insignificant.