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Interleukin (IL)-37 suppresses systemic and local inflammation. It is expressed in the epidermis, the external layer of the skin, and is decreased in inflammatory skin diseases including atopic dermatitis (AD) and psoriasis. Therefore, an agent applied topically on the skin that can increase IL-37 could be promising for treating AD and psoriasis; however, the mechanism regulating IL-37 remains largely unknown. Given that IL-37 expression is induced in differentiated keratinocytes, a major component of the epidermis, and that activation of aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor, promotes keratinocyte differentiation, we hypothesized that AHR might be involved in the IL-37 expression in human keratinocytes. We analyzed normal epidermal human keratinocytes (NHEKs) treated with tapinarof and

Background Endothelin-1 (EDN1) can evoke histamine-independent pruritus in mammals and is upregulated in the lesional epidermis of atopic dermatitis (AD). EDN1 increases the production of interleukin 25 (IL-25) from keratinocytes to accelerate T helper type 2 immune deviation. Plasma EDN1 levels are positively correlated with the clinical severity and itch intensity of AD. Therefore, we hypothesized that the inhibition of EDN1 might be useful for treating atopic inflammation and itch and investigated the effects of the topical application of the EDN1 receptor antagonist bosentan on the skin inflammation and itch in a murine AD model. Methods We analyzed the mite-induced AD-like NC/Nga murine model, which was topically applied with bosentan or ethanol control every day for 3 weeks. We also subjected in vitro primary sensory neuron culture systems to nerve elongation and branching assays after EDN1 stimulation. Results Topical application of bosentan significantly attenuated the development of mite-induced AD-like skin inflammation, dermatitis scores, ear thickness, scratching bouts, and serum level of thymus and activation-regulated chemokine in NC/Nga mice. Bosentan application also significantly reduced the gene expression of Il13, Il17, and Ifng in the treated lesions. Histologically, the number of infiltrated dermal cells, the epidermal EDN1 expression, and the number of intraepidermal nerve fibers were significantly inhibited upon bosentan application. While EDN1 significantly elongated the neurites of dorsal root ganglion cells in a dose- and time-dependent manner, bosentan treatment attenuated this. Conclusions EDN1 plays a significant role in mite-induced inflammation and itch. Topical bosentan is a potential protective candidate for AD.

Atopic dermatitis (AD) is a multifactorial T-helper (Th)2-mediated skin disease frequently associated with elevated serum immunoglobulin (Ig)E and food allergy is also a Th2- and IgE-mediated adverse immunological reaction. Our previous study indicated the relation of egg allergy history and disease severity of AD. Thus, the purpose of the study was to investigate the levels of IgE specific to major food allergens (egg, milk, wheat) and Th2 chemokines (chemokine [C-C motif] ligand [CCL]17/thymus and activation regulated chemokine [TARC] and CCL22/macrophage-derived chemokine [MDC]) and the relationship between them. A total of 743 nursery school children were enrolled. Dermatologist-based physical examination and a questionnaire survey were also conducted. Significantly increased levels of disease severity markers (CCL17/TARC and CCL22/MDC) were confirmed in children with AD. The levels of CCL22/MDC in all of the children were markedly high compared with those reported in adults. IgE specific to egg white, ovomucoid, wheat and mite antigen were significantly higher in the AD group than in the non-AD group. Among them, IgE specific to egg allergens were well associated with disease severity markers, and IgE specific to ovomucoid seemed particularly well correlated with the presence of egg allergy history. In conclusion, the markedly high level of CCL22/MDC in children as compared with those reported in adults may partly explain the AD-prone nature of children and their spontaneous remission afterwards. Mild but significant correlation of IgE specific to egg allergens and Th2 chemokines may explain correlation of disease severity and comorbidity of egg allergy in our previous study.

The electron temperature T e and density N e of atmospheric-pressure non-equilibrium dielectric barrier discharge argon (Ar) plasma are measured with optical emission spectroscopy. Continuum emission due to bremsstrahlung is applied to the analysis of the electron temperature and density with the spectrometric system in the visible wavelength range calibrated absolutely. The assumption of the Maxwellian electron energy distribution function (EEDF) results in T e ≃ 0.29 eV and N e ≃ 1.1 × 1016 cm−3, whereas the Druyvesteyn EEDF leads to the result T e ≃ 0.79 eV and N e ≃ 1.4 × 1014 cm−3. To confirm the validity of these values, several line intensities of the excited states of the Ar atom are observed experimentally and compared with the theoretical population densities calculated by the Ar collisional–radiative (CR) model that includes atomic collisional processes. It is confirmed that the order of the observed excited-state number densities agrees well with that calculated numerically by the CR model with the Druyvesteyn EEDF, while the Maxwellian EEDF gives poor results.

Skin barrier dysfunction, including reduced filaggrin (FLG) and loricrin (LOR) expression, plays a critical role in atopic dermatitis (AD) development. Since aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor, mediates keratinocyte differentiation, it is a potential target for AD treatment. Recently, clinical studies have shown that tapinarof, an AHR modulator, attenuated the development of AD. To examine the molecular mechanism involved in this, we analyzed tapinarof-treated normal human epidermal keratinocytes (NHEKs). Tapinarof upregulated FLG and LOR mRNA and protein expression in an AHR-dependent manner. Tapinarof also induced the secretion of IL-24, a cytokine that activates Janus kinase (JAK)-signal transducer and activator of transcription (STAT), leading to the downregulation of FLG and LOR expression. Knockdown of either IL-24 or STAT3 expression by small interfering RNA (siRNA) transfection augmented the upregulation of FLG and LOR expression induced by tapinarof, suggesting that inhibition of the IL-24/STAT3 axis during AHR activation supports the improvement of skin barrier dysfunction. Furthermore, tapinarof alone could restore the downregulation of FLG and LOR expression induced by IL-4, a key cytokine of AD, and its combination with JAK inhibitors enhanced this effect. These findings provide a new strategy for treating AD using AHR modulators and JAK inhibitors.

Background Scratch injury induces Koebner phenomenon in psoriasis. Smoking is also a risk factor for psoriasis. Keratinocytes can produce various psoriasis-related molecules including TNF, IL1 A, IL1B, IL6, IL12B, IL17C, IL23 A, IL36 A, IL36B, IL36 G, CXCL1, CXCL2, CXCL8, CXCL9, CXCL10, CCL20, IFNB, and CAMP. However, the scratch-induced molecular profiling remains elusive. Objective To profile the induction pattern of above-mentioned psoriasis-related and keratinocyte-derived molecules by scratch injury in the presence or absence of anti-psoriatic drugs or benzo[a]pyrene, a major environmental pollutant of tobacco smoke. Methods Confluent normal human keratinocytes were scratched and molecules were assayed by qRT-PCR, ELISA and Western blotting with or without drugs and benzo[a]pyrene. Results Among the 18 molecules, the scratch injury on a confluent keratinocyte sheet significantly and selectively upregulated the mRNA expression of four cyto/chemokines, CXCL8, CCL20, IL36G, and TNF, in a scratch-line-number-dependent manner under either low- or high-calcium condition. However, significant protein secretion was only demonstrated for CXCL8 and CCL20. The IL36 G protein was not secreted, but its intracellular level was significantly upregulated by scratch injury, whereas neither the secretion nor the intracellular level of TNF protein was affected by scratch injury. Dexamethasone, but not maxacalcitol nor the phosphodiesterase 4 inhibitor apremilast, partially inhibited the CXCL8 and CCL20 secretion. Benzo[a]pyrene significantly and synergistically enhanced the scratch-induced CCL20 secretion that may explain why smoking is a risk factor for psoriasis. Conclusion CCL20 and to a less extent CXCL8 may play a key role in triggering the Koebner phenomenon after scratch injury to keratinocytes.

We report resistivity measurements under pressure for Kondo-lattice ferromagnet CeRh$_6$Ge$_4$, and present that a quantum ferromagnetic (FM) phase transition is easily achieved. In most clean metallic ferromagnets, a quantum critical point (QCP) at zero field is avoided by changing the FM transition to a discontinuous transition or to an antiferromagnetic transition. In CeRh$_6$Ge$_4$, to the contrary, the Curie temperature of 2.5 K decreases continuously as increasing pressure without any clear signature that the transition changes to first order. The obvious non Fermi liquid behavior is observed in the vicinity of the quantum FM phase transition. The experimental data do not contradict a picture in which CeRh$_6$Ge$_4$ shows the FM QCP at zero field. Band structure calculation suggests the unusual electronic state of CeRh$_6$Ge$_4$ among Ce-based Kondo lattices. CeRh$_6$Ge$_4$ deserves further investigations and will be a key material to understand the matter of the FM QCP., Comment: 5 pages, 6 figures

The immunohistological localization of peroxisome proliferator-activated receptor a (PPARa) and PPAR g was examined in 28 pilosebaceous units in 10 paraffin-embedded normal human skin specimens. Rabbit polyclonal antibody against human PPARa and monoclonal antibody against human PPARg were used as specific primary antibodies. The nuclear and cytoplasmic expression of PPARa was detected in basal to differentiated sebocytes. In contrast, the expression of PPARg was confined to nuclei of suprabasal to early-differentiated sebocytes. The nuclear PPARg expression was present only occasionally in the basal sebocytes. These results suggest that PPARa and PPARg are integral parts of sebocyte differentiation in human sebaceous glands.

Filaggrin (FLG) mutation is a well-confirmed genetic aberration in atopic dermatitis (AD). Genome-wide association studies on AD have revealed other susceptibility genes, for example, Ovo-like 1 (OVOL1). Nonetheless, the relation between FLG and OVOL1 is unclear. Because aryl hydrocarbon receptor (AHR; a ligand-activated transcription factor), plays a role in FLG expression in keratinocytes, we hypothesized that AHR regulates FLG expression via OVOL1. To demonstrate this mechanism, we analyzed FLG expression in OVOL1-overexpressing or OVOL1-knockdown normal human epidermal keratinocytes (NHEKs). Furthermore, we tested whether AHR activation by 6-formylindolo(3,2-b)carbazole (FICZ), an endogenous AHR ligand, or Glyteer, clinically used soybean tar, upregulates FLG and OVOL1 expression in NHEKs. We found that (1) OVOL1 regulates FLG expression; (2) AHR activation upregulates OVOL1; and (3) AHR activation upregulates FLG via OVOL1. Moreover, nuclear translocation of OVOL1 was less pronounced in AD skin compared with normal skin. IL-4-treated NHEKs, an in vitro AD skin model, also showed inhibition of the OVOL1 nuclear translocation, which was restored by FICZ and Glyteer. Thus, targeting the AHR–OVOL1–FLG axis may provide new therapeutics for AD.

Ti 3d electronic structure of Ti2O3 has been investigated by means of soft X-ray photoemission spectroscopy (SXES) in the Ti 2p–3d absorption region. In the SXES spectra, the Raman peaks due to the a 1 g – e g π and a 1 g – e g σ excitations are observed at 1.3 and 3.3 eV below the incident photon energy, respectively. The intensity of the a 1 g – e g σ peak in the SXES spectrum measured between the 2p3/2–3d and 2p1/2–3d absorption peaks depends on the polarization of the incident photon E; the peak observed clearly in case of E parallel to the c-axis, almost disappears in case of E perpendicular to the c-axis.

The validity of the computational method for particle-laden liquid flows, MICS (Multiphase Incompressible flow solver with Collocated grid System), was shown through the comparison with experimental results in terms of unsteady wakes behind particles and interaction between particles and surrounding flows. In this paper, MICS is improved to the computational method for gas-liquid-solid multiphase flows in order to deal with the particle movements in the liquid flow with large deformation of the free surface. MICS is based on the computational method for incompressible flows, in which the treatment for density and mass conservation has been improved in the collocated grid. The external forces for the particles are evaluated from the results of the fluid computations and a model of the distinct element method (DEM). The MICS was applied to the particle movements in a free-surface flow and its applicability is discussed.

The measurements of electrical resistivity, magnetic susceptibility, specific heat, thermopower and powder x-ray diffraction under pressure have been performed on single crystals of Y 1- x Ca x TiO...

有限体積法により離散化された移流方程式に対する高次精度スキームについて考察した. 計算セル境界のフラックスを5次スプライン関数により空間内挿するFVM-QSIスキームを示すとともに, 保存性を損なわずに数値振動を抑制するためのフラックス制御法 (DC法とFP法) を提案した. 移流方程式へ適用した結果, DC法を用いたFVM-QSIスキームにより精度の高い安定な計算が行えること, またFP法ではDC法より精度は低下するが, 計算時間が短縮化されることを示した. さらに, 2次元キャビティ内の非圧縮性流体計算へ適用した結果, DC法を用いたFVM-QSIスキームにより, 既往の5次精度TVDスキームよりも精度が高い数値解が得られること, また計算時間の点においても本手法は十分実用的であることなどが示された.

後流渦などの流れ場への影響をもたらす固体粒子を含む粒子-流体混合系に対する数値解析法 (MICS) を提案し, その適用性について検討を加えた. 粒子近傍の流れや粒子に作用する流体力を正確に評価するため, コロケート格子配置に基づく非圧縮性流体解析法を混合系全体に適用する. 密度分布や流体の連続性に対して考察を加えた高次精度の解法により, 粒子に対する流体力を求める. また, 他の粒子との接触力を算定するために, 個別要素法モデルを利用する. 既往の実験結果に基づく基礎的な検証により, 抗力係数や非定常後流渦の特性などが適切に再現されることが示された. さらに, 壁面近傍を落下する粒子の運動や接触移動する粒径が異なる粒子群などへ計算手法を適用し, 実験結果との比較を通じてその有効性を確認した.

A parallel computational method has been proposed to calculate the pressure field in the threedimensional incompressible flows. The detailed numerical procedures are presented to solve the pressure Poisson equations which are derived with the CBP (Cell-Boundary Pressure) scheme on the collocated grid system. The C-HSMAC method, which is effective to reduce the numerical error related to the continuity of the fluid mass, is improved with the Bi-CGSTAB method and the reasonable treatment on the convergence. Then this method is parallelized with a domain decomposition method using overlapping grid points. As a result of the computations, the validity of the improved C-HSMAC method is confirmed. In addition, it is shown that the speed up of the parallel C-HSMAC method is sufficiently high in the large scale computations.

This paper deals with an implicit numerical algorithm (3D C-ISMAC method) to obtain velocity profiles in the steady three-dimensional flow field. In contrast to the usual implicit methods, the 3D C-ISMAC method, which is based on an implicit SMAC method proposed for the staggered grid system, enables us to utilize higher-order schemes for discretization as well as to largely decrease the necessary computational time. The proposed 3D C-ISMAC method was applied to cavity flows with a fifth-order QSI scheme for convection terms. As a result, it was shown that the computational speed becomes about 13 times faster than a usual explicit method and that the computational accuracy of the QSI scheme is still preserved in the 3D C-ISMAC method.

Population cohort studies are important for understanding the current status of the target disease and its relation to comorbidity, gender, age, or environmental factors. To better understand atopic dermatitis (AD) and its related diseases, we initiated in 2001 a population cohort study of nursery school children from Ishigaki Island, Okinawa, Japan. The cohort study comprised a dermatologist-based physical examination, questionnaire administration, and blood sample analysis. The mean prevalence of AD was 6.3%. Questionnaire-based bronchial asthma and egg allergy in the children and paternal and sibling AD were statistically significant risk factors for AD. Boys with AD had a high incidence of asthma that was coexistent with a high serum total immunoglobulin E level. Also a high incidence of egg allergy was associated with greater AD severity as assessed by TARC/CCL17.

SUMMARY: Stock enhancement is used in Japan as a tool to help the replenishment of wild populations of red sea bream Pagrus major. In this study, we analyzed the genetic diversity and composition of wild red sea bream at seven locations around Shikoku Island, South-west Japan, using three microsatellite loci. This analysis was done to test the hypothesis that: (i) red sea bream comprises a single Mendelian population along Japan; and (ii) stock enhancement programs around Shikoku Island are causing genetic differentiation among wild stocks. The results indicated that some locations from the Shikoku area were not significantly different from the rest of Japan, supporting the hypothesis of a single Mendelian population. Significant departures from Hardy–Weinberg equilibrium and significant pairwise FST among locations indicated genetic instability within this region. We suggest that the stock enhancement programs made in the region are the possible cause of this genetic instability. A management scheme for the hatcheries involved in the stock enhancement of red sea bream is presented.

In order to diagnose the effectiveness of electrical insulation, it is necessary to obtain information regarding the electric field distribution in insulating materials. We have investigated the measurement of electric field vector distributions in liquid dielectrics using an original method. Electric field distributions could be measured in time intervals of milli-seconds by an optical system. In this study, the electric field in a liquid containing space charges was measured, and the change in the electric field caused by the charges in the liquid was examined. Moreover, the space charge distribution in the liquid was also studied. We believe that our study can aid a better understanding of the movement of charges in liquid dielectrics.

We have investigated the measurement of nonuniform electric field vector distributions in liquid dielectrics using an original method based on electrooptic Kerr effect and CT method. Recently, we developed an optical system that could measure electric field distributions of the order of a mili-second. The temporal change of the electric field distribution obtained by this system would allow us to study a behavior of a space charge and an electrical conduction in liquid insulations. In this study, we carried out the electric field in a liquid containing space charge. The space charge could not be evaluated quantitatively, so liquids left for scores of minutes from the first sequence of the applied voltage were used. By changing the time required for leaving, the quantity of charge in liquids was changed. It was well known that the electric field strength in liquids containing charges was not a static field. The change of the electric field caused by charges in liquids was very interesting.

We measured temperature dependence of elastic modulus for the high-quality single crystals of Y 1-x Ca x TiO 3 (x = 0,0.1 and 0.2) using an ultrasonic technique. A step like elastic anomaly due to the volume magnetostriction induced by a ferromagnetic transition was observed in longitudinal C 11 and C 33 for x = 0 and 0.1, although no anomaly was observed for x = 0.2. With increasing x, the magnitude of anomaly decreases, reflecting that the amplitude of the antiferromagnetic orbital order parameter, where the orbital ordering is the origin of the ferromagnetism of YTiO 3 , is reduced with increasing Ca concentration.

We measured various elastic moduli of single-crystalline Y 1 - x Ca x TiO 3 ( x = 0 , and 0.2) as a function of temperature by means of an ultrasonic technique. Remarkable elastic softening has been found in transverse C 44 for the sample with x = 0 around 60 K, indicating structural symmetry lowering corresponding to the e yz strain. In contrast, the sample with x = 0.2 shows large softening in C 55 in response to e zx around 130 K. These results reveal that Y 1 - x Ca x TiO 3 ( x = 0 , and 0.2) undergo a structural transition and the crystal symmetry of the low temperature phase is changed by Ca-doping.

The Ti 3 d electronic structure of Ti 2 O 3 across metal–insulator transition (MIT) has been investigated by means of polarization-dependent soft X-ray absorption spectroscopy (XAS) at the Ti 2 p edge. The XAS spectra exhibit a remarkable linear dichroism (LD) between the polarization vectors of the incident light parallel and perpendicular to the Ti ion pair along the c -axis. LD intensity is significantly reduced at 520 K in the metallic phase in comparison with that at 300 K in the insulating phase, indicating a large change in a 1 g and e g π orbital occupations. The results are qualitatively consistent with a recent theory, where the MIT is due to the change of the 3 d electronic configuration in the Ti pair along the c -axis driven by a change in the t 2 g level splitting relative to the on-site exchange interaction.